Use of apomorphine in Parkinsonian patients with neuropsychiatric complications to oral treatment

Neuropsychiatric side effects often complicate anti-Parkinsonian therapy and pose a significant problem in the optimal management of idiopathic Parkinson's disease. Several publications report a relative lack of neuropsychiatric side effects in Parkinsonian patients treated with subcutaneous apomorphine. To investigate this further, we have used subcutaneous apomorphine to treat 12 non-demented IPD patients with previous oral drug-related neuropsychiatric problems. Treatment with apomorphine allowed alteration of anti-Parkinsonian medication and led to the abolition or reduction of neuropsychiatric complications in all patients. The mechanism remains unclear but may be due, in part, to a reduction in oral medication or a psychotropic action of apomorphine, possibly due to the piperidine moiety in its structure, or both

Echo Delay and Overlap with Emitted Orientation Sounds and Doppler-shift Compensation in the Bat, Rhinolophus ferrumequinum

The compensation of Doppler-shifts by the bat, Rhinolophusferrumequinum, functions only when certain temporal relations between the echo and the emitted orientation sound are given. Three echo configurations were used: a) Original orientation sounds were electronically Doppler-shifted and played back either cut at the beginning (variable delay) or at the end (variable duration) of the echo. b) Artificial constant frequency echoes with variable delay or duration were clamped to the frequency of the emitted orientation sound at different Doppler-shifts. c) The echoes were only partially Doppler-shifted and the Doppler-shifted component began after variable delays or had variable durations. With increasing delay or decreasing duration of the Doppler-shifted echo the compensation amplitude for a sinusoidally modulated + 3 kHz Dopplershift (modulation rate 0.08 Hz) decreases for all stimulus configurations (Figs. 1, 2, 3). The range of the Doppler-shift compensation system is therefore limited by the delay due to acoustic travel time to about 4 m distance between bat and target. In this range the overlap duration of the echo with the emitted orientation sound is always sufficiently long, when compared with data on the orientation pulse length during target approach from Schnitzler (1968) (Fig. 5)

Predicting secondary organic aerosol phase state and viscosity and its effect on multiphase chemistry in a regional-scale air quality model

Atmospheric aerosols are a significant public health hazard and have substantial impacts on the climate. Secondary organic aerosols (SOAs) have been shown to phase separate into a highly viscous organic outer layer surrounding an aqueous core. This phase separation can decrease the partitioning of semi-volatile and low-volatile species to the organic phase and alter the extent of acidcatalyzed reactions in the aqueous core. A new algorithm that can determine SOA phase separation based on their glass transition temperature (Tg), oxygen to carbon (O V C) ratio and organic mass to sulfate ratio, and meteorological conditions was implemented into the Community Multiscale Air Quality Modeling (CMAQ) system version 5.2.1 and was used to simulate the conditions in the continental United States for the summer of 2013. SOA formed at the ground/surface level was predicted to be phase separated with core shell morphology, i.e., aqueous inorganic core surrounded by organic coating 65.4% of the time during the 2013 Southern Oxidant and Aerosol Study (SOAS) on average in the isoprene-rich southeastern United States. Our estimate is in proximity to the previously reported 70% in literature. The phase states of organic coatings switched between semi-solid and liquid states, depending on the environmental conditions. The semi-solid shell occurring with lower aerosol liquid water content (western United States and at higher altitudes) has a viscosity that was predicted to be 102 1012 Pa s, which resulted in organic mass being decreased due to diffusion limitation. Organic aerosol was primarily liquid where aerosol liquid water was dominant (eastern United States and at the surface), with a viscosity < 102 Pa s. Phase separation while in a liquid phase state, i.e., liquid liquid phase separation (LLPS), also reduces reactive uptake rates relative to homogeneous internally mixed liquid morphology but was lower than aerosols with a thick viscous organic shell. The sensitivity cases performed with different phase-separation parameterization and dissolution

Α-Pinene-Derived organic coatings on acidic sulfate aerosol impacts secondary organic aerosol formation from isoprene in a box model

Fine particulate matter (PM2.5) is known to have an adverse impact on public health and is an important climate forcer. Secondary organic aerosol (SOA) contributes up to 80% of PM2.5 worldwide and multiphase reactions are an important pathway to form SOA. Aerosol-phase state is thought to influence the reactive uptake of gas-phase precursors to aerosol particles by altering diffusion rates within particles. Current air quality models do not include the impact of diffusion-limiting organic coatings on SOA formation. This work examines how α-pinene-derived organic coatings change the predicted formation of SOA from the acid-catalyzed multiphase reactions of isoprene epoxydiols (IEPOX). A box model, with inputs provided from field measurements taken at the Look Rock (LRK) site in Great Smokey Mountains National Park during the 2013 Southern Oxidant and Aerosol Study (SOAS), was modified to incorporate the latest laboratory-based kinetic data accounting for organic coating influences. Including an organic coating influence reduced the modeled reactive uptake when relative humidity was in the 55–80% range, with predicted IEPOX-derived SOA being reduced by up to 33%. Only sensitivity cases with a large increase in Henry's Law values of an order of magnitude or more or in particle reaction rates resulted in the large statistically significant differences form base model performance. These results suggest an organic coating layer could have an impact on IEPOX-derived SOA formation and warrant consideration in regional and global scale models

The preparation of HEMA-MPC films for ocular drug delivery

There is a need to prolong drug residence time using a biocompatible formulation in the subconjunctival space after surgery to treat glaucoma. Drug releasing discs were prepared with 2-(hydroxyethyl)methacrylate (HEMA) and 2-methacryloyl-oxyethyl phosphorylcholine (MPC). The ratio of bound water (Wb) to free water (Wf) ratio increased from 1:0.3 to 1:6.8 with increasing MPC (0 to 50%, w/w). The optimal balance between water content, SR and mechanical strength were obtained with 10% MPC (w/w) hydrogels. Water-alcohol mixtures were examined to facilitate loading of poorly soluble drugs, and they showed greater hydrogel swelling than either water or alcohol alone. The SR was 1.2 ± 0.02 and 3.3 ± 0.1 for water and water:ethanol (1:1) respectively. HEMA-MPC (10%) discs were loaded with dexamethasone using either water:ethanol (1:1) or methanol alone. Drug release was examined in an outflow rig model that mimics the subconjunctival space in the eye. Dexamethasone loading increased from 0.3 to 1.9 mg/disc when the solvent was changed from water:ethanol (1:1) to methanol with the dexamethasone half-life (t½) increasing from 1.9 to 9.7 days respectively. These encouraging results indicate that HEMA-MPC hydrogels have the potential to sustain the residence time of a drug in the subconjunctival space of the eye

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Ear Movements in a Hipposiderid Bat

High-speed photography and an acoustic doppler method have shown that rapid ear movements of Rhinolophus ferrumequinum are closely correlated to the production of the constant frequency signals used for echolocation. In addition to independent “searching” movements, the pinnae make alternating movements with an excursion of up to 1 cm at the tip, thus describing an arc of about 30°. The simultaneous movements (forwards by one ear, backwards by the other) may take less than 20 ms and are generally associated with the emission of one ultrasonic pulse through the nose-leaf. The one to one correspondence is not always exact but is seldom much in error even at the highest recorded pulse repetition rates of up to 60–80 pulses/s