COVID-19 vaccine safety in Scotland - background rates of adverse events of special interest.

OBJECTIVES: Mass COVID-19 vaccination commenced in December 2020 in Scotland. Monitoring vaccine safety relies on accurate background incidence rates (IRs) for health outcomes potentially associated with vaccination. This study aimed to quantify IRs in Scotland of adverse events of special interest (AESI) potentially associated with COVID-19 vaccination. STUDY DESIGN AND METHODS: IRs and 95% confidence intervals (CIs) for 36 AESI were calculated retrospectively for the pre-COVID-19 pandemic period (01 January 2015-31 December 2019) and the COVID-19 pandemic period (01 April 2020-30 November 2020), with age-sex stratification, and separately by calendar month and year. Incident cases were determined using International Classification of Diseases-10th Revision (ICD-10)-coded hospitalisations. RESULTS: Prepandemic population-wide IRs ranged from 0.4 (0.3-0.5 CIs) cases per 100,000 person-years (PYRS) for neuromyelitis optica to 478.4 (475.8-481.0 CIs) cases per 100,000 PYRS for acute renal failure. Pandemic population-wide IRs ranged from 0.3 (0.2-0.5 CIs) cases per 100,000 PYRS for Kawasaki disease to 483.4 (473.2-493.7 CIs) cases per 100,000 PYRS for acute coronary syndrome. All AESI IRs varied by age and sex. Ten AESI (acute coronary syndrome, acute myocardial infarction, angina pectoris, heart failure, multiple sclerosis, polyneuropathies and peripheral neuropathies, respiratory failure, rheumatoid arthritis and polyarthritis, seizures and vasculitis) had lower pandemic than prepandemic period IRs overall. Only deep vein thrombosis and pulmonary embolism had a higher pandemic IR. CONCLUSION: Lower pandemic IRs likely resulted from reduced health-seeking behaviours and healthcare provision. Higher IRs may be associated with SARS-CoV-2 infections. AESI IRs will facilitate future vaccine safety studies in Scotland.

Duplications and losses of genes encoding known elements of the stress defence system of the Aspergilli contribute to the evolution of these filamentous fungi but do not directly influence their environmental stress tolerance.

The contribution of stress protein duplication and deletion events to the evolution of the Aspergilli was studied. We performed a large-scale homology analysis of stress proteins and generated and analysed three stress defence system models based on Saccharomyces cerevisiae, Schizosaccharomyces pombe and Aspergillus nidulans. Although both yeast-based and A. nidulans-based models were suitable to trace evolutionary changes, the A. nidulans-based model performed better in mapping stress protein radiations. The strong Mantel correlation found between the positions of species in the phylogenetic tree on the one hand and either in the A. nidulans-based or S. cerevisiae-based models on the other hand demonstrated that stress protein expansions and reductions contributed significantly to the evolution of the Aspergilli. Interestingly, stress tolerance attributes correlated well with the number of orthologs only for a few stress proteins. Notable examples are Ftr1 iron permease and Fet3 ferro-O2-oxidoreductase, elements of the reductive iron assimilation pathway, in the S. cerevisiae-based model, as well as MpkC, a HogA-like mitogen activated protein kinase in the A. nidulans-based model. In the case of the iron assimilation proteins, the number of orthologs showed a positive correlation with H2O2-induced stress tolerance while the number of MpkC orthologs correlated positively with Congo Red induced cell wall stress, sorbitol induced osmotic stress and H2O2 induced oxidative stress tolerances. For most stress proteins, changes in the number of orthologs did not correlate well with any stress tolerance attributes. As a consequence, stress tolerance patterns of the studied Aspergilli did not correlate with either the sets of stress response proteins in general or with the phylogeny of the species studied. These observations suggest that stress protein duplication and deletion events significantly contributed to the evolution of stress tolerance attributes of Aspergilli. In contrast, there are other processes, which may counterbalance the effects of stress gene duplications or deletions including (i) alterations in the structures of stress proteins leading to changes in their biological activities, (ii) varying biosynthesis of stress proteins, (iii) rewiring stress response regulatory networks or even (iv) acquiring new stress response genes by horizontal gene transfer. All these multilevel changes are indispensable for the successful adaptation of filamentous fungi to altering environmental conditions, especially when these organisms are entering new ecological niches.

