Effects of Pedunculopontine Area and Pallidal DBS on Gait Ignition in Parkinson's Disease

BackgroundFreezing of gait is a disabling feature of Parkinson's disease, and so far no established treatment exists. Deep brain stimulation of the pedunculopontine area has been proposed to treat refractory gait disorders, yet data on measurable effects, especially in combination with stimulation of other targets, are scarce.MethodsAcute effects of either low frequency pedunculopontine stimulation or high frequency stimulation of the posteroventral lateral globus pallidus internus and a combination of both in a 66-year-old man with advanced Parkinson's disease were assessed. Four weeks after the intervention, the gait was examined with patient blinded in each condition using computerized gait analysis.ResultsIsolated pedunculopontine or pallidal stimulation had a mild impact on gait ignition and freezing of gait, but combined stimulation had a marked effect.ConclusionsCombined multifocal stimulation may be a promising option for gait ignition and freezing of gait in advanced Parkinson's disease.     

Comparative Modeling of the Human Monoamine Transporters: Similarities in Substrate Binding

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Management of Anemia in Children Receiving Chronic Peritoneal Dialysis

Little information exists regarding the efficacy, modifiers, and outcomes of anemia management in children with CKD or ESRD. We assessed practices, effectors, and outcomes of anemia management in 1394 pediatric patients undergoing peritoneal dialysis (PD) who were prospectively followed in 30 countries. We noted that 25% of patients had hemoglobin levels below target (<10 g/dl or <9.5 g/dl in children older or younger than 2 years, respectively), with significant regional variation; levels were highest in North America and Europe and lowest in Asia and Turkey. Low hemoglobin levels were associated with low urine output, low serum albumin, high parathyroid hormone, high ferritin, and the use of bioincompatible PD fluid. Erythropoiesis-stimulating agents (ESAs) were prescribed to 92% of patients, and neither the type of ESA nor the dosing interval appeared to affect efficacy. The weekly ESA dose inversely correlated with age when scaled to weight but did not correlate with age when normalized to body surface area. ESA sensitivity was positively associated with residual diuresis and serum albumin and inversely associated with serum parathyroid hormone and ferritin. The prevalence of hypertension and left ventricular hypertrophy increased with the degree of anemia. Patient survival was positively associated with achieved hemoglobin and serum albumin and was inversely associated with ESA dose. In conclusion, control of anemia in children receiving long-term PD varies by region. ESA requirements are independent of age when dose is scaled to body surface area, and ESA resistance is associated with inflammation, fluid retention, and hyperparathyroidism. Anemia and high ESA dose requirements independently predict mortality.Almost three decades after the advent of recombinant erythropoietin, the management of renal anemia has become a recent focus of attention and changing paradigms. Whereas correction of hemoglobin (Hb) levels to near-normal has previously been recommended on the basis of association studies linking more severe anemia to morbidity and mortality with dialysis,^1–3 interventional clinical trials consistently demonstrate that near-normalization of Hb increases the risk of vascular events and mortality in adults receiving maintenance hemodialysis and in those with CKD who are not undergoing dialysis.^4–6 This has prompted ongoing reevaluation and revisions of treatment targets in patients exposed to erythropoiesis-stimulating agents (ESAs).⁷The appropriateness of applying treatment recommendations established in adult hemodialysis populations at high cardiovascular risk and adults with CKD to children undergoing dialysis is questionable because cardiovascular events are far less common in children with CKD. Furthermore, two thirds of children requiring dialysis initially opt for peritoneal dialysis (PD), and there are no systematic studies in the adult PD population to inform the optimal Hb target range in these patients. The risk profile of patients receiving PD may differ from that of the hemodialysis setting because of the absence of dialysis-induced intermittent hemoconcentration and lack of contact activation of the complement and coagulation systems.Further aspects to consider in pediatric anemia management are the greater physical activity of children and the need for optimal cognitive functioning at school.^8,9 The significant physiologic variation of the normal Hb range with age¹⁰ and the relative ESA sensitivity that reportedly increases with age during early childhood are also noteworthy.¹¹The registry of the International Pediatric Peritoneal Dialysis Network (IPPN) prospectively collects detailed clinical, biochemical, dialysis, and medication-related information (including ESA types and doses and modalities of iron supplementation) from a substantial number of children undergoing long-term PD around the world. In-depth analysis of this unique database has allowed us to (1) gain insight into the demographic characteristics of renal anemia and its treatment in the pediatric PD population worldwide, (2) explore the relationship between ESA dose requirements and body dimensions, (3) identify factors contributing to ESA resistance in children, and (4) associate anemia control with patient outcomes.     

