Advanced Multicompartment Diffusion MRI Models and Their Application in Multiple Sclerosis.

Conventional MR imaging techniques are sensitive to pathologic changes of the brain and spinal cord seen in MS, but they lack specificity for underlying axonal and myelin integrity. By isolating the signal contribution from different tissue compartments, newly developed advanced multicompartment diffusion MR imaging models have the potential to detect specific tissue subtypes and associated injuries with increased pathologic specificity. These models include neurite orientation dispersion and density imaging, diffusion basis spectrum imaging, multicompartment microscopic diffusion MR imaging with the spherical mean technique, and models enabled through high-gradient diffusion MR imaging. In this review, we provide an appraisal of the current literature on the physics principles, histopathologic validation, and clinical applications of each of these techniques in both brains and spinal cords of patients with MS. We discuss limitations of each of the methods and directions that future research could take to provide additional validation of their roles as biomarkers of axonal and myelin injury in MS.

Binary Colloidal Nanoparticle Concentration Gradients in a Centrifugal Field at High Concentration.

Binary colloidal nanoparticles have been found to form different types of crystalline phases at varied radial positions in a centrifugal field by Chen et al. ( ACS Nano 2015, 9, 6944-50). The variety of binary phase behaviors resulted from the two different nanoparticle concentration gradients, but to date, the gradients can only be empirically controlled. For the first time, we are able to measure, fit, and simulate binary hard-sphere colloidal nanoparticle concentration gradients at high particle concentrations up to 30 vol %, which enables tailor-made gradients in a centrifugal field. By this means, a continuous range of binary particle concentration ratios can be accessed in one single experiment to obtain an extended phase diagram. By dispersing two differently sized silica nanoparticles labeled with two different fluorescence dyes in a refractive index matching solvent, we can use a multi-wavelength analytical ultracentrifuge (MWL-AUC) to measure the individual concentration gradient for each particle size in sedimentation-diffusion equilibrium. The influence of the remaining slight turbidity at high concentration can be corrected using the MWL spectra from the AUC data. We also show that the experimental concentration gradients can be fitted using a noninteracting nonideal sedimentation model. By using these fitted parameters, we are able to simulate nanoparticle concentration gradients, which agreed with the subsequent experiments at a high concentration of 10 vol % and thus allowed for the simulation of binary concentration gradients of hard-sphere nanoparticles in preparative ultracentrifuges (PUCs). Finally we demonstrated that by simulating the concentration gradients in PUCs, a continuous and extended binary nanoparticle phase diagram can be obtained by simply studying the structure evolution along the centrifugal field for one single sample instead of a large number of experiments with discrete compositions as in conventional studies.

Suppression of tumor-derived Semaphorin 7A and genetic ablation of host-derived Semaphorin 7A impairs tumor progression in a murine model of advanced breast carcinoma.

Solid tumors can generate a plethora of neurogenesis-related molecules that enhance their growth and metastasis. Among them, we have identified axonal guidance molecule Semaphorin 7A (SEMA7A) in breast cancer. The goal of this study was to determine the therapeutic effect of suppressing SEMA7A levels in the 4T1 murine model of advanced breast carcinoma. We used anti-SEMA7A short hairpin RNA (shRNA) to gene silence SEMA7A in 4T1 mammary tumor cells. When implanted into the mammary fat pads of syngeneic mice, SEMA7A shRNA-expressing 4T1 tumors exhibited decreased growth rates, deferred metastasis and reduced mortality. In vitro, SEMA7A shRNA-expressing 4T1 cells had weakened proliferative, migratory and invasive abilities, and decreased levels of mesenchymal factors. Atomic force microscopy studies showed that SEMA7A shRNA-expressing 4T1 cells had an increase in cell stiffness that corresponded with their decreased malignant potential. Genetic ablation of host-derived SEMA7A further enhanced the antitumor effects of SEMA7A shRNA gene silencing in 4T1 cells. Our preclinical findings demonstrate a critical role for SEMA7A in mediating mammary tumor progression.

Estimation of tile drainage contribution to streamflow and nutrient loads at the watershed scale based on continuously monitored data.