Strategies for ensuring quality data from Indian investigational sites.

The topic of ensuring quality and compliance is and must be a top priority in the conduct of clinical trials, as warranted by regulatory guidelines as well as the inherent responsibility of the professionals conducting such research. Fast-growing emerging clinical geographies such as India demand special attention due to rapid growth and associated factors that may put study quality at risk. In this paper, we used the basic principle of PDCA (Plan, Do, Check, and Adjust) to structure the processes of a clinical trial from protocol to final analysis in order to highlight the interactive nature of involved people and processes required to ensure quality of data and site functioning.

Optimization of coprogen production in Neurospora crassa.

Coprogen production of Neurospora crassa was dependent on glucose, aspartate and iron contents as well as on initial pH of the culture media. Surplus iron and acidic pH hindered the production of coprogen as well as the transcription of the sid1 gene (NCU07117) encoding putative L-ornithine-N5-monooxygenase, the first enzyme in the coprogen biosynthetic pathway. High glucose (40 g/l) and aspartate (21 g/l) concentrations were beneficial for coprogen synthesis, but neither glucose nor aspartate affected the sid1 transcription. Moreover, efficient coprogen production was observed after glucose had been consumed, which suggested that N. crassa accumulated iron even in non-growing, carbon-starving cultures.

gamma-Hydroxybutyrate (GHB) induces GABA(B) receptor independent intracellular Ca2+ transients in astrocytes, but has no effect on GHB or GABA(B) receptors of medium spiny neurons in the nucleus accumbens.

We report on cellular actions of the illicit recreational drug gamma-hydroxybutyrate (GHB) in the brain reward area nucleus accumbens. First, we compared the effects of GHB and the GABA(B) receptor agonist baclofen. Neither of them affected the membrane currents of medium spiny neurons in rat nucleus accumbens slices. GABAergic and glutamatergic synaptic potentials of medium spiny neurons, however, were reduced by baclofen but not GHB. These results indicate the lack of GHB as well as postsynaptic GABA(B) receptors, and the presence of GHB insensitive presynaptic GABA(B) receptors in medium spiny neurons. In astrocytes GHB induced intracellular Ca(2+) transients, preserved in slices from GABA(B) receptor type 1 subunit knockout mice. The effects of tetrodotoxin, zero added Ca(2+) with/without intracellular Ca(2+) store depletor cyclopiazonic acid or vacuolar H-ATPase inhibitor bafilomycin A1 indicate that GHB-evoked Ca(2+) transients depend on external Ca(2+) and intracellular Ca(2+) stores, but not on vesicular transmitter release. GHB-induced astrocytic Ca(2+) transients were not affected by the GHB receptor-specific antagonist NCS-382, suggesting the presence of a novel NCS-382-insensitive target for GHB in astrocytes. The activation of astrocytes by GHB implies their involvement in physiological actions of GHB. Our findings disclose a novel profile of GHB action in the nucleus accumbens. Here, unlike in other brain areas, GHB does not act on GABA(B) receptors, but activates an NCS-382 insensitive GHB-specific target in a subpopulation of astrocytes. The lack of either post- or presynaptic effects on medium spiny neurons in the nucleus accumbens distinguishes GHB from many drugs and natural rewards with addictive properties and might explain why GHB has only a weak reinforcing capacity.

Desynchronisation of spontaneously recurrent experimental seizures proceeds with a single rhythm.

