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DYT-TOR1A or DYT1 early-onset generalized dystonia is an inherited movement disorder characterized by sustained muscle contractions causing twisting, repetitive movements, or abnormal postures. The majority of the DYT1 dystonia patients have a trinucleotide GAG deletion in DYT1/TOR1A. Trihexyphenidyl (THP), an antagonist for excitatory muscarinic acetylcholine receptor M1, is commonly used to treat dystonia. Dyt1 heterozygous ΔGAG knock-in (KI) mice, which have the corresponding mutation, exhibit impaired motor-skill transfer. Here, the effect of THP injection during the treadmill training period on the motor-skill transfer to the accelerated rotarod performance was examined. THP treatment reversed the motor-skill transfer impairment in Dyt1 KI mice. Immunohistochemistry showed that Dyt1 KI mice had a significant reduction of the dorsolateral striatal cholinergic interneurons. In contrast, Western blot analysis showed no significant alteration in the expression levels of the striatal enzymes and transporters involved in the acetylcholine metabolism. The results suggest a functional alteration of the cholinergic system underlying the impairment of motor-skill transfer and the pathogenesis of DYT1 dystonia. Training with THP in a motor task may improve another motor skill performance in DYT1 dystonia.

In 2014, the Navajo Nation Council passed the Healthy Diné Nation Act (HDNA), a 2% tax on unhealthy foods and beverages and a waiver of the 5% sales tax on healthy foods and water, to support health promotion and disease prevention among the Navajo people. Very little research has assessed implementation accuracy of food or beverage taxes and none were implemented within a sovereign Tribal nation. This study assessed the accuracy of HDNA tax implementation among 47 stores located on the Navajo Nation. A pair of tax-exempt items [e.g. a bottle of water and fresh fruit] and a pair of HDNA-tax eligible items [e.g. sugary beverage and candy bar] were purchased between July-December 2019. Receipts were retained to assess taxation. A total of 87.2% of stores accurately implemented the 2% tax on unhealthy items while 55.3% of the stores accurately implemented the 6% tax waiver on healthy items. In all, 51.1% of the stores accurately applied both taxes. There were no significant differences across store type (convenience or grocery stores and trading posts) or geographic region. In conclusion, almost all stores on the Navajo Nation accurately applied a 2% tax on unhealthy foods and beverages, while the proportion of stores applying a waiver on healthy foods was lower. Successful HDNA tax implementation among stores remains an important priority in achieving the goal to support health promotion and disease prevention among Navajo communities.

Successful emergency vaccination campaigns rely on effective deployment and vaccination plans. This applies to localised outbreaks as well as for pandemics. In the wake of the 2009 H1N1 influenza pandemic, analysis of the global Vaccine Deployment Initiative, through which the World Health Organization (WHO) donated pandemic influenza vaccines to countries in need, revealed that an absence of vaccine deployment plans in many countries significantly hindered vaccine deployment. Through the Pandemic Influenza Preparedness Framework adopted by the World Health Assembly in 2011, WHO is engaging in several capacity building activities to improve pandemic influenza preparedness and response and make provisions for access to vaccines and sharing of other benefits. The Framework calls for the development and exercise of operational plans for deployment of influenza vaccines to enhance pandemic preparedness. To this end, WHO has supported the development of PIPDeploy, an interactive, in-person table top simulation exercise to facilitate learning for emergency preparedness. It employs various game design elements including a game board, time pressure, leaderboards and teams to enhance participants’ motivation. PIPDeploy formed part of five WHO Pandemic Influenza Vaccine Deployment Workshops attended by national-level managers responsible for pandemic influenza vaccine response predominantly in non-producing countries. The purpose of this study was to describe the features and application of PIPDeploy, and present findings of the evaluation of participants’ experiences during the simulation involving a “hot wash” discussion and collection of quantitative data. The simulation’s instructional approach was widely accepted by participants, who reported that the format was novel and engaging. They reflected on its utility for identifying gaps in their own vaccine deployment plans and regulatory frameworks for importation of vaccine products. All participants found the simulation relevant to their professional objectives. A range of other potential applications were suggested, including PIPDeploy’s adaptation to sub-national contexts and to other epidemic diseases.

