Evidence for widespread changes in the structure, composition, and fire regimes of western North American forests.

Implementation of wildfire- and climate-adaptation strategies in seasonally dry forests of western North America is impeded by numerous constraints and uncertainties. After more than a century of resource and land use change, some question the need for proactive management, particularly given novel social, ecological, and climatic conditions. To address this question, we first provide a framework for assessing changes in landscape conditions and fire regimes. Using this framework, we then evaluate evidence of change in contemporary conditions relative to those maintained by active fire regimes, i.e., those uninterrupted by a century or more of human-induced fire exclusion. The cumulative results of more than a century of research document a persistent and substantial fire deficit and widespread alterations to ecological structures and functions. These changes are not necessarily apparent at all spatial scales or in all dimensions of fire regimes and forest and nonforest conditions. Nonetheless, loss of the once abundant influence of low- and moderate-severity fires suggests that even the least fire-prone ecosystems may be affected by alteration of the surrounding landscape and, consequently, ecosystem functions. Vegetation spatial patterns in fire-excluded forested landscapes no longer reflect the heterogeneity maintained by interacting fires of active fire regimes. Live and dead vegetation (surface and canopy fuels) is generally more abundant and continuous than before European colonization. As a result, current conditions are more vulnerable to the direct and indirect effects of seasonal and episodic increases in drought and fire, especially under a rapidly warming climate. Long-term fire exclusion and contemporaneous social-ecological influences continue to extensively modify seasonally dry forested landscapes. Management that realigns or adapts fire-excluded conditions to seasonal and episodic increases in drought and fire can moderate ecosystem transitions as forests and human communities adapt to changing climatic and disturbance regimes. As adaptation strategies are developed, evaluated, and implemented, objective scientific evaluation of ongoing research and monitoring can aid differentiation of warranted and unwarranted uncertainties.

Demographic trends in community functional tolerance reflect tree responses to climate and altered fire regimes.

Forests of the western United States are undergoing substantial stress from fire exclusion and increasing effects of climate change, altering ecosystem functions and processes. Changes in broad-scale drivers of forest community composition become apparent in their effect on survivorship and regeneration, driving demographic shifts. Here we take a community functional approach to forest demography, by investigating mean drought or shade functional tolerance in community assemblages. We created the Community Mean Tolerance Index (CMTI), a response metric utilizing drought/shade tolerance trade-offs to identify communities undergoing demographic change from a functional trait perspective. We applied the CMTI to Forest Inventory and Analysis data to investigate demographic trends in drought and shade tolerance across the southern Rocky Mountains. To find the major drivers of change in community tolerance within and across forest types, we compared index trends to climate and fire-exclusion-driven disturbance, and identified areas where demographic change was most pronounced. We predicted that greater shifts in drought tolerance would occur at lower forest type ecotones where climate stress is limiting and that shifts in shade tolerance would correspond to excursions from the historic fire regime leading to greater changes in forest types adapted to frequent, low-intensity fire. The CMTI was applied spatially to identify sites likely to transition to oak shrubfield, where disturbance history combined with a species-driven demographic shift toward drought tolerance. Within forest types, lower elevations are trending toward increased drought tolerance, while higher elevations are trending toward increased shade tolerance. Across forest types, CMTI difference peaked in mid-elevation ponderosa pine and mixed-conifer forests, where fire exclusion and autecology drive demographic changes. Peak CMTI difference was associated with fire exclusion in forest types adapted to frequent fire. At higher elevations, site-level stand dynamics appear to be influencing demographic tolerance trends more than broad climate drivers. Through a community demographic approach to functional traits, the CMTI highlights areas and forest types where ecosystem function is in the process of changing, before persistent vegetation type change occurs. Applied to regional plot networks, the CMTI provides an early warning of shifts in community functional processes as climate change pressures continue.

Effect of high-frequency subthalamic neurostimulation on gait and freezing of gait in Parkinson's disease: a systematic review and meta-analysis.

