Association between magnetic resonance imaging patterns and baseline disease features in multiple myeloma: analyzing surrogates of tumour mass and biology.

OBJECTIVE: To assess associations between bone marrow infiltration patterns and localization in magnetic resonance imaging (MRI) and baseline clinical/prognostic parameters in multiple myeloma (MM). METHODS: We compared baseline MM parameters, MRI patterns and localization of focal lesions to the mineralized bone in 206 newly diagnosed MM patients. RESULTS: A high tumour mass (represented by International Staging System stage III) was significantly associated with severe diffuse infiltration (p = 0.015) and a higher number of focal lesions (p = 0.006). Elevated creatinine (p = 0.003), anaemia (p < 0.001) and high LDH (p = 0.001) correlated with severe diffuse infiltration. A salt and pepper diffuse pattern had a favourable prognosis. A higher degree of destruction of mineralized bone (assessed by X-ray or computed tomography) was associated with an increasing number of focal lesions on MRI (p < 0.001). Adverse cytogenetics (del17p/gain1q21/t(4;14)) were associated with diffuse infiltration (p = 0.008). The presence of intraosseous focal lesions exceeding the mineralized bone had a borderline significant impact on prognosis. CONCLUSIONS: Diffuse bone marrow infiltration on MRI correlates with adverse cytogenetics, lowered haemoglobin values and high tumour burden in newly diagnosed MM whereas an increasing number of focal lesions correlates with a higher degree of bone destruction. Focal lesions exceeding the cortical bone did not adversely affect the prognosis. KEY POINTS: • Diffuse MRI correlates with adverse cytogenetics, lowered haemoglobin and high tumour burden. • Higher numbers of MRI focal lesions correlate with increasing degree of bone destruction. • Focal lesions exceeding the cortical bone borderline significantly influence survival. • Moderate/severe diffuse infiltration and more than 23 focal lesions adversely affect survival.

A magnetic resonance imaging-based prognostic scoring system to predict outcome in transplant-eligible patients with multiple myeloma.

Diffuse and focal bone marrow infiltration patterns detected by magnetic resonance imaging have been shown to be of prognostic significance in all stages of monoclonal plasma cell disorders and have, therefore, been incorporated into the definition of the disease. The aim of this retrospective analysis was to develop a rapidly evaluable prognostic scoring system, incorporating the most significant information acquired from magnetic resonance imaging. Therefore, the impact of bone marrow infiltration patterns on progression-free and overall survival in 161 transplant-eligible myeloma patients was evaluated. Compared to salt and pepper/minimal diffuse infiltration, moderate/severe diffuse infiltration had a negative prognostic impact on both progression-free survival (P<0.001) and overall survival (P=0.003). More than 25 focal lesions on whole-body magnetic resonance imaging or more than seven on axial magnetic resonance imaging were associated with an adverse prognosis (progression-free survival: P=0.001/0.003 and overall survival: P=0.04/0.02). A magnetic resonance imaging-based prognostic scoring system, combining grouped diffuse and focal infiltration patterns, was formulated and is applicable to whole-body as well as axial magnetic resonance imaging. The score identified high-risk patients with median progression-free and overall survival of 23.4 and 55.9 months, respectively (whole-body-based). Multivariate analyses demonstrated that the magnetic resonance imaging-based prognostic score stage III (high-risk) and adverse cytogenetics are independent prognostic factors for both progression-free and overall survival (whole-body-based, progression-free survival: hazard ratio=3.65, P<0.001; overall survival: hazard ratio=5.19, P=0.005). In conclusion, we suggest a magnetic resonance imaging-based prognostic scoring system which is a robust, easy to assess and interpret parameter summarizing significant magnetic resonance imaging findings in transplant-eligible patients with multiple myeloma.

Appearance of monoclonal plasma cell diseases in whole-body magnetic resonance imaging and correlation with parameters of disease activity.