Nitrogen losses from artificially drained watersheds degrade water quality at local and regional scales. In this study, we used an end-member mixing analysis (EMMA) together with high temporal resolution water quality and streamflow data collected in the 122 km2 Otter Creek watershed located in northeast Iowa. We estimated the contribution of three end-members (groundwater, tile drainage, and quick flow) to streamflow and nitrogen loads and tested several combinations of possible nitrate concentrations for the end-members. Results indicated that subsurface tile drainage is responsible for at least 50% of the watershed nitrogen load between April 15 and November 1, 2015. Tiles delivered up to 80% of the stream N load while providing only 15-43% of the streamflow, whereas quick flows only marginally contributed to N loading. Data collected offer guidance about areas of the watershed that should be targeted for nitrogen export mitigation strategies.

Sexuality, Self-Esteem and Partnership Quality in Infertile Women and Men.

Introduction: Infertile couples often report quality-of-life impairments, especially in terms of sexuality, self-esteem and partnership quality. So far, there have been no systematic studies of the sex lives and behaviour of infertile women and men before and after the emergence of their mutual desire for a child. Materials and Methods: From February 2010 to August 2010 all couples starting treatment either at Heidelberg University's Women's Hospital or at the Fertility Center Berlin were asked to fill out the Self-Esteem and Relationship Questionnaire (SEAR). A total of n = 158 women and n = 153 men participated in the study. Results: Decreasing tendencies were observable for both partners in the domains Sexual Relationship Satisfaction and Confidence and in the subscales Self-Esteem and Overall Relationship Satisfaction. There were especially clear indications of a loss of spontaneous sexuality during the experience of infertility. We were also able to establish that infertility has a negative impact on women's self-esteem. Discussion: The results of this study indicate that SEAR can be used as a feasible instrument for identifying infertile women and men whose infertility has a negative effect on their relationship quality and/or sex lives.

Nuclear deformation and neutron excess as competing effects for dipole strength in the pygmy region.

The electromagnetic dipole strength below the neutron-separation energy has been studied for the xenon isotopes with mass numbers A=124, 128, 132, and 134 in nuclear resonance fluorescence experiments using the γELBE bremsstrahlung facility at Helmholtz-Zentrum Dresden-Rossendorf and the HIγS facility at Triangle Universities Nuclear Laboratory Durham. The systematic study gained new information about the influence of the neutron excess as well as of nuclear deformation on the strength in the region of the pygmy dipole resonance. The results are compared with those obtained for the chain of molybdenum isotopes and with predictions of a random-phase approximation in a deformed basis. It turned out that the effect of nuclear deformation plays a minor role compared with the one caused by neutron excess. A global parametrization of the strength in terms of neutron and proton numbers allowed us to derive a formula capable of predicting the summed E1 strengths in the pygmy region for a wide mass range of nuclides.

Foodborne outbreaks of shigellosis in the USA, 1998-2008.

We examined reported outbreaks of foodborne shigellosis in the USA from 1998 to 2008 and summarized demographic and epidemiological characteristics of 120 confirmed outbreaks resulting in 6208 illnesses. Most reported foodborne shigellosis outbreaks (n = 70, 58%) and outbreak-associated illnesses (n = 3383, 54%) were restaurant-associated. The largest outbreaks were associated with commercially prepared foods distributed in multiple states and foods prepared in institutional settings. Foods commonly consumed raw were implicated in 29 (24%) outbreaks and infected food handlers in 28 (23%) outbreaks. Most outbreaks (n = 86, 72%) were caused by Shigella sonnei. Targeted efforts to reduce contamination during food handling at multiple points in the food processing and distribution system, including food preparation in restaurants and institutional settings, could prevent many foodborne disease outbreaks and outbreak-related illnesses including those due to Shigella.

Basic molecular fingerprinting of immature cerebellar cortical inhibitory interneurons and their precursors.

While the development of cerebellar granule and Purkinje neurons has been extensively studied, little is known about the developmental mechanisms that lead to the generation and diversification of inhibitory GABAergic interneurons of the cerebellar cortex. To address this issue, we compared gene expression in complete, early postnatal murine cerebella to that in cerebella from which immature inhibitory interneurons and their precursors had been stripped based on their expression of green fluorescent protein (GFP) from the Pax2 locus. We identified some 300 candidate genes selectively enriched within immature cerebellar cortical inhibitory interneurons and/or their precursors, many of which were also expressed in their adult descendants and/or the embryonic cerebellar ventricular epithelium that gives rise to these cells. None of the genes identified, among them Tcfap2alpha, Tcfap2beta, Lbxcor1 and Lbx1, was cell-type specific. Rather, gene expression, and also splicing, changed dynamically during development and rather reflects stage of differentiation than lineage. Consistently, cluster analysis of transcriptional regulators and genes specific for adult cerebellar GABAergic cells does not suggest a hierarchical lineage relationship or an early commitment of subtypes of cerebellar cortical inhibitory interneurons. Together, these data support the notion that diversification of cerebellar inhibitory interneurons is highly regulative and subject to local signaling to postmigratory precursors.