The aim of this meta-analysis was to summarize the short- and long-term effects of bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) on gait and freezing of gait (FOG) in Parkinson's disease and to detect predictors of post-stimulation outcome. A comprehensive review of the literature was conducted up to October 2015 using Medline Ovid databases for studies analyzing the effect of bilateral STN-DBS on FOG and/or gait. Sixteen studies with available data for the gait item (no. 29) of the Unified Parkinson's Disease Rating Scale (UPDRS) and six studies with the FOG item (no. 14) were included. Data were summarized for the following follow-up periods: 6-15, 24-48 and >48 months. For the medication (Med)-Off/stimulation(Stim)-On condition compared with baseline Med-Off, STN-DBS significantly improved gait on average from 2.43 to 0.96, 2.53 to 1.31 and 2.56 to 1.40 points at 6-15, 24-48 and >48 months, respectively (P < 0.05). Pre-operative levodopa responsiveness of UPDRS-III and Med-Off severity of gait were the predictors of this beneficial effect. STN-DBS significantly improved FOG for the Med-Off/Stim-On condition compared with baseline on average from 2.26 to 0.82, 2.43 to 1.13 and 2.48 to 1.38 points at 6-15, 24-48 and >48 months, respectively (P < 0.05). There was no significant effect in the Med-On/Stim-On condition. This meta-analysis showed a robust improvement of gait and FOG by STN-DBS for more than 4 years in the Med-Off/Stim-On condition. No beneficial effect was found for the On state of medication. Pre-operative levodopa responsiveness of global motor performance (UPDRS-III) is the strongest predictor of the effect of deep brain stimulation on gait.

Transcriptome assessment of the Pompe (Gaa-/-) mouse spinal cord indicates widespread neuropathology.

Pompe disease, caused by deficiency of acid alpha-glucosidase (GAA), leads to widespread glycogen accumulation and profound neuromuscular impairments. There has been controversy, however, regarding the role of central nervous system pathology in Pompe motor dysfunction. We hypothesized that absence of GAA protein causes progressive activation of neuropathological signaling, including pathways associated with cell death. To test this hypothesis, genomic data (Affymetrix Mouse Gene Array 2.0ST) from the midcervical spinal cord in 6 and 16 mo old Pompe (Gaa-/-) mice were evaluated (Broad Institute Molecular Signature Database), along with spinal cord histology. The midcervical cord was selected because it contains phrenic motoneurons, and phrenic-diaphragm dysfunction is prominent in Pompe disease. Several clinically important themes for the neurologic etiology of Pompe disease emerged from this unbiased genomic assessment. First, pathways associated with cell death were strongly upregulated as Gaa-/- mice aged, and motoneuron apoptosis was histologically verified. Second, proinflammatory signaling was dramatically upregulated in the Gaa-/- spinal cord. Third, many signal transduction pathways in the Gaa-/- cervical cord were altered in a manner suggestive of impaired synaptic function. Notably, glutamatergic signaling pathways were downregulated, as were "synaptic plasticity pathways" including genes related to neuroplasticity. Fourth, many genes and pathways related to cellular metabolism are dysregulated. Collectively, the data unequivocally confirm that systemic absence of GAA induces a complex neuropathological cascade in the spinal cord. Most importantly, the results indicate that Pompe is a neurodegenerative condition, and this underscores the need for early therapeutic intervention capable of targeting the central nervous system.

Neurostimulation for Parkinson's disease with early motor complications.

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT).

BACKGROUND: SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) is a rare syndrome characterized by the sudden onset of excruciating unilateral periorbital pain that is accompanied by conjunctival injection and lacrimation or further autonomic signs. Similar to patients with chronic cluster headache, Leone and Lyons showed a beneficial effect of deep brain stimulation of the posterior hypothalamic region in two patients with a chronic SUNCT. CASE: Here, we present the case of a man with a chronic SUNCT responding to deep brain stimulation of the posterior hypothalamic area. CONCLUSION: This case supports the idea of a central origin of SUNCT and shows that deep brain stimulation of the hypothalamic region can be effective in the treatment of the chronic form of this rare disorder.

Cerebral cortices of East african early hominids.

An endocast of the frontal lobe of a reconstructed skull, which is approximately 2 million years old, from the Koobi Fora region of Kenya appears to represent the oldest human-like cortical sulcal pattern in the fossil record, while the endocast from another skull from the same region produces an endocast that appears apelike in its frontal lobe and similar to endocasts from earlier South African australopithecines. New analysis of paleoanatomical evidence thus indicates that at least two taxa of early hominids coexisted in East Africa.

Deep brain stimulation of the internal globus pallidus in dystonia: target localisation under general anaesthesia.