The aim of our study was to assess in which way different infiltration patterns of monoclonal plasma cell diseases in whole-body (wb) magnetic resonance imaging (MRI) are associated with clinical stages, plasma cell content in bone marrow samples and established serum markers of disease activity. Institutional review board approval was obtained. We performed wb-MRI in 547 consecutive, unselected and untreated patients with monoclonal gammopathy of undetermined significance (MGUS, n=138), smoldering myeloma (SMM, n=157) and multiple myeloma (MM, n=252) on two 1.5 T MRI-scanners with body array coils. The studies were evaluated in consensus by two experienced radiologists blinded to the diagnosis. We observed focal lesions in 23.9% (MGUS), 34.4% (SMM) and 81.3% (MM), respectively. A diffuse infiltration pattern was detected in 38.4%, 45.9% and 71%, respectively. The differences between all infiltration patterns were significant (p<0.0001). The presence of focal lesions and the presence of a diffuse bone marrow infiltration was associated with an increased plasma cell percentage in bone marrow samples (median 22% vs. 14%, 26% vs. 10%, both p<0.0001) and monoclonal protein concentration (median 18 g/dl vs. 13 g/dl, p=0.003, 20 g/dl vs. 11 g/dl, p<0.0001). Further categorization of the diffuse infiltration patterns in wb-MRI into "salt-and-pepper," moderate and severe identified significant associations with M-protein (median g/dl for S+P/moderate/severe 23/18/25, p=0.04), plasma cell percentage in the bone marrow (median 25%/24%/40%, p=0.02), and age (median years 67/60/57, p<0.0001). Bone marrow infiltration in wb-MRI is significantly different between the various stages of plasma cell disease and correlates well with established markers of disease activity.

[Safety of patient care on an interprofessional training ward in visceral surgery]. / Sicherheit der Patientenversorgung auf einer viszeralchirurgischen interprofessionellen Ausbildungsstation.

BACKGROUND: Interprofessional training wards (ITW) are increasingly being integrated into teaching and training concepts in visceral surgery clinics. OBJECTIVE: How safe is patient care on an ITW in visceral surgery? MATERIAL AND METHODS: Data collection took place from November 2021 to December 2022. In this nonrandomized prospective evaluation study the frequency and severity of adverse events (AE) in 3 groups of 100 patients each in a tertiary referral center hospital for visceral surgery were investigated. The groups consisted of patients on the ITW and on the conventional ward before and after implementation of the ITW. The Global Trigger Tool (GTT) was used to search for AE. Simultaneously, a survey of the treatment was conducted according to the Picker method to measure patient reported outcome. RESULTS: Baseline characteristics and clinical outcome parameters of the patients in the three groups were comparable. The GTT analysis found 74 nonpreventable and 5 preventable AE in 63 (21%) of the patients and 12 AE occurred before the hospital stay. During the hospital stay 50 AE occurred in the operating theater and 17 on the conventional ward. None of the five preventable AE (in 1.7% of the patients) was caused by the treatment on the ITW. Patients rated the safety on the ITW better than in 90% of the hospitals included in the Picker benchmark cohort and as good as on the normal ward. CONCLUSION: The GTT-based data as well as from the patients' point of view show that patient care on a carefully implemented ITW in visceral surgery is safe.

Heterochromatin and gene positioning: inside, outside, any side?

All cellular processes depend on the expression and repression of the right sets of genes at the right time. As each cell contains the same DNA, transcriptional and epigenetic factors have to maintain tight control over gene expression. Even a small divergence from the correct transcriptional program can lead to severe defects and even death. Having deciphered the complete linear genetic information, we need to clarify how this information is organized into the dynamic and highly heterogeneous three-dimensional space of the eukaryotic cell nucleus. Observations on the higher order organization of DNA into differentiated condensation levels date back to the early twentieth century, and potential implications of these structural features to gene expression were postulated shortly after. In particular, proximity of genes to condensed regions of heterochromatin was proposed to negatively influence their expression and, henceforward, the concept of heterochromatin as subnuclear silencing compartment emerged. Methodological advances fueled a flurry of recent studies, which only, in part, led support to this concept. In this review, we address how (hetero)chromatin structure and proximity might influence gene expression and discuss the challenges and means to unravel this fundamental biological question.