Decay of 1+ states as a new probe of the structure of 0+ shape isomers.

The nuclides 98Mo and 100Mo have been studied in photon-scattering experiments by using bremsstrahlung produced from electron beams with kinetic energies from 3.2 to 3.8 MeV. Six electromagnetic dipole transitions in 98Mo and 19 in 100Mo were observed for the first time in the energy range from 2 to 4 MeV. A specific feature in the two nuclides is the de-excitation of one state with spin J = 1 to the 0+ ground state as well as to the first excited 0+ state, which cannot be explained in standard models. We present a model that allows us to deduce the mixing coefficients for the two 0+ shape-isomeric states from the experimental ratio of the transition strengths from the J = 1 state to the 0+ ground state and to the 0+ excited state.

Genetic heterogeneity in rapid onset dystonia-parkinsonism: description of a new family.

Rapid onset dystonia-parkinsonism (RDP) is a rare movement disorder with autosomal dominant inheritance, characterised by sudden onset of dystonic spasms and slowness of movement. To date, three families have been described that share linkage to the same location on chromosome 19q13, designated DYT12. Very recently, mutations in the ATP1A3 gene at the DYT12 locus have been demonstrated in seven unrelated patients, including the three previously linked families. A large RDP family is reported here, with eight definitely and one possibly affected members, that is not linked to the DYT12 region and has no mutation in the ATP1A3 gene. Predominant cranial-cervical involvement of dystonia occurred in this family, which has also been described in patients with idiopathic torsion dystonia linked to the DYT6 region on chromosome 8 and is a rare finding in DYT1 dystonia. Molecular genetic analysis also excluded linkage to the DYT6 locus and the GAG deletion in DYT1, suggesting at least one additional RDP gene.

Transverse structure of nucleon parton distributions from lattice QCD.

This work presents the first calculation in lattice QCD of three moments of spin-averaged and spin-polarized generalized parton distributions in the proton. It is shown that the slope of the associated generalized form factors decreases significantly as the moment increases, indicating that the transverse size of the light-cone quark distribution decreases as the momentum fraction of the struck parton increases.

Combined standard graft-versus-host disease (GvHD) prophylaxis with mycophenolate mofetil (MMF) in allogeneic peripheral blood stem cell transplantation from unrelated donors.

In this open single-centre phase II study, MMF was added on day +10 after allogeneic transplantation to standard immunosuppressive prophylaxis consisting of cyclosporine and methotrexate to decrease the incidence of GvHD. In all, 30 patients aged 20-59 years with advanced haematological malignancies received an unmanipulated blood-stem-cell graft (median of 8.5 x 10(6) CD34(+) and 349 x 10(6) CD3(+) cells per bodyweight) from matched unrelated (n=26), or mismatched donors (n=4). Prior to transplantation, 13 patients underwent fractionated total body irradiation and cyclophosphamide, one patient additional etoposide. In all, 16 patients received reduced conditioning of fludarabin, busulfan, and antithymocyte globulin. All patients engrafted in a median of 12 days, and 19 developed acute GvHD>/=II, including two patients with GvHD III and three with GvHD IV. Subsequently, nine patients developed limited and two patients extensive chronic GvHD. With a median follow-up of 28 months, the overall survival is 53.3% and disease-free survival 50%, respectively. Only two deaths were due to GvHD IV. Out of 13 patients, 10 being CMV IgG positive became positive for pp65. In conclusion, this MMF schedule seems to be safe and feasible in the prophylaxis of severe acute GvHD for high-risk patients, restricted by an increased risk for reactivating CMV in seropositive patients.

Hereditary myoclonus-dystonia associated with epilepsy.

A five-generation Dutch family with inherited myoclonus-dystonia (M-D) is described. Genetic analysis revealed a novel truncating mutation within the epsilon-sarcoglycan gene (SGCE). In three of five gene carriers, epilepsy and/or EEG abnormalities were associated with the symptoms of myoclonus and dystonia. The genetic and clinical heterogeneity of M-D is extended. EEG changes and epilepsy should not be considered exclusion criteria for the clinical diagnosis of M-D.