UNLABELLED: Deep brain stimulation (DBS) of the internal globus pallidus (Gpi) is an effective therapy for various types of dystonia. The authors describe their technical approach for securing appropriate placement of the stimulating electrodes within the Gpi under general anaesthesia, including MRI based individualised anatomical targeting combined with electrophysiological mapping of the Gpi using micro-recording (MER) as well as macrostimulation and report the subsequent clinical outcome and complications using this method. METHOD: We studied 42 patients (male-female ratio 25:17; mean age 43.6 years, range 9 to 74 years) consecutively operated at the Department of Neurosurgery, University Hospital Schleswig-Holstein, Campus Kiel, between 2001 - 2006. One patient underwent unilateral implantation after a right-sided pallidotomy 30 years before and strictly unilateral symptoms; all other implantations were bilateral. Two patients had repeat surgery after temporary removal of uni- or bilateral implants secondary to infection. Overall, 86 DBS electrodes were implanted. In 97% of the implantations, at least three microelectrodes were inserted simultaneously for MER and test stimulation. Initial anatomical targeting was based on stereotactic atlas coordinates and individual adaptation by direct visualisation of the Gpi on the stereotactic T2 or inversion-recovery MR images. The permanent electrode was placed according to the results of MER and test stimulations for adverse effects. FINDINGS: The average improvement from baseline in clinical ratings using either the Burke-Fahn-Marsden-Dystonia (BFMDRS) or Toronto-Western-Spasmodic-Torticollis (TWSTR) rating scale at the last post-operative follow-up (mean 16.4 ; range 3-48 months) was 64.72% (range 20.39 to 98.52%). The post-operative MRI showed asymptomatic infarctions of the corpus caudatus in three patients and asymptomatic small haemorrhages in the lateral basal ganglia in two patients. One patient died due to a recurrent haemorrhage which occurred three months after the operation. The electrodes were implanted as follows: central trajectory in 64%, medial trajectory in 20%, anterior in 9% and lateral dorsal trajectories in 3.5% each. The reduction in BFMDRS or TWSTR motor score did not differ between the group implanted in the anatomically defined (central) trajectory bilateral (-64.15%, SD 23.8) and the physiologically adopted target (uni- or bilateral) (-63.39%, SD 23.1) indicating that in both groups equally effective positions were chosen within Gpi for chronic stimulation (t-test, p > 0.4). CONCLUSIONS: The described technique using stereotactic MRI for planning of the trajectory and direct visualisation of the target, intra-operative MER for delineating the boundaries of the target and macrostimulation for probing the distance to the internal capsule by identifying the threshold for stimulation induced tetanic contractions is effective in DBS electrode implantation in patients with dystonia operated under general anaesthesia. The central trajectory was chosen in only 64%, despite individual adaptation of the target due to direct visualisation of the Gpi in inversion recovery MRI in 43% of the patients, demonstrating the necessity of combining anatomical with neurophysiological information.

Deep brain stimulation for movement disorders and its neuropsychological implications.

Deep brain stimulation (DBS) has gained increasing attention as a therapy for movement disorders. Neuropsychological alterations can accompany the disease evolution and medical therapy of PD. Also, interfering abruptly with the biological balance by means of a surgical intervention into complex circuits with motor but also cognitive and limbic functions, could potentially cause severe problems. Because cognitive or emotional impairments may have an even stronger impact on quality of life, than motor symptoms, care must be taken to perform surgery in the safest possible way to exclude adverse effects in these domains. Detailed neuropsychological evaluations may become helpful to further understand the mechanisms underlying some aspects of the clinical pictures both pre- and postoperatively and to define risk populations, that should be excluded from this intervention.

Life-threatening DBS withdrawal syndrome in Parkinson's disease can be treated with early reimplantation.