MeCP2 Rett mutations affect large scale chromatin organization.

Rett syndrome is a neurological, X chromosomal-linked disorder associated with mutations in the MECP2 gene. MeCP2 protein has been proposed to play a role in transcriptional regulation as well as in chromatin architecture. Since MeCP2 mutant cells exhibit surprisingly mild changes in gene expression, we have now explored the possibility that Rett mutations may affect the ability of MeCP2 to bind and organize chromatin. We found that all but one of the 21 missense MeCP2 mutants analyzed accumulated at heterochromatin and about half of them were significantly affected. Furthermore, two-thirds of all mutants showed a significantly decreased ability to cluster heterochromatin. Three mutants containing different proline substitutions (P101H, P101R and P152R) were severely affected only in heterochromatin clustering and located far away from the DNA interface in the MeCP2 methyl-binding domain structure. MeCP2 mutants affected in heterochromatin accumulation further exhibited the shortest residence time on heterochromatin, followed by intermediate binding kinetics for clustering impaired mutants. We propose that different interactions of MeCP2 with methyl cytosines, DNA and likely other heterochromatin proteins are required for MeCP2 function and their dysfunction lead to Rett syndrome.

3D-Image analysis platform monitoring relocation of pluripotency genes during reprogramming.

Nuclear organization of chromatin is an important level of genome regulation with positional changes of genes occurring during reprogramming. Inherent variability of biological specimens, wide variety of sample preparation and imaging conditions, though pose significant challenges to data analysis and comparison. Here, we describe the development of a computational image analysis toolbox overcoming biological variability hurdles by a novel single cell randomizing normalization. We performed a comparative analysis of the relationship between spatial positioning of pluripotency genes with their genomic activity and determined the degree of similarity between fibroblasts, induced pluripotent stem cells and embryonic stem cells. Our analysis revealed a preferred positioning of actively transcribed Sox2, Oct4 and Nanog away from the nuclear periphery, but not from pericentric heterochromatin. Moreover, in the silent state, we found no common nuclear localization for any of the genes. Our results suggest that the surrounding gene density hinders relocation from an internal nuclear position. Altogether, our data do not support the hypothesis that the nuclear periphery acts as a general transcriptional silencer, rather suggesting that internal nuclear localization is compatible with expression in pluripotent cells but not sufficient for expression in mouse embryonic fibroblasts. Thus, our computational approach enables comparative analysis of topological relationships in spite of stark morphological variability typical of biological data sets.

Cartilage imaging of the hand and wrist using 3-T MRI.

The prevalence of osteoarthritis of the hand and wrist is high, and a thorough assessment of even subtle cartilage injuries is necessary before surgical interventions. Although magnetic resonance imaging (MRI) has been established as an important diagnostic tool for the evaluation of hand and wrist disorders, the focus has been on the assessment of the triangular fibrocartilage complex, tendons, ligaments, and the detection of avascular necrosis or occult fractures rather than on cartilage imaging. 3-T MR systems have become more and more widely available and yield an improved signal-to-noise ratio and thus a higher spatial resolution than 1.5-T systems. In principle, this should be especially beneficial for depicting the thin cartilage layers of the hand and wrist. This review focuses on cartilage imaging of the hand and wrist with 3-T MRI and addresses these four topics: (1) the advantages of 3-T versus 1.5- and 1-T MRI, (2) dedicated sequence protocols at 3 T including novel three-dimensional sequences, (3) imaging findings in common cases of overuse or sports injury, and (4) functional cartilage imaging techniques of the hand and wrist, for instance, delayed gadolinium-enhanced MRI of the cartilage.

