Clinical markers for identifying cholinergic deficits in Parkinson's disease

BackgroundCholinergic projection systems degeneration is associated with dopamine nonresponsive features of Parkinson's disease (PD). Cholinergic deficits are variable in nondemented PD. Identification of cholinergic deficits in PD may help with selection of suitable patients for targeted cholinergic drug treatment in PD. The objective of this retrospective multivariate predictor analysis study was to identify clinical markers indicative of cholinergic deficits in PD patients, as assessed by acetylcholinesterase ([11C]PMP) positron emission tomography.MethodsOne hundred thirty‐seven PD patients (34 female) participated; median modified Hoehn and Yahr score was 2.5 (range, 1‐4), average age 65.6 ± 7.4 years, and average duration of motor disease symptoms of 6.0 ± 4.2 years. Subjects were dichotomized as “normocholinergic” or “hypocholinergic” based on a 5th percentile cutoff from normal for the basal forebrain‐cortical and pedunculopontine nucleus‐thalamic cholinergic projection systems. Previously identified clinical indices of cholinergic denervation were used for statistical prediction of cholinergic deficits. Logistic regression determined which risk factors predicted cholinergic deficits. Sensitivity, specificity, and accuracy were determined for the (combinations of) significant predictor variables.ResultsForty‐nine (35.8%) hypocholinergic PD subjects were identified. The combination of rapid eye movement (REM) sleep behavior disorder (RBD) symptoms and fall history showed highest diagnostic accuracy (81.1%) for predicting combined thalamic and cortical cholinergic deficits. A combined assessment of 8.5 m walk time and lower score on the Montreal cognitive assessment scale provided diagnostic accuracy of 80.7% for predicting isolated cortical cholinergic denervation.ConclusionAssessment of clinical indices of cholinergic denervation may be useful for identifying suitable subjects for trials of targeted cholinergic drug treatments in PD. © 2014 International Parkinson and Movement Disorder SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110743/1/mds26061.pd

Intrapartum fetal heart rate patterns : quantification and trend detection

The present studies were designed and performed to investigate different aspects of the reliability of EFM, including the effects of methodologic changes in the assessment of tracings on the reliability of EFM. Analysis of FHR patterns. The validity and the relatively low reproducibility of FHR assessment may be improved by standardization. To that purpose it was tried to develop a classification of FHR patterns consisting of different sets of criteria applicable to each FHR pattern, exactly defined, mutually exclusive and complementary. For comparibility, such a classification should resemble classifications that were used previously but lacked these characteristics • The latter classifications were used in completely visual analyses. It was tried to answer the question as to whether the use of the developed classification and the use of a template in visual analysis further reduce observer variation. Finally it was investigated whether the validity of EFM might be improved by using a standardized duration of the tracings of such a length that unexpected fetal acidosis will probably not occur before the end of the tracing (<120 min.), and the influence of biologic variability of the FHR on the analysis will be limite

Spin-orbit driven Peierls transition and possible exotic superconductivity in CsW2_{2}O6_{6}

We study \textit{ab initio} a pyrochlore compound, CsW$_{2}$O$_{6}$, which exhibits a yet unexplained metal-insulator transition. We find that (1) the reported low-$T$ structure is likely inaccurate and the correct structure has a twice larger cell; (2) the insulating phase is not of a Mott or dimer-singlet nature, but a rare example of a 3D Peierls transition, with a simultaneous condensation of three density waves; (3) spin-orbit interaction plays a crucial role, forming well-nested bands. The high-$T$ (HT) phase, if stabilized, could harbor a unique $e_{g}+ie_{g}$ superconducting state that breaks the time reversal symmetry, but is not chiral. This state was predicted in 1999, but never observed. We speculate about possible ways to stabilize the HT phase while keeping the conditions for superconductivity

Potassium Channelopathies in Pulmonary Arterial Hypertension

A debilitating illness, pulmonary arterial hypertension (PAH) arises from deleterious remodeling of pulmonary arterioles, leading to increased pulmonary artery pressure, a rise in pulmonary vascular resistance, right sided heart failure and death. The pathogenesis of the disease is incompletely understood; however, certain established pathological features have guided medical treatments to improve mortality rates. For instance, an imbalance of vasoconstrictor molecules, such as endothelin-1, to vasodilator compounds, such as nitric oxide, contributes to excessive pulmonary arterial constriction, and a propensity for pulmonary arterial smooth muscle and endothelial cell proliferation. Therapeutic strategies may aim to restore this imbalance with the use of endothelin receptor antagonists, prostacyclin analogs, and other vasodilating agents. Mutations in the BMPR2 gene, the most common genetic cause of PAH, leads to aberrant TGF-ß signaling, which promotes uncontrollable cell proliferation and pathological changes in pulmonary arterioles. Genetic studies have revealed PAH-associated mutations in several other genes within the TGF-ß signaling pathway. More recently, our research group discovered loss-of-function mutations in the KCNK3 gene encoding the KCNK3 two-pore domain potassium channel in patients with idiopathic and familial PAH. KCNK3 (also referred to as TASK-1, or K2P3.1) represents the first ion channelopathy as a cause of PAH. KCNK3 is expressed in human pulmonary artery smooth muscle and endothelial cells. Loss of KCNK3 channel currents leads to membrane depolarization and predisposes to deleterious pulmonary arterial remodeling. Chapter 1 of my thesis explores the impact of KCNK3 mutations on potassium channel function in cellular models of heterozygous conditions, as all patients with PAH-associated KCNK3 mutations in our study were heterozygous at the KCNK3 gene locus. Furthermore, we explored function of mutant and non-mutant KCNK3 channels in cultured human pulmonary artery smooth muscle cells to better define the electrophysiological consequence of KCNK3 dysfunction, and used a KCNK3-activating pharmacological agent, ONO-RS-082, to gauge the therapeutic potential of KCNK3 as a pharmacological target in PAH. Moreover, the study of KCNK3 channel activity when assembled with the closely related KCNK9 channel provided a platform for exploring the lung-specific phenotype in patients with heterozygous KCNK3 mutations, despite widespread tissue expression KCNK3 in the body. In Chapter 2 of my thesis work, the discovery of a second potassium channelopathy in PAH is characterized. Heterozygous mutations in the ABCC8 gene, encoding the sulfonylurea receptor 1 (SUR1) protein, were found in pediatric and adult patients with idiopathic and familial PAH. SUR1, a beta subunit of the ATP-sensitive potassium channel (KATP), assembles with the pore-forming Kir6.2 alpha subunit to form KATP, a channel sensitive to inhibition by intracellular ATP. At the plasma membrane, KATP inwardly rectifying potassium currents contribute to the resting potential, and may play a pathophysiological role in PAH via dysfunction in pulmonary artery smooth muscle and/or endothelial cells. In this chapter, eight ABCC8 mutations associated with PAH were functionally characterized, and pharmacological agents were employed to examine the therapeutic potential in targeting SUR1-containing KATP channels in PAH. Altogether, the research presented in this dissertation identifies and explores potassium channel dysfunction as a pathogenic mechanism in PAH, due to heterozygous genetic mutations in KCNK3 and ABCC8. Evidence of restoration of mutant KCNK3 and KATP channel function by pharmacological agents suggests that targeting potassium channels as a therapeutic strategy may alleviate the severe morbidity and mortality burden in patients with PAH