INTRODUCTION: The deep brain stimulation (DBS) withdrawal syndrome (DBS-WDS) is a rare, life-threatening complication in Parkinson's disease (PD) patients with long disease duration and stimulation when stimulation is terminated for extended periods mostly due to infection of the DBS-hardware. METHODS, RESULTS: In five patients explantation became necessary because of infection after a mean of 11.4 years (range 4-15 years) of DBS and a mean disease duration of 24.6 years (range 3-22 years). Mean UPDRS motor-score pre-explantation was 38 points (range 24-55 points) which increased to a mean of 78.4 points (range 58-90 points) after explantation, despite optimal Levodopa dosing. Reimplantation of the hardware after 23 days (range 3-45 days) under antibiotic treatment led to an improvement to a mean of 40 points (range 25-73 points) and a complication free survival. CONCLUSION: Early reimplantation of the DBS-hardware is a treatment option of the DBS-WDS when the life-threatening urgency overrides surgical standards. Observation of the syndrome indicates pharmacological unresponsiveness of the dopaminergic system in advanced PD and long-term DBS.

German registry of paediatric deep brain stimulation in patients with childhood-onset dystonia (GEPESTIM).

BACKGROUND: Data on paediatric deep brain stimulation (DBS) is limited, especially for long-term outcomes, because of small numbers in single center series and lack of systematic multi-center trials. OBJECTIVES: We seek to systematically evaluate the clinical outcome of paediatric patients undergoing DBS. METHODS: A German registry on paediatric DBS (GEPESTIM) was created to collect data of patients with dystonia undergoing DBS up to the age of 18 years. Patients were divided into three groups according to etiology (group 1 inherited, group 2 acquired, and group 3 idiopathic dystonia). RESULTS: Data of 44 patients with a mean age of 12.8 years at time of operation provided by 6 German centers could be documented in the registry so far (group 1 n = 18, group 2 n = 16, group 3 n = 10). Average absolute improvement after implantation was 15.5 ± 18.0 for 27 patients with pre- and postoperative Burke-Fahn-Marsden Dystonia Rating scale movement scores available (p < 0.001) (group 1: 19.6 ± 19.7, n = 12; group 2: 7.0 ± 8.9, n = 8; group 3: 19.2 ± 20.7, n = 7). Infection was the main reason for hardware removal (n = 6). 20 IPG replacements due to battery expiry were necessary in 15 patients at 3.7 ± 1.8 years after last implantation. DISCUSSION: Pre- and postoperative data on paediatric DBS are very heterogeneous and incomplete but corroborate the positive effects of DBS on inherited and acquired dystonia. Adverse events including relatively frequent IPG replacements due to battery expiry seem to be a prominent feature of children with dystonia undergoing DBS. The registry enables collaborative research on DBS treatment in the paediatric population and to create standardized management algorithms in the future.

Mechanical ventilation promotes redox status alterations in the diaphragm.

Oxidative stress is an important mediator of diaphragm muscle atrophy and contractile dysfunction during prolonged periods of controlled mechanical ventilation (MV). To date, specific details related to the impact of MV on diaphragmatic redox status remain unknown. To fill this void, we tested the hypothesis that MV-induced diaphragmatic oxidative stress is the consequence of both an elevation in intracellular oxidant production in conjunction with a decrease in the antioxidant buffering capacity. Adult rats were assigned to one of two experimental groups: 1) control or 2) 12 h of MV. Compared with controls, diaphragms from MV animals demonstrated increased oxidant production, diminished total antioxidant capacity, and decreased glutathione levels. Heme oxygenase-1 (HO-1) mRNA and protein levels increased (23.0- and 5.1-fold, respectively) following MV. Thioredoxin reductase-1 and manganese superoxide dismutase mRNA levels were also increased in the diaphragm following MV (2.4- and 1.6-fold, respectively), although no change was detected in the levels of either protein. Furthermore, copper-zinc superoxide dismutase and glutathione peroxidase mRNA were not altered following MV, although protein content decreased -1.3- and -1.7-fold, respectively. We conclude that MV promotes increased oxidant production and impairment of key antioxidant defenses in the diaphragm; collectively, these changes contribute to the MV-induced oxidative stress in this key inspiratory muscle.

Characterization of an autosomal rudimentary-shaped wing mutation in Drosophila melanogaster that affects pyrimidine synthesis.

A new autosomal mutation, rudimental (ral), which causes rudimentary-shaped wings in Drosophila melanogaster, has been isolated following ethyl methanesulfonate (EMS) mutagenesis. The wing phenotype of rudimental is identical to that of the X-linked rudimentary (r) mutation, which affects the first three enzymes in the pyrimidine biosynthetic pathway. The autosomal mutant maps very close to ebony (3-70.7) at 70.42 on the right arm of chromosome 3. Analysis of the enzyme activities of orotate phosphoribosyltransferase (OPRTase) and orotidylate decarboxylase (ODCase) indicates that the rala26a allele has less than wild-type activity for both enzymes. This result is discussed in light of the fact that the OPRTase and ODCase activities are part of an enzyme complex, as are the carbamyl phosphate synthetase (CPSase), aspartate transcarbamylase (ATCase) and dihydroorotase (DHOase) activities, which are encoded by the complex rudimentary locus. We suggest that rudimental is also a complex lucus.