A new instrument for the assessment of patient-defined benefit in the treatment of allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a common disease that affects health-related quality of life (HRQoL). Current and future health policy demands the assessment of patient-relevant treatment benefit for evaluation of treatments. METHODS: We developed, validated and tested a standardized instrument for the assessment of patient-relevant needs and benefits in AR. In an open survey of patients with AR, 100 need and benefit items were generated. The items were condensed to a 25-item list by an expert panel. On this list, patient rates the personal importance of 25 treatment needs on a scale ranging from 'not at all' to 'very' before treatment (Patient Needs Questionnaire, PNQ). At the end of the treatment, patient rates the extent, to which these needs were achieved by treatment from 'did not help at all' to 'helped a lot' (Patient Benefit Questionnaire). The patient benefit index (PBI) is computed to provide a global weighted benefit parameter. This disease-specific instrument was validated in n = 104 patients with AR. RESULTS: The PBI-AR showed good acceptability and feasibility in clinical routine. Reduction in nose and eye symptoms was rated most important. The PBI amounted to 2.2 (PBI ranges from 0 = 'no benefit' to 4 = 'maximum benefit'). Reliability of the PNQ was high (Cronbach's alpha = 0.9).The PBI was significantly correlated with relevant external validation criteria, such as patient satisfaction (R = 0.54) and HRQoL (R = 0.26). CONCLUSION: The PBI-AR is a feasible, reliable and valid instrument for the standardized assessment of patient-relevant benefits in the treatment of AR.

Invasive zygomycosis in patients with graft-versus-host disease after allogeneic stem cell transplantation.

Invasive mold infections are a threat to immunosuppressed patients such as patients with graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Up to 10% of SCT recipients develop invasive aspergillosis (IA). Invasive zygomycosis (IZ) may occur during treatment against IA. Here we report 4 SCT patients with GVHD diagnosed with IZ. All patients had received myeloablative hematopoietic SCT and developed chronic GVHD requiring systemic immunosuppression. Underlying diseases were acute lymphocytic leukemia (2), osteomyelofibrosis, and multiple myeloma. All patients had developed pulmonary infiltration that led to initiation of antifungal therapy. Treatment for IA was voriconazole, caspofungin, or itraconazole. Organs involved with zygomycosis were lung, nasal sinus, skin, and kidney. Treatment with liposomal amphotericin and posaconazole was initiated in all patients, and 2 patients also had surgical debridement as well. Despite intensive treatment, no patient survived. IZ is becoming more common in patients with GVHD on successful treatment for IA. Even non-specific symptoms are suspicious in this group of patients and need to be evaluated by vigorous diagnostics. Despite effective antifungals and surgical intervention, the prognosis is grim in patients with active GVHD, as immunoreconstitution is mandatory for successful management.

Measurements of the quadriceps femoris function after meniscus refixation at the stable athlete's knee.

INTRODUCTION: The purpose of this study was to monitor the muscular changes regarding the isokinetic strength and torque pattern of the quadriceps femoris at the stable athlete's knee after meniscus tear refixation. MATERIALS AND METHODS: Therefore 15 athletes (10 male, 5 female) performing recreational or competitional sports at least five times a week before injury were retrospectively examined in the average 2.5 years after isolated arthroscopic meniscus refixation using Inside Out technique. Next to function and sport activity focused scores the isokinetic peak torque (PT) and in the EMG have been analyzed compared to the uninjured knee. RESULTS: The mean age was 31.26 years. The time between injury and surgery was in the average 13.7 days. According to our first results the data suggest a complete recovery of functional and muscular pattern after meniscus refixation at the stable athlete's knee. No significant EMG changes for quadriceps femoris were detectable. The PT was fully recovered. The functional and sport activity score analysis (Lysholm and Tegner score) showed no changes in the postoperative long-term follow up compared to the preinjured status. CONCLUSION: Examining isokinetic PT and the EMG of the quadriceps femoris, these data show no side-to-side differences. Regarding the function and sports activity score system, the functionally high demand patients seem to profit by this procedure.