Spatiotemporal transcription of connexin45 during brain development results in neuronal expression in adult mice.

Characterization of the expression pattern of connexins in neural tissue is a necessary prerequisite for understanding the functional relevance of the corresponding gap junction channels in brain. Here we describe the cell type-specific expression of connexin45 in the CNS and the spatiotemporal expression pattern from embryonic day 19.5 to adult brain using a recently described connexin45 LacZ-reporter mouse. The connexin45 gene is highly expressed during embryogenesis and up to 2 weeks after birth in nearly all brain regions. Afterward its expression is restricted to the thalamus, the CA3 region of hippocampus and the cerebellum. In adult mouse brain, the pattern of LacZ-staining in combination with the analysis of different neuronal and glial marker proteins strongly suggests that connexin45 is expressed in neurons, but presumably not in astrocytes or mature oligodendrocytes. Expression of the LacZ/connexin45 reporter gene in subsets of neurons, such as cerebral cortical, hippocampal and thalamic neurons as well as basket and stellate cells of cerebellum should be corroborated by functional investigations of connexin45 protein in electrical synapses. Based on its expression pattern during development, we suggest that the connexin45-containing gap junction channels have a rather ubiquitous role during brain development and may contribute to functional specification in certain subsets of neurons in the adult brain.

Morphological development and neurochemical differentiation of cerebellar inhibitory interneurons in microexplant cultures.

The cerebellar cortex comprises a rather limited variety of interneurons, prominently among them inhibitory basket and stellate cells and Golgi neurons. To identify mechanisms subserving the positioning, morphogenesis, and neurochemical maturation of these inhibitory interneurons, we analyzed their development in primary microexplant cultures of the early postnatal cerebellar cortex. These provide a well-defined, patterned lattice within which the development of individual cells is readily accessible to experimental manipulation and observation. Pax-2-positive precursors of inhibitory interneurons were found to effectively segregate from granule cell perikarya. They emigrate from the core explant and avoid the vicinity of granule cells, which also emigrate and aggregate into small clusters around the explant proper. This contrasts with the behavior of Purkinje neurons, which remain within the explant proper. During migration, a subset of Pax-2-positive cells gradually acquires a GABAergic phenotype, and subsequently also expresses the type 2 metabotropic receptor for glutamate, or parvalbumin, markers for Golgi neurons and basket or stellate cells, respectively. The latter eventually orient their dendrites such that they take a preferentially perpendicular orientation relative to granule cell axons. Both the neurochemical maturation of basket/stellate cells and the specific orientation of their dendrites are independent of their continuous contact with radially oriented glia or Purkinje cell dendrites projecting from the core explant. Numbers of parvalbumin-positive basket/stellate cells and the prevalence of glutamate-positive neurites, which form a dense network preferentially within cell clusters containing granule cell perikarya and their dendrites, are subject to regulation by chronic depolarization. In contrast, brain-derived neurotrophic factor results in a drastic decrease of numbers of basket/stellate cells. These findings document that granule cell axons (parallel fibers) are the major determinant of basket/stellate cell dendritic orientation. They also show that the neurochemical maturation of cerebellar interneurons is sensitive to regulation by activity and neurotrophic factors.

Phenotypic features of myoclonus-dystonia in three kindreds.

BACKGROUND: Myoclonus-dystonia (M-D) is a movement disorder with involuntary jerks and dystonic contractions. Autosomal dominant alcohol-responsive M-D is associated with mutations in the epsilon-sarcoglycan gene (SGCE) (six families) and with a missense change in the D2 dopamine receptor (DRD2)gene (one family). OBJECTIVE: To investigate the clinical phenotype associated with M-D including motor symptoms, psychiatric disorders, and neuropsychological deficits. METHODS: Fifty individuals in three M-D families were evaluated and a standardized neurologic examination and DNA analysis were performed. Psychiatric profiles were established with the Diagnostic Interviews for Genetic Studies (DIGS) and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Cognition was evaluated with standardized neuropsychological tests. RESULTS: Distinct truncating mutations in the SGCE gene were identified in each family. Additionally, a missense alteration in the DRD2 gene was previously found in one family. Motor expression was variable, with onset of myoclonus or dystonia or both affecting the upper body and progression to myoclonus and dystonia in most cases. Psychiatric profiles revealed depression, obsessive-compulsive disorder, substance abuse, anxiety/panic/phobic disorders, and psychosis in two families, and depression only in the third family. Averaged scores from cognitive testing showed impaired verbal learning and memory in one family, impaired memory in the second family, and no cognitive deficits in the third family. CONCLUSIONS: Cognitive deficits may be associated with M-D. Psychiatric abnormalities correlate with the motor symptoms in affected individuals. Assessment of additional M-D families with known mutations is needed to determine whether these are characteristic phenotypic manifestations of M-D.