Here we investigate the temporal properties of recurrent seizure-like events (SLEs) in a low-[Mg(2+)] model of experimental epilepsy. Simultaneous intra- and extracellular electric signals were recorded in the CA3 region of rat hippocampal slices whereby cytosolic [Ca(2+)] transients were imaged by fluorescence detection. Recurrence pattern analysis was applied to give a measure of synchrony of simultaneously recorded intra- and extracellular electric signals and the SLE frequencies were extracted by complex wavelet analysis. Slices from the juvenile, but not the young adult rats, displayed several high-amplitude triplets of electric and [Ca(2+)] transients, termed paroxysmal spikes, followed by an SLE. Occurrence of the full-blown SLE was associated with decreased synaptic activity between the paroxysmal spikes that were seen as incomplete SLE starting sequences. The time series of recurrent SLEs provide evidence for a single SLE rhythm as continuously declining from about 200 Hz to below 1 Hz at the onset and termination of SLE, respectively, with an intermediate spectral discontinuity, tentatively identified with the tonic/clonic transition. All other frequency components were the harmonics of the fundamental rhythm, whereby the gamma and the theta band oscillations were not detected as separate activities. Recurrence showed decreasing temporal synchrony of intra- and extracellular signals during the SLE, suggesting that coincidence is destroyed by the SLE. Blockade of gap junctions with 200 microM carbenoxolone ceased recurrent SLEs. Release of gap junction blockade shortened both SLEs and their tonic phase indicating that persistent changes occurred via an altered gap junction coupling. We conclude that the initially precise temporal synchrony is gradually destroyed during ictal events with a single rhythm of continuously decreasing frequency. Blockade of gap junction coupling might prevent epileptic synchronisation.

The impact of corticothalamic feedback on the output dynamics of a thalamocortical neurone model: the role of synapse location and metabotropic glutamate receptors.

The spatio-temporal integration of cortical excitatory postsynaptic potentials was investigated in a multi-compartment model of a thalamocortical neurone. Consistent with experimental data, cortical excitatory postsynaptic potentials contained a metabotropic glutamate receptor-mediated component and were generated by synapses located on distal dendrites. Within this framework, three synaptic distributions (each with equal maximal synaptic conductances) were compared: symmetric, with synapses distributed equally between all dendritic trees, single-dendrite, where synapses were allocated on all distal segments of one dendrite, and single-segment, which comprised one synapse on a single dendritic compartment. We addressed three main issues: (1) the propagation of cortical excitatory postsynaptic potentials to the soma, (2) the interaction of cortical excitatory postsynaptic potentials with proximally generated retinal excitatory postsynaptic potentials, and (3) the effectiveness of cortical excitatory postsynaptic potentials in entraining and perturbing the delta oscillation. The somatic and dendritic amplitudes of the cortical excitatory postsynaptic potentials depended on the distribution of the synapses, being largest and smallest, respectively, for the symmetric distribution, and smallest and largest, respectively, for the single-segment distribution. When a retinal excitatory postsynaptic potential followed a subthreshold cortical excitatory postsynaptic potential with a short (2-200 ms) delay, its ability to evoke action potentials was increased, with single-segment cortical excitatory postsynaptic potentials having the longest-lasting facilitatory effect. When a retinal excitatory postsynaptic potential arrived with a longer delay (210-400 ms), the effect of the cortical excitatory postsynaptic potential was to decrease the number of retinally evoked action potentials. These facilitatory and depressant effects of the cortical excitatory postsynaptic potentials were dependent on the presence of their metabotropic glutamate receptor, and were enhanced by increasing the strength of this glutamate receptor component. Axial resistivity and distal dendritic A-type current had little qualitative effect on these modulatory actions of the cortical excitatory postsynaptic potential. Cortical excitatory postsynaptic potentials were more effective than retinal excitatory postsynaptic potentials in perturbing the phase of the delta oscillation, indicating that they are ideally suited to entraining this form of rhythmic activity. Again, this effect was closely dependent on the presence of metabotropic glutamate receptor but was largely independent of synapse distribution. These results indicate that the distribution of activated synapses and the presence of metabotropic glutamate receptor are crucial factors in determining the effect of cortical feedback excitation on thalamocortical neurons. Moreover, the distinct postsynaptic receptor composition of cortical inputs renders them ideally suited to synchronising low-frequency oscillatory activity in thalamocortical neurons.