Processive DNA synthesis is associated with localized decompaction of constitutive heterochromatin at the sites of DNA replication and repair.

Constitutive heterochromatin is considered as a functionally inert genome compartment, important for its architecture and stability. How such stable structure is maintained is not well understood. Here, we apply four different visualization schemes to label it and investigate its dynamics during DNA replication and repair. We show that replisomes assemble over the heterochromatin in a temporally ordered manner. Furthermore, heterochromatin undergoes transient decompaction locally at the active sites of DNA synthesis. Using selective laser microirradiation conditions that lead to damage repaired via processive DNA synthesis, we measured similarly local decompaction of heterochromatin. In both cases, we could not observe large-scale movement of heterochromatin to the domain surface. Instead, the processive DNA synthesis machinery assembled at the replication/repair sites. Altogether, our data are compatible with a progression of DNA replication/repair along the chromatin in a dynamic mode with localized and transient decompaction that does not globally remodels the whole heterochromatin compartment.

HIV-1 nuclear import in macrophages is regulated by CPSF6-capsid interactions at the nuclear pore complex.

Nuclear entry of HIV-1 replication complexes through intact nuclear pore complexes is critical for successful infection. The host protein cleavage-and-polyadenylation-specificity-factor-6 (CPSF6) has been implicated in different stages of early HIV-1 replication. Applying quantitative microscopy of HIV-1 reverse-transcription and pre-integration-complexes (RTC/PIC), we show that CPSF6 is strongly recruited to nuclear replication complexes but absent from cytoplasmic RTC/PIC in primary human macrophages. Depletion of CPSF6 or lack of CPSF6 binding led to accumulation of HIV-1 subviral complexes at the nuclear envelope of macrophages and reduced infectivity. Two-color stimulated-emission-depletion microscopy indicated that under these circumstances HIV-1 complexes are retained inside the nuclear pore and undergo CA-multimer dependent CPSF6 clustering adjacent to the nuclear basket. We propose that nuclear entry of HIV-1 subviral complexes in macrophages is mediated by consecutive binding of Nup153 and CPSF6 to the hexameric CA lattice.

Clinical and bacteriological characteristics associated with clustering of multidrug-resistant tuberculosis.

SETTING: The impact of the genetic characteristics of Mycobacterium tuberculosis on the clustering of multidrug-resistant tuberculosis (MDR-TB) has not been analyzed together with clinical and demographic characteristics. OBJECTIVE: To determine factors associated with genotypic clustering of MDR-TB in a community-based study. DESIGN: We measured the proportion of clustered cases among MDR-TB patients and determined the impact of clinical and demographic characteristics and that of three M. tuberculosis genetic characteristics: lineage, drug resistance-associated mutations, and rpoA and rpoC compensatory mutations. RESULTS: Of 174 patients from California and Texas included in the study, the number infected by East-Asian, Euro-American, Indo-Oceanic and East-African-Indian M. tuberculosis lineages were respectively 70 (40.2%), 69 (39.7%), 33 (19.0%) and 2 (1.1%). The most common mutations associated with isoniazid and rifampin resistance were respectively katG S315T and rpoB S531L. Potential compensatory mutations in rpoA and rpoC were found in 35 isolates (20.1%). Hispanic ethnicity (OR 26.50, 95%CI 3.73-386.80), infection with an East-Asian M. tuberculosis lineage (OR 30.00, 95%CI 4.20-462.40) and rpoB mutation S531L (OR 4.03, 95%CI 1.05-23.10) were independent factors associated with genotypic clustering. CONCLUSION: Among the bacterial factors studied, East-Asian lineage and rpoB S531L mutation were independently associated with genotypic clustering, suggesting that bacterial factors have an impact on the ability of M. tuberculosis to cause secondary cases.