Hepatic veno-occlusive disease (VOD) with complete occlusion of liver venules after tandem autologous stem cell transplantation-- successful treatment with high-dose methylprednisolone and defibrotide.

Veno-occlusive disease (VOD) is a life-threatening complication following allogeneic or autologous stem cell transplantation. We report on a patient with a high grade B-cell lymphoma who presented 28 days after the second autologous stem cell transplantation with weight gain, ascites, hyperbilirubinemia, and liver venules occlusion as demonstrated by sonography. Starting with high-dose methylprednisolone treatment followed by defibrotide maintenance therapy the patient showed dramatic complete response of VOD, resulting in a normal sonography of the liver and normalization of laboratory values. The response of the occlusion of nearly all liver venules underlines the value of anti-inflammatory treatment combined with new thrombolytic medication such as defibrotide for the treatment of severe VOD.

Myoclonus dystonia: possible association with obsessive-compulsive disorder and alcohol dependence.

BACKGROUND: Inherited myoclonus-dystonia (M-D) is a disorder that is characterized primarily by myoclonic jerks and is often accompanied by dystonia. In addition to motor features, psychiatric disease is reported in some families. METHODS: To determine whether the same genetic etiology underlies both neurologic and psychiatric signs, the authors studied psychiatric symptoms in nonmanifesting carriers (NMC), noncarriers (NC), and manifesting carriers (MC) in three families demonstrating linkage of M-D to the 7q21 locus. Interviewers administered the computerized version of the Composite International Diagnostic Interview. Algorithms for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of obsessive-compulsive disorder (OCD), generalized anxiety disorder, major affective disorder, alcohol abuse, alcohol dependence, drug abuse, and drug dependence were used. Rates of disorders among the MC, NMC, and NC were compared. RESULTS: Of 55 participating individuals, 16 were MC, 11 were NMC, and 28 were NC. The rate of OCD was greater in carriers (5/27) compared with NC (0/28) (p = 0.023). It was also greater in the symptomatic gene carriers (4/16) compared with the asymptomatic group (1/11) (p = 0.022). Alcohol dependence was increased in the symptomatic carriers (7/16) (p = 0.027), but not in the carrier group overall (7/27). CONCLUSION: OCD may be associated with the DYT11 M-D gene; however, a larger sample is necessary to confirm this finding. Alcohol dependence is highly associated with expressing symptoms of M-D. This may be explained by self-medication with alcohol to improve motor symptoms of M-D.

Developmental expression of heterotrimeric G-proteins in the murine cerebellar cortex.

We utilized the murine cerebellum to analyze the expression of G-proteins during vertebrate neural differentiation. Combining reverse transcription-polymerase chain reaction and immunocytochemistry, we monitored the expression and cellular localization, within the nascent cerebellar cortex, of G-proteins subunits known to mediate signal transduction in the adult cerebellum. The mRNAs encoding subunits Galphaq, Galphao, Galphai-2, and Galphaz are expressed in the cerebellar anlage at least from embryonic day 14 onward, and relative levels of these mRNAs do not change appreciably from E14 to adulthood. Galphao, Galphaz, and Galphai-2 could be localized to granule cell neuroblasts and postmigratory, mature granule cells, but not to early postmitotic, premigratory, and migrating granule neurons. All of the Galpha subunits analyzed could also be localized to the cell somata of postmitotic Purkinje neurons, irrespective of age. In contrast, Purkinje cell dendrites stained for Galphao only up to postnatal day 8, dendritic immunoreactivity for Galphaz increased during dendritogenesis, and appreciable levels of Galphai-2 and Galphaq were seen in Purkinje cell dendrites only transiently during the 2nd and 3rd postnatal week. Of the G-beta and -gamma subunits analyzed (beta1, beta2, gamma2, gamma3, gamma5, and gamma7), only expression of gamma3 varied with development. It could be localized to Purkinje cell somata and dendrites in early postnatal, but not in adult animals. These changes in the cellular distribution and subcellular segregation of G-proteins are correlated to tangible aspects of cerebellar cortical histogenesis and suggest a role for G-protein-mediated signaling in their mechanistic implementation.