Epilepsy syndrome-associated balance dysfunction assessed by static posturography

AbstractPurposeTo compare subclinical balance dysfunction in patients with various epilepsy syndromes with apparently healthy subjects.MethodsTwenty-seven patients with localization-related epilepsy (LRE), 19 with primary generalized epilepsy (PGE), who had no subjective complaints of impaired balance and no abnormal neurologic findings on examination, and 22 apparently healthy subjects, underwent static posturography using the Posture Scale Analyzer (PSA) system.ResultsSway index was higher in patients compared to healthy subjects in all tests, significant for single leg stance (p=0.005). Patients with PGE had a higher sway index compared to patients with LRE in six of the tests, also significant for single leg stance (p=0.027). This difference was not affected by the type of AED treatment or disease duration.ConclusionPosturography can improve balance function assessment in patients with epilepsy, demonstrate subclinical impairment in seemingly asymptomatic patients, and further characterize balance deficits in different epilepsy syndromes

Conductance Phases in Aharonov-Bohm Ring Quantum Dots

The regimes of growing phases (for electron numbers N~0-8) that pass into regions of self-returning phases (for N>8), found recently in quantum dot conductances by the Weizmann group are accounted for by an elementary Green function formalism, appropriate to an equi-spaced ladder structure (with at least three rungs) of electronic levels in the quantum dot. The key features of the theory are physically a dissipation rate that increases linearly with the level number (and tentatively linked to coupling to longitudinal optical phonons) and a set of Fano-like meta-stable levels, which disturb the unitarity, and mathematically the change over of the position of the complex transmission amplitude-zeros from the upper-half in the complex gap-voltage plane to the lower half of that plane. The two regimes are identified with (respectively) the Blaschke-term and the Kramers-Kronig integral term in the theory of complex variables.Comment: 20 pages, 4 figure

Generalized "Quasi-classical" Ground State for an Interacting Two Level System

We treat a system (a molecule or a solid) in which electrons are coupled linearly to any number and type of harmonic oscillators and which is further subject to external forces of arbitrary symmetry. With the treatment restricted to the lowest pair of electronic states, approximate "vibronic" (vibration-electronic) ground state wave functions are constructed having the form of simple, closed expressions. The basis of the method is to regard electronic density operators as classical variables. It extends an earlier "guessed solution", devised for the dynamical Jahn-Teller effect in cubic symmetry, to situations having lower (e.g., dihedral) symmetry or without any symmetry at all. While the proposed solution is expected to be quite close to the exact one, its formal simplicity allows straightforward calculations of several interesting quantities, like energies and vibronic reduction (or Ham) factors. We calculate for dihedral symmetry two different $q$-factors ("$q_z$" and "$q_x$") and a $p$-factor. In simplified situations we obtain $p=q_z +q_x -1$. The formalism enables quantitative estimates to be made for the dynamical narrowing of hyperfine lines in the observed ESR spectrum of the dihedral cyclobutane radical cation.Comment: 28 pages, 4 figure

Insulin-Producing Cells Generated from Dedifferentiated Human Pancreatic Beta Cells Expanded In Vitro

Expansion of beta cells from the limited number of adult human islet donors is an attractive prospect for increasing cell availability for cell therapy of diabetes. However, attempts at expanding human islet cells in tissue culture result in loss of beta-cell phenotype. Using a lineage-tracing approach we provided evidence for massive proliferation of beta-cell-derived (BCD) cells within these cultures. Expansion involves dedifferentiation resembling epithelial-mesenchymal transition (EMT). Epigenetic analyses indicate that key beta-cell genes maintain open chromatin structure in expanded BCD cells, although they are not transcribed. Here we investigated whether BCD cells can be redifferentiated into beta-like cells.Redifferentiation conditions were screened by following activation of an insulin-DsRed2 reporter gene. Redifferentiated cells were characterized for gene expression, insulin content and secretion assays, and presence of secretory vesicles by electron microscopy. BCD cells were induced to redifferentiate by a combination of soluble factors. The redifferentiated cells expressed beta-cell genes, stored insulin in typical secretory vesicles, and released it in response to glucose. The redifferentiation process involved mesenchymal-epithelial transition, as judged by changes in gene expression. Moreover, inhibition of the EMT effector SLUG (SNAI2) using shRNA resulted in stimulation of redifferentiation. Lineage-traced cells also gave rise at a low rate to cells expressing other islet hormones, suggesting transition of BCD cells through an islet progenitor-like stage during redifferentiation.These findings demonstrate for the first time that expanded dedifferentiated beta cells can be induced to redifferentiate in culture. The findings suggest that ex-vivo expansion of adult human islet cells is a promising approach for generation of insulin-producing cells for transplantation, as well as basic research, toxicology studies, and drug screening

Treatment of limited stage follicular lymphoma with Rituximab immunotherapy and involved field radiotherapy in a prospective multicenter Phase II trial-MIR trial