The underlying causes of age-related hearing loss (ARHL) are not well understood, but it is clear from heritability estimates that genetics plays a role in addition to environmental factors. Genome-wide association studies (GWAS) in human populations can point to candidate genes that may be involved in ARHL, but follow-up analysis is needed to assess the role of these genes in the disease process. Some genetic variants may contribute a small amount to a disease, while other variants may have a large effect size, but the genetic architecture of ARHL is not yet well-defined. In this study, we asked if a set of 17 candidate genes highlighted by early GWAS reports of ARHL have detectable effects on hearing by knocking down expression levels of each gene in the mouse and analysing auditory function. We found two of the genes have an impact on hearing. Mutation of Dclk1 led to late-onset progressive increase in ABR thresholds and the A430005L14Rik (C1orf174) mutants showed worse recovery from noise-induced damage than controls. We did not detect any abnormal responses in the remaining 15 mutant lines either in thresholds or from our battery of suprathreshold ABR tests, and we discuss the possible reasons for this., Highlights • Dclk1 may play a role in progressive age-related hearing loss. • A430005L14Rik may play a role in the susceptibility of the auditory system to noise-damage. • Fifteen other candidate genes (from GWAS) knocked out or knocked down in mutant mice do not lead to changes in ABRs.

The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinson's disease (PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS-ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing., Highlights • The thalamic target for surgery for tremor is not readily visible on conventional MRI. • Probabilistic tractography is used to segment the thalamus based on connectivity. • The best target area is connected to the contralateral dentate cerebellar nucleus. • GPU processing is used to segment the thalamus in a clinically feasible timescale. • This technique can map out the DRT tract with clear mesencephalic crossing.

Visibility in Hong Kong has deteriorated significantly over 40 years with visibility below 8km in the absence of fog, mist, or precipitation, increasing from 6.6 days in 1968 to 54.1 days in 2007. We assessed the short-term mortality effects of daily loss of visibility. During 1996-2006, we obtained mortality data for non-accidental and cardiorespiratory causes, visibility recorded as visual range in kilometers, temperature, and relative humidity from an urban observatory, and concentrations of four criteria pollutants. A generalized additive Poisson regression model with penalized cubic regression splines was fitted to control for time variant covariates. For non-accidental mortality, an interquartile range (IQR) of 6.5km decrease in visibility at lag0-1 days was associated with an excess risk (ER%) [95% CI] of 1.13 [0.49, 1.76] for all ages and 1.37 [0.65, 2.09] for ages 65 years and over; for cardiovascular mortality of 1.31 [0.13, 2.49] for all ages, and 1.72 [0.44, 3.00] for ages 65 years and over; and for respiratory mortality of 1.92 [0.49, 3.35] for all ages and 1.76 [0.28, 3.25] for ages 65 years and over. The estimated ER% for daily mortality derived from both visibility and air pollutant data were comparable in terms of magnitude, lag pattern, and exposure-response relationships especially when using particulate matter with aerodynamic diameter < or = 10 microm to predict the mortality associated with visibility. Visibility provides a useful proxy for the assessment of environmental health risks from ambient air pollutants and a valid approach for the assessment of the public health impacts of air pollution and the benefits of air quality improvement measures in developing countries where pollutant monitoring data are scarce.

The role of SGK1 (serum- and glucocorticoid-induced protein kinase 1) in the glucocorticoid induction of alpha-ENaC (epithelial Na+ channel alpha subunit) gene transcription was explored by monitoring the transcriptional activity of a luciferase-linked, alpha-ENaC reporter gene construct (pGL3-KR1) expressed in H441 airway epithelial cells. Dexamethasone evoked a concentration-dependent (EC50 approximately 4 microM) increase in transcriptional activity dependent upon a glucocorticoid response element in the alpha-ENaC sequence. Although dexamethasone also activated endogenous SGK1, artificially increasing cellular SGK1 activity by expressing a constitutively active SGK1 mutant (SGK1-S422D) in hormone-deprived cells did not activate pGL3-KR1. Moreover, expression of catalytically inactive SGK1 (SGK1-K127A) suppressed the activation of endogenous SGK1 without affecting the transcriptional response to dexamethasone. Increasing cellular PI3K (phosphoinositide 3-kinase) activity by expressing a membrane-anchored form of the catalytic PI3K-P110alpha subunit [CD2 (cluster of differentiation 2)-P110alpha] also activated endogenous SGK1 without affecting pGL3-KR1activity. A catalytically inactive form of CD2-P110alpha (R1130P), on the other hand, prevented the dexamethasone-induced activation of SGK1, but did not inhibit the activation of pGL3-KR1. However, expression of SGK1-S422D or CD2-P110alpha enhanced the transcriptional responses to maximally effective concentrations of dexamethasone and this effect occurred with no change in EC50. Dexamethasone-induced (0.3-300 nM) activation of pGL3-KR1 was unaffected by inhibitors of PI3K (PI-103 and wortmanin) and by rapamycin, a selective inhibitor of the TORC1 (target of rapamycin complex 1) signalling complex. Dexamethasone-induced activation of the alpha-ENaC gene promoter can thus occur independently of SGK1/PI3K, although this pathway does provide a mechanism that allows this transcriptional response to dexamethasone to be enhanced.