Changes in breathing pattern upon 100% oxygen in children at early school age.

Nitrogen multiple-breath washout (N2MBW) is an increasingly used tidal breathing test in young children to assess ventilation inhomogeneity. However, the test requires 100% oxygen to perform. We aimed to examine the potential influence of pure oxygen on breathing pattern in school-aged children. We performed tidal breathing measurements under room air followed by N2MBW in 16 former preterm children and 24 healthy controls. We compared tidal volume (VT), coefficient of variation of VT (CVVT), respiratory rate (RR), and minute ventilation (VE) between tidal breathing and N2MBW, and between the start and end of tidal breathing. Mean (range) age was 6.8 (5.9, 9.0) years. VT, RR and VE showed no significant change upon oxygen-exposure, while CVVT significantly decreased by 5% (95% CI: 1.2, 9.0; p=0.012). However CVVT was also the only parameter which significantly decreased during tidal breathing. Overall, pure oxygen has no systematic effect on breathing pattern in young school-aged children. N2MBW can reliably be used as tracer gas in this age group.

Neuromyelitis optica spectrum disorder coinciding with hematological immune disease: A case report.

INTRODUCTION: Recently defined consensus criteria for the diagnosis of neuromyelitis optica spectrum disorders (NMOSD) allow establishing the diagnosis in patients without elevated AQP4-Ab and optic nerve involvement. According to the new extended definition, NMOSD is closely associated with extensive spinal cord inflammation occurring in the course of systemic autoimmune diseases as sarcoidosis or lupus erythematodes. NMOSD occurring in the course of hematological disease have not yet been reported in the literature. CASE REPORT: A 38 year old male subsequently developed thrombocytopenia, hemolytic anemia and agranulocytosis over a 23 month period. Three months after an episode of agranulocytosis, he noticed ascending sensory disturbances and progressive weakness of his legs. Within two days, symptoms worsened to give almost complete paraplegia and loss of sensation below a midthoracic level. MRI revealed signal hyperintensity and edema in T2-weighted sequences reaching from the 2nd cervical to the 9th thoracic vertebral body. Two years later, he developed a second episode with lesions in the spinal cord and periventricular areas of brain stem and thalamus. CONCLUSION: The relapsing time course and the topographical pattern of central nervous system lesions restricted to axial brain structures and the spinal cord fulfill the criteria that have recently been defined for AQP4-Ab-negative NMO-spectrum disease. Systematic studies on the association of hematological autoimmune phenomena and spinal cord disease are needed to clarify whether this coincidence is just a casual phenomenon or whether it points to a yet undiscovered but perhaps therapeutically interesting link of immunological mechanisms affecting both organ systems.

DNA repair and recombination factor Rad51 is over-expressed in human pancreatic adenocarcinoma.

Molecular processes that could contribute to differences in chemo- and radioresistance include variations in DNA repair mechanisms. In mammalian cells, the product of the rad51 gene mediates DNA repair via homologous recombination. We describe that in contrast to conventional monolayer cell systems Rad51 protein accumulates to high-levels in three-dimensional cell culture models as well as in orthotopic xeno-transplants of human pancreatic cancer cells. Strikingly, over-expression of wild-type Rad51 was also found in 66% of human pancreatic adenocarcinoma tissue specimens. Functional analysis revealed that Rad51 over-expression enhances survival of cells after induction of DNA double strand breaks. These data suggest that perturbations of Rad51 expression contribute to the malignant phenotype of pancreatic cancer. Oncogene (2000).

Pain therapy in haemophilia in Germany. Patient survey (BESTH study).