Longitudinal growth on an everolimus‐ versus an MMF‐based steroid‐free immunosuppressive regimen in paediatric renal transplant recipients

Concerns have been raised that mammalian target of rapamycin inhibitors in pediatric transplant recipients might interfere with longitudinal bone growth by inhibition of growth factor signaling and growth plate chondrocyte proliferation. We therefore undertook a prospective nested, case‐control study on longitudinal growth over 2 years in steroid‐free pediatric renal transplant recipients. Fourteen patients on a steroid‐free maintenance immunosuppressive regimen consisting of low‐dose everolimus (EVR) in conjunction with low‐dose cyclosporine (CsA) were compared to a matched cohort of 14 steroid‐free patients on a standard dose mycophenolate mofetil (MMF) regimen in conjunction with a standard dose calcineurin inhibitor (CNI). The mean change in height standard deviation (SD) score in the first study year was 0.31 ± 0.71 SD score in the EVR group compared to 0.31 ± 0.64 SD score in the MMF group (P = 0.20). For the entire study period of 2 years, the change in height SD score in the EVR group was 0.43 ± 0.81 SDS compared to 0.75 ± 0.85 SDS in the MMF group (P = 0.32). The percentage of prepubertal patients experiencing catch‐up growth, defined as an increase in height SD score ≥0.5 in 2 years, was similar in the EVR group (5/8, 65%) and the MMF group (6/8, 75%; P = 1.00). Longitudinal growth over 2 years in steroid‐free pediatric patients on low‐dose EVR and CsA is not different to that of a matched steroid‐free control group on an immunosuppressive regimen with standard‐dose CNI and MMF. Hence, low‐dose EVR does not appear to negatively impact short‐term growth in pediatric renal transplant recipients.     

13th St. Gallen International Breast Cancer Conference 2013: Primary Therapy of Early Breast Cancer Evidence,Controversies, Consensus – Opinion of a German Team of Experts (Zurich 2013)

Zusammenfassung

Alle zwei Jahre findet in St. Gallen (Schweiz) die internationale Konsensuskonferenz zur Behandlung des primären Mammakarzinoms statt. Da sich das internationale Panel in St. Gallen aus Experten unterschiedlicher Länder zusammensetzt, spiegelt der Konsensus ein internationales Meinungsbild wider. Vor diesem Hintergrund erscheint es aus deutscher Sicht sinnvoll, die Abstimmungsergebnisse für den Therapiealltag in Deutschland zu konkretisieren. Eine deutsche Arbeitsgruppe mit acht Brustkrebsexperten, von denen zwei Mitglieder des internationalen St. Gallen-Panels sind, hat daher die Abstimmungsergebnisse der St. Gallen-Konsensuskonferenz (2013) für den Klinikalltag in Deutschland kommentiert. Inhaltliche Schwerpunkte der diesjährigen St. Gallen-Konferenz waren operative Fragestellungen der Brust und der Axilla, strahlentherapeutische und systemische Therapieoptionen sowie die klinische Relevanz der Tumorbiologie. Intensiv diskutiert wurde der klinische Einsatz von Multigen-Assays, inkl. ihrer Bedeutung für die individuelle Therapieentscheidung.     

Calretinin inputs are confined to motoneurons for upward eye movements in monkey

Motoneurons of extraocular muscles are controlled by different premotor pathways, whose selective damage may cause directionally selective eye movement disorders. The fact that clinical disorders can affect only one direction, e.g., isolated up‐/downgaze palsy or up‐/downbeat nystagmus, indicates that up‐ and downgaze pathways are organized separately. Recent work in monkey revealed that a subpopulation of premotor neurons of the vertical eye movement system contains the calcium‐binding protein calretinin (CR). With combined tract‐tracing and immunofluorescence, the motoneurons of vertically pulling eye muscles in monkey were investigated for the presence of CR‐positive afferent terminals. In the oculomotor nucleus, CR was specifically found in punctate profiles contacting superior rectus and inferior oblique motoneurons, as well as levator palpebrae motoneurons, all of which participate in upward eye movements. Double‐immunofluorescence labeling revealed that CR‐positive terminals lacked the γ‐aminobutyric acid (GABA)‐synthesizing enzyme glutamate decarboxylase, which is present in inhibitory afferents to all motoneurons mediating vertical eye movements. Therefore, CR‐containing afferents are considered to be excitatory. In conclusion, a strong CR input is confined to motoneurons mediating upgaze, which derive from premotor pathways mediating saccades and smooth pursuit, but not from secondary vestibulo‐ocular neurons in the magnocellular part of the medial vestibular nucleus. The functional significance of CR in these connections is unclear, but it may serve as a useful marker to locate upgaze pathways in the human brain. J. Comp. Neurol. 521:3154–3166, 2013. © 2013 Wiley Periodicals, Inc.     

Anticipatory pleasure and approach motivation in schizophrenia-like negative symptoms

Previous research of negative symptoms in schizophrenia has emphasized an anticipatory pleasure deficit, yet the relationship of this deficit to patients' motivation in everyday life is poorly understood. This study tested the link between anticipatory pleasure and two broad motivational systems that are said to regulate the intensity of approach and avoidance behavior, the Behavioral Inhibition system (BIS) and the Behavioral Activation System (BAS). It was hypothesized that high vulnerability for negative symptoms would be associated with low reward responsiveness and that this association will be mediated by the amount of anticipated pleasure. Students (n=171) with varying vulnerability for negative symptoms (assessed by the Community Assessment of Psychic Experiences) completed questionnaires regarding (a) anticipatory and consummatory pleasure, and (b) responsiveness to threat and reward. As hypothesized, anticipatory pleasure correlated significantly negatively with subclinical negative symptoms (r=−0.21) and significantly positively with BAS (r=0.55). Furthermore, evidence for a partial mediation effect was found. The findings support the notion of a close association between negative symptoms, the ability to anticipate pleasure and approach motivation that is evident even in healthy persons. It is suggested that the behavioral deficits immanent to negative symptoms reflect difficulties in the ability to translate emotions into motivation.