Momentum dependence of the electron-phonon coupling and self-energy effects in YBa_2Cu_3O_7 within the local density approximation

Using the local density approximation (LDA) and a realistic phonon spectrum we determine the momentum and frequency dependence of $\alpha^2F({\bf k},\omega)$ in YBa$_2$Cu$_3$O$_7$ for the bonding, antibonding, and chain band. The resulting self-energy $\Sigma$ is rather small near the Fermi surface. For instance, for the antibonding band the maximum of $Re \Sigma$ as a function of frequency is about 7 meV at the nodal point in the normal state and the ratio of bare and renormalized Fermi velocities 1.18. These values are a factor 3-5 too small compared to the experiment showing that only a small part of $\Sigma$ can be attributed to phonons. Furthermore, the frequency dependence of the renormalization factor $Z({\bf k},\omega)$ is smooth and has no anomalies at the observed kink frequencies which means that phonons cannot produce well-pronounced kinks in stoichiometric YBa$_2$Cu$_3$O$_7$, at least, within the LDA.Comment: Figure 1 slightly revised, text shortened, accepted as a PR

Outcome Measure Use in Occupational Therapy for Upper Extremity Rehabilitation: Results of a Survey of Therapist Clinical Practices

Occupational therapists can work in a variety of settings, and therefore use multiple frames of references, models of practice, and different outcome measures based on the populations they are treating. This study includes a literature review of the outcome measures used in occupational therapy and hand therapy, as well as the frames of references used, and the goal setting strategies employed in hand therapy. The purpose of this study is to identify assessments and outcomes measures used by occupational therapists specializing in hand therapy practice and to determine if that choice is affected by their chosen frames of reference, membership in professional organizations, and the measurement tools identified in their professional journals. This study benefits the occupational therapy community because it provides information on current trends in assessment and outcome measurement used for clients with upper extremity injuries and the primary frames of references therapists use with their clients. This study helps occupational therapists working primarily as hand therapists better understand their own practice by providing information that supports, recognizes, and reflects on the methods they use in treatment. A survey was sent to 154 hand therapists in Minnesota. The results of this study indicated that few therapists differentiated between assessments and outcome measures and that frequently used assessment tools were also frequently identified as outcome measures. The survey results indicate 94% of therapists using the DASH or QuickDASH identified it as both an assessment and an outcome measure. Goal attainment and self report on progress were also identified by some respondents as an outcome measure. The biomechanical frame of reference was frequently used regardless of practice setting or experience and the majority of assessments and outcomes identified reflect this frame of reference (FOR). Other models and FORs therapists identified using were not represented in assessment or outcome measures selection. Therapists with less experience used a broader range of models and FOR, while therapists with over 15 years of experience identified very few. Three primary goal setting strategies with varying levels of client-centeredness were used by over 63% of respondents and included: Goals being set during specific client discussion, goals being set based on assessment results and are then described to client, and goals written based on client comments and in response to written self report assessments

Lattice dynamics and electron-phonon interaction in (3,3) carbon nanotubes

We present a detailed study of the lattice dynamics and electron-phonon coupling for a (3,3) carbon nanotube which belongs to the class of small diameter based nanotubes which have recently been claimed to be superconducting. We treat the electronic and phononic degrees of freedom completely by modern ab-initio methods without involving approximations beyond the local density approximation. Using density functional perturbation theory we find a mean-field Peierls transition temperature of approx 40K which is an order of magnitude larger than the calculated superconducting transition temperature. Thus in (3,3) tubes the Peierls transition might compete with superconductivity. The Peierls instability is related to the special 2k_F nesting feature of the Fermi surface. Due to the special topology of the (n,n) tubes also a q=0 coupling between the two bands crossing the Fermi energy at k_F is possible which leads to a phonon softening at the Gamma point.Comment: 4 pages, 3 figures; to be published in Phys. Rev. Let