Electrotonic profile and passive propagation of synaptic potentials in three subpopulations of hippocampal CA1 interneurons.

To elucidate the role of dendritic morphology in signal transfer, the passive propagation of somatic and dendritic potentials was compared in multi-compartment models of three interneuron subpopulations in the CA1 region. Nine calbindin-, 15 calretinin- and 10 parvalbumin-containing cells were modelled incorporating the detailed geometry, the currents of the action potentials in the soma, and the AMPA, N-methyl-D-aspartate and GABA-B receptor-mediated postsynaptic currents in the dendrites. The cable properties show characteristic differences among the subpopulations. The morphotonic length of calbindin and calretinin cell dendrites is larger than of parvalbumin cells. Thus parvalbumin cells are more compact than calbindin or calretinin cells unless the ratio of their axial and membrane resistivities exceeds the ratios of the other two cell types by more than 33%. In calbindin cells, the distal parts of the extremely long dendrites that invade the alveus are virtually isolated from the soma for passively propagating signals. The synaptic potentials evoked at a given morphotonic distance from the soma show larger differences locally on the dendrites than on the soma in all subpopulations. Both the somatic and dendritic amplitude ratios are the smallest in PV cells. In calbindin cells the somatic amplitude of synaptic potentials evoked at the same morphotonic distance from the soma is similar regardless of the number of branchpoints along their path. In calretinin and parvalbumin cells, from dendrites with long primary segments synaptic potentials reach the soma with larger amplitude than from dendrites that are branching close to the soma. The dendrites with the larger impact on somatic membrane potential are usually the dendrites that enter the stratum lacunosum-moleculare. These results indicate that dendritic morphology plays a role in changing the effectiveness of synaptic potentials evoked at different dendritic locations, and in this way is likely to be an important factor in determining the integrative properties of the different neuron populations.

Backpropagation of the delta oscillation and the retinal excitatory postsynaptic potential in a multi-compartment model of thalamocortical neurons.

Uniform and non-uniform somato-dendritic distributions of the ion channels carrying the low-threshold Ca(2+) current (I(T)), the hyperpolarization-activated inward current (I(h)), the fast Na(+) current (I(Na)) and the delayed rectifier current (I(K)) were investigated in a multi-compartment model of a thalamocortical neuron for their suitability to reproduce the delta oscillation and the retinal excitatory post-synaptic potential recorded in vitro from the soma of thalamocortical neurons. The backpropagation of these simulated activities along the dendritic tree was also studied. A uniform somato-dendritic distribution of the maximal conductance of I(T) and I(K) (g(T) and g(K), respectively) was sufficient to simulate with acceptable accuracy: (i) the delta oscillation, and its phase resetting by somatically injected current pulses; as well as (ii) the retinal excitatory postsynaptic potential, and its alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate and/or N-methyl-D-aspartate components. In addition, simulations where the dendritic g(T) and g(K) were either reduced (both by up to 34%) or increased (both by up to 15%) of their respective value on the soma still admitted a successful reproduction of the experimental activity. When the dendritic distributions were non-uniform, models where the proximal and distal dendritic g(T) was up to 1.8- and 1. 2-fold larger, respectively, than g(T(s)) produced accurate simulations of the delta oscillation (and its phase resetting curves) as well as the synaptic potentials without need of a concomitant increase in proximal or distal dendritic g(K). Furthermore, an increase in proximal dendritic g(T) and g(K) of up to fourfold their respective value on the soma resulted in acceptable simulation results. Addition of dendritic Na(+) channels to the uniformly or non-uniformly distributed somato-dendritic T-type Ca(2+) and K(+) channels did not further improve the overall qualitative and quantitative accuracy of the simulations, except for increasing the number of action potentials in bursts elicited by low-threshold Ca(2+) potentials. Dendritic I(h) failed to produce a marked effect on the simulated delta oscillation and the excitatory postsynaptic potential. In the presence of uniform and non-uniform dendritic g(T) and g(K), the delta oscillation propagated from the soma to the distal dendrites with no change in frequency and voltage-dependence, though the dendritic action potential amplitude was gradually reduced towards the distal dendrites. The amplitude and rising time of the simulated retinal excitatory postsynaptic potential were only slightly decreased during their propagation from their proximal dendritic site of origin to the soma or the distal dendrites. These results indicate that a multi-compartment model with passive dendrites cannot fully reproduce the experimental activity of thalamocortical neurons, while both uniform and non-uniform somato-dendritic g(T) and g(K) distributions are compatible with the properties of the delta oscillation and the retinal excitatory postsynaptic potential recorded in vitro from the soma of these neurons. Furthermore, by predicting the existence of backpropagation of low-threshold Ca(2+) potentials and retinal postsynaptic potentials up to the distal dendrites, our findings suggest a putative role for the delta oscillation in the dendritic processing of neuronal activity, and support previous hypotheses on the interaction between retinal and cortical excitatory postsynaptic potentials on thalamocortical neuron dendrites.