The present study delineates the large-scale, organic responses of growth in the dorsal pallium to targeted genetic ablations of the principal PP (preplate) neurons of the neocortex. Ganciclovir treatment during prenatal development [from E11 (embryonic age 11) to E13] of mice selectively killed cells with shared S-phase vulnerability and targeted expression of a GPT [golli promoter transgene; GPT linked to HSV-TK (herpes simplex virus-thymidine kinase), τ-eGFP and lacZ reporters] localized in PP neurons and their intermediate progenitor neuroblasts. The volume, area and thickness of the pallium were measured in an E12-P4 (postnatal age 4) longitudinal study with comparisons between ablated (HSV-TK+/0) and control (HSV-TK0/0) littermates. The extent of ablations was also systematically varied, and the effect on physical growth was assessed in an E18 cross-sectional study. The morphological evidence obtained in the present study supports the conclusion that genetically targeted ablations delay the settlement of the principal PP neurons of the dorsal pallium. This leads to progressive and substantial reductions of growth, despite compensatory responses that rapidly replace the ablated cells. These growth defects originate from inductive cellular interactions in the proliferative matrix of the ventricular zone of the pallium, but are amplified by subsequent morphogenic and trophic cellular interactions. The defects persist during the course of prenatal and postnatal development to demonstrate a constrained dose-response relationship with the extent of specific killing of GPT neurons. The defects propagate simultaneously in both the horizontal and vertical cytoarchitectural dimensions of the developing pallium, an outcome that produces a localized shortfall of volume in the telencephalic vesicles.

Highlights • α4β2∗ nAChRs stimulate IPSCs in FS interneurons, in layer V of the mouse PFC (Fr2). • In P16–P63 mice, nicotine increased both IPSC and mIPSC frequencies. • GABAergic terminals adjacent to PV+ cells expressed α4 nAChR. • The percentage of FS cells with somatic α4β2∗ currents decreased with age. • Hence, nAChRs may be able to induce local circuit disinhibition in Fr2 PFC., Nicotinic acetylcholine receptors (nAChRs) produce widespread and complex effects on neocortex excitability. We studied how heteromeric nAChRs regulate inhibitory post-synaptic currents (IPSCs), in fast-spiking (FS) layer V neurons of the mouse frontal area 2 (Fr2). In the presence of blockers of ionotropic glutamate receptors, tonic application of 10 μM nicotine augmented the spontaneous IPSC frequency, with minor alterations of amplitudes and kinetics. These effects were studied since the 3rd postnatal week, and persisted throughout the first two months of postnatal life. The action of nicotine was blocked by 1 μM dihydro-β-erythroidine (DHβE; specific for α4∗ nAChRs), but not 10 nM methyllycaconitine (MLA; specific for α7∗ nAChRs). It was mimicked by 10 nM 5-iodo-3-[2(S)-azetidinylmethoxy]pyridine (5-IA; which activates β2∗ nAChRs). Similar results were obtained on miniature IPSCs (mIPSCs). Moreover, during the first five postnatal weeks, approximately 50% of FS cells displayed DHβE-sensitive whole-cell nicotinic currents. This percentage decreased to ∼5% in mice older than P45. By confocal microscopy, the α4 nAChR subunit was immunocytochemically identified on interneurons expressing either parvalbumin (PV), which mainly labels FS cells, or somatostatin (SOM), which labels the other major interneuron population in layer V. GABAergic terminals expressing α4 were observed to be juxtaposed to PV-positive (PV+) cells. A fraction of these terminals displayed PV immunoreactivity. We conclude that α4β2∗ nAChRs can produce sustained regulation of FS cells in Fr2 layer V. The effect presents a presynaptic component, whereas the somatic regulation decreases with age. These mechanisms may contribute to the nAChR-dependent stimulation of excitability during cognitive tasks as well as to the hyperexcitability caused by hyperfunctional heteromeric nAChRs in sleep-related epilepsy.