Sex-linked auxotrophic and putative auxotrophic mutants of Drosophila melanogaster.

Thirty-two mutants with improved growth response on a yeast-sucrose compared with a defined medium have been characterized with respect to ribonucleoside supplementability. Twenty mutants respond to either pyrimidine ribonucleoside. Four mutants respond to one or both purine ribonucleosides. Eight mutants ("putative" auxotrophs) do not respond to dietary RNA supplementation. Mapping and complementation studies suggest that eleven loci are represented: one, rudimentary, probably accounts for all pyrimidine requirers; there are three purine loci and seven at which the putative auxotrophs are found.

A genetic and biochemical analysis of the temperature sensitive, normal-winged alleles of the rudimentary locus of Drosophila melanogaster.

The genetic and biochemical characteristics of a particular class of mutants at the rudimentary locus are described. The mutants are pyrimidine auxotrophs, like classical rudimentary alleles, but they are unique in that they do not alter the size or shape of the wing (Falk and Nash 1974b). Aspartate transcarbamylase and dihydroorotase activities have been measured in seven different normal-winged mutants, and the results indicate that these strains are enzymologically "leaky" mutants. Previous studies have shown that three genetic functions (corresponding to the first three enzymes of pyrimidine synthesis) are associated with the rudimentary locus. Four of the seven mutants appear to affect all three of these functions. Each of the four is temperature sensitive, and a biochemical analysis of the temperature sensitivity of one of these mutants, (r)pyr1-3, suggests that a process affecting the synthesis or assembly of these enzymes is altered at high temperatures.

The genetic analysis of achiasmate segregation in Drosophila melanogaster. III. The wild-type product of the Axs gene is required for the meiotic segregation of achiasmate homologs.

The regular segregation of achiasmate chromosomes in Drosophila melanogaster females is ensured by two distinct segregational systems. The segregation of achiasmate homologs is assured by the maintenance of heterochromatic pairing; while the segregation of heterologous chromosomes is ensured by a separate mechanism that may not require physical association. AxsD (Aberrant X segregation) is a dominant mutation that specifically impairs the segregation of achiasmate homologs; heterologous achiasmate segregations are not affected. As a result, achiasmate homologs frequently participate in heterologous segregations at meiosis I. We report the isolation of two intragenic revertants of the AxsD mutation (Axsr2 and Axsr3) that exhibit a recessive meiotic phenotype identical to that observed in AxsD/AxsD females. A third revertant (Axsr1) exhibits no meiotic phenotype as a homozygote, but a meiotic defect is observed in Axsr1/Axsr2 females. Therefore mutations at the AxsD locus define a gene necessary and specific for homologous achiasmate segregation during meiosis. We also characterize the interactions of mutations at the Axs locus with two other meiotic mutations (ald and ncd). Finally, we propose a model in which Axs+ is required for the normal separation of paired achiasmate homologs. In the absence of Axs+ function, the homologs are often unable to separate from each other and behave as a single segregational unit that is free to segregate from heterologous chromosomes.

Gilles de la Tourette syndrome after long-term chlorpromazine therapy.

Following 6 years of continuous chlorpromazine therapy for schizophrenia, a young woman developed multifocal tics and vocalizations characteristic of Tourette syndrome. The symptoms first appeared when chlorpromazine was withdrawn. They were permanent, although partially ameliorated by chronic haloperidol therapy. Because of her age and past history, these symptoms were attributed to chronic neuroleptic therapy analogous to neuroleptic-induced tardive dyskinesia, rather than to Tourette syndrome per se. These symptoms suggest that chronic receptor-site blockade can result in hypersensitivity of dopamine receptor sites, and that this may play a role in the pathophysiology of Gilles de la Tourette syndrome. This is the first evidence that hypersensitivity of dopamine receptors is involved in the pathophysiology of Tourette syndrome.