<p>Abstract</p> <p>Background</p> <p>The optimal treatment of early stage follicular Lymphoma is a matter of debate. Radiation therapy has frequently been applied with a curative approach beside watchful waiting. Involved field, extended field and total nodal radiation techniques are used in various protocols, but the optimal radiation field still has to be defined. Follicular lymphoma is characterized by stable expression of the CD20 antigen on the tumour cells surface. The anti CD20 antibody Rituximab (Mabthera^®) has shown to be effective in systemic therapy of FL in primary treatment, relapse and maintenance therapy.</p> <p>Methods/design</p> <p>The MIR (Mabthera^®and Involved field Radiation) study is a prospective multicenter trial combining systemic treatment with the anti CD20 antibody Rituximab (Mabthera^®) in combination with involved field radiotherapy (30 - 40 Gy). This trial aims at testing the combination's efficacy and safety with an accrual of 85 patients.</p> <p>Primary endpoint of the study is progression free survival. Secondary endpoints are response rate to Rituximab, complete remission rate at week 18, relapse rate, relapse pattern, relapse free survival, overall survival, toxicity and quality of life.</p> <p>Discussion</p> <p>The trial evaluates the efficacy of Rituximab to prevent out-filed recurrences in early stage nodal follicular lymphoma and the safety of the combination of Rituximab and involved field radiotherapy. It also might show additional risk factors for a later recurrence (e.g. remission state after Rituximab only).</p> <p>Trial Registration</p> <p>ClinicalTrials (NCT): <a href="http://www.clinicaltrials.gov/ct2/show/NCT00509184">NCT00509184</a></p

Fluorescence-Tagged Transgenic Lines Reveal Genetic Defects in Pollen Growth—Application to the Eif3 Complex

BACKGROUND: Mutations in several subunits of eukaryotic translation initiation factor 3 (eIF3) cause male transmission defects in Arabidopsis thaliana. To identify the stage of pollen development at which eIF3 becomes essential it is desirable to examine viable pollen and distinguish mutant from wild type. To accomplish this we have developed a broadly applicable method to track mutant alleles that are not already tagged by a visible marker gene through the male lineage of Arabidopsis. METHODOLOGY/PRINCIPAL FINDINGS: Fluorescence tagged lines (FTLs) harbor a transgenic fluorescent protein gene (XFP) expressed by the pollen-specific LAT52 promoter at a defined chromosomal position. In the existing collection of FTLs there are enough XFP marker genes to track nearly every nuclear gene by virtue of its genetic linkage to a transgenic marker gene. Using FTLs in a quartet mutant, which yields mature pollen tetrads, we determined that the pollen transmission defect of the eif3h-1 allele is due to a combination of reduced pollen germination and reduced pollen tube elongation. We also detected reduced pollen germination for eif3e. However, neither eif3h nor eif3e, unlike other known gametophytic mutations, measurably disrupted the early stages of pollen maturation. CONCLUSION/SIGNIFICANCE: eIF3h and eIF3e both become essential during pollen germination, a stage of vigorous translation of newly transcribed mRNAs. These data delimit the end of the developmental window during which paternal rescue is still possible. Moreover, the FTL collection of mapped fluorescent protein transgenes represents an attractive resource for elucidating the pollen development phenotypes of any fine-mapped mutation in Arabidopsis

The UK national breast cancer screening programme for survivors of Hodgkin lymphoma detects breast cancer at an early stage

BACKGROUND: Supradiaphragmatic radiotherapy (SRT) to treat Hodgkin's lymphoma (HL) at a young age increases the risk of breast cancer (BC). A national notification risk assessment and screening programme (NRASP) for women who were treated with SRT before the age of 36 years was instituted in the United Kingdom in 2003. In this study, we report the implementation and screening results from the largest English Cancer Network. METHODS: A total of 417 eligible women were identified through cancer registry/hospital databases and from follow-up (FU) clinics. Screening results were collated retrospectively, and registry searches were used to capture BC cases. RESULTS: Of the 417 women invited for clinical review, 243 (58%) attended. Of these 417 women, 23 (5.5%) have been diagnosed with BC, a standardised incidence ratio of 2.9 compared with the age-matched general population. Of five invasive BCs diagnosed within the NRASP, none involved axillary lymph nodes compared with 7 of 13 (54%) diagnosed outside the programme (P<0.10). The mean latency for BC cases was 19.5±8.35 years and the mean FU duration for those unaffected by BC was 14.6±9.11 years (P<0.01), suggesting that those unaffected by BC remain at high risk. Recall and negative biopsy rates were acceptable (10.5 and 0.8%, respectively). CONCLUSIONS: The NRASP appears to detect BC at an early stage with acceptable biopsy rates, although numbers are small. Determination of NRASP results on a national basis is required for the accurate evaluation of screening efficacy in women previously treated with SRT

Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system

DNA-based gene therapy has considerable therapeutic potential, but the challenges associated with delivery continue to limit progress. Messenger RNA (mRNA) has the potential to provide for transient production of therapeutic proteins, without the need for nuclear delivery and without the risk of insertional mutagenesis. Here we describe the sustained delivery of therapeutic proteins in vivo in both rodents and non-human primates via nanoparticle-formulated mRNA. Nanoparticles formulated with lipids and lipid-like materials were developed for delivery of two separate mRNA transcripts encoding either human erythropoietin (hEPO) or factor IX (hFIX) protein. Dose-dependent protein production was observed for each mRNA construct. Upon delivery of hEPO mRNA in mice, serum EPO protein levels reached several orders of magnitude (>125 000-fold) over normal physiological values. Further, an increase in hematocrit (Hct) was established, demonstrating that the exogenous mRNA-derived protein maintained normal activity. The capacity of producing EPO in non-human primates via delivery of formulated mRNA was also demonstrated as elevated EPO protein levels were observed over a 72-h time course. Exemplifying the possible broad utility of mRNA drugs, therapeutically relevant amounts of human FIX (hFIX) protein were achieved upon a single intravenous dose of hFIX mRNA-loaded lipid nanoparticles in mice. In addition, therapeutic value was established within a hemophilia B (FIX knockout (KO)) mouse model by demonstrating a marked reduction in Hct loss following injury (incision) to FIX KO mice