UNLABELLED: One of many challenges in the treatment of persons with haemophilia is the selection and application of appropriate pain-relieving therapies. The current situation of pain management for persons with haemophilia in Germany was evaluated using a survey with the intention of identifying potential areas for improvement. Results of 685 respondents showed that 86% experienced episodes of pain and that pain was already present in 66% of children and adolescents. Joint pain was the most common type of pain (92%), remarkably so even in 80% of young patients. Half of the patients received pharmacological therapy for the pain and 46% of the patients received physiotherapy. Priority and sequence of the contacted physicians and therapists for diagnosis and therapy is described. Satisfaction with pain therapy was expressed by 56% of participants and 18% felt their pain not treated sufficiently. CONCLUSION: The results of the survey will be used to develop measures for improvement of long-term care of haemophilia patients regarding pain therapy.

Gene repositioning within the cell nucleus is not random and is determined by its genomic neighborhood.

BACKGROUND: Heterochromatin has been reported to be a major silencing compartment during development and differentiation. Prominent heterochromatin compartments are located at the nuclear periphery and inside the nucleus (e.g., pericentric heterochromatin). Whether the position of a gene in relation to some or all heterochromatin compartments matters remains a matter of debate, which we have addressed in this study. Answering this question demanded solving the technical challenges of 3D measurements and the large-scale morphological changes accompanying cellular differentiation. RESULTS: Here, we investigated the proximity effects of the nuclear periphery and pericentric heterochromatin on gene expression and additionally considered the effect of neighboring genomic features on a gene's nuclear position. Using a well-established myogenic in vitro differentiation system and a differentiation-independent heterochromatin remodeling system dependent on ectopic MeCP2 expression, we first identified genes with statistically significant expression changes by transcriptional profiling. We identified nuclear gene positions by 3D fluorescence in situ hybridization followed by 3D distance measurements toward constitutive and facultative heterochromatin domains. Single-cell-based normalization enabled us to acquire morphologically unbiased data and we finally correlated changes in gene positioning to changes in transcriptional profiles. We found no significant correlation of gene silencing and proximity to constitutive heterochromatin and a rather unexpected inverse correlation of gene activity and position relative to facultative heterochromatin at the nuclear periphery. CONCLUSION: In summary, our data question the hypothesis of heterochromatin as a general silencing compartment. Nonetheless, compared to a simulated random distribution, we found that genes are not randomly located within the nucleus. An analysis of neighboring genomic context revealed that gene location within the nucleus is rather dependent on CpG islands, GC content, gene density, and short and long interspersed nuclear elements, collectively known as RIDGE (regions of increased gene expression) properties. Although genes do not move away/to the heterochromatin upon up-/down-regulation, genomic regions with RIDGE properties are generally excluded from peripheral heterochromatin. Hence, we suggest that individual gene activity does not influence gene positioning, but rather chromosomal context matters for sub-nuclear location.

Propionyl-IIGL tetrapeptide antagonizes beta-amyloid excitotoxicity in rat nucleus basalis.

A putative tetrapeptide beta-amyloid (Abeta) antagonist (propionyl-Ile-Ile-Gly-Leu [Pr-IIGL]) based on the [31-34] sequence of Abeta was previously shown to rescue astrocytes from Abeta-induced membrane depolarization and subsequent long-term elevations of the intracellular Ca2+ concentration in vitro. Here we provide in vivo evidence that the Pr-IIGL tetrapeptide effectively attenuates the excitotoxic action of Abeta(1-42) on cholinergic neurons of the rat magnocellular nucleus basalis (MBN). We also demonstrate by means of microdialysis that administration of Pr-IIGL abolished Abeta(1-42)-induced increases in extracellular aspartate and glutamate concentrations in the MBN, which coincide with a significant preservation of cholinergic MBN neurons and their cortical projections. This neuroprotective effect was associated with preserved exploratory behavior in an open-field paradigm, and improved memory retention in a step-through passive avoidance task. Our data presented here indicate for the first time the efficacy of short, modified functional Abeta antagonists in ameliorating Abeta excitotoxicity in vivo.