Nonspecific membrane effects of CH-103: hydrophobicity, surface activity and membrane fluidity studies in comparison with propranolol and practolol.

The partition coefficient, surface activity and membrane fluidizing/disordering effects of CH-103, a beta-adrenergic receptor antagonist, were compared to those of propranolol and practolol as reference compounds. Changes in membrane fluidity were followed by measuring the steady-state fluorescence anisotropy of bull sperm cells with 1-[4-(trimethylammonium)-phenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH) as a fluorescence probe. The octanol/buffer (pH 7.0) partition coefficients for CH-103, propranolol and practolol were 32.9, 5.08 and 0.013, respectively; the surface activity of the compounds decreased in the same order. CH-103 and propranolol significantly increased the fluidity of the membrane in a concentration-dependent manner, whereas practolol reduced fluidity. These physicochemical parameters correlated with the effects of these drugs on rat sarcolemmal Ca2+, Mg(2+)-ATPase, a manifestation of their nonspecific membrane activity. Our results suggest that the physicochemical properties of CH-103, similarly to those of propranolol, are the main determinants of its nonspecific membrane activity.

Transesophageal pacemaker therapy in atrial flutter after procainamide pretreatment.

Transesophageal atrial stimulation was applied in 56 patients to terminate atrial flutter. Extrastimulation and atrial burst techniques were applied using programmable stimulator (Medtronic 5328) and hexapolar esophageal electrode catheters. Thirty patients were randomized to receive digoxin pretreatment (group A), and 26 patients were randomized to receive procainamide pretreatment (group B). Efficacy of each pretreatment was evaluated by observing the change in the rhythm. In group A, transesophageal pacemaker therapy successfully converted atrial flutter to sinus rhythm in 13 patients and to atrial fibrillation in 14 patients, whereas the arrhythmia remained unchanged in the 3 remaining patients in the digitalized group. In group B, after procainamide pretreatment, sinus rhythm appeared in 19 and atrial fibrillation in 5, and no change was observed in the remaining 2 patients. Procainamide is more efficacious than digoxin (P < 0.05) in facilitating cardioversion by transesophageal stimulation.

Model of a thalamocortical neurone with dendritic voltage-gated ion channels.

To investigate the functional role of dendrites of thalamocortical neurones, we have used our one-compartmental model to construct a multi-compartmental model with dendritic regions chosen according to a representative soma-to-dendritic terminal path of an X cell of the cat dorsal lateral geniculate nucleus. The multi-compartmental model with dendritic low-threshold CA2+ and delayed rectifier K+ channels yields more accurate results than the one-compartmental model when simulating tonic firing and oscillatory activities, and provides a useful means for the study of propagation of excitation on the dendrites.

Model of a thalamocortical neurone with dendritic voltage-gated ion channels.

To investigate the functional role of dendrites of thalamocortical neurones, we have used our one-compartmental model to construct a multi-compartmental model with dendritic regions chosen according to a representative soma-to-dendritic terminal path of an X cell of the cat dorsal lateral geniculate nucleus. The multi-compartmental model with dendritic low-threshold Ca2+ and delayed rectifier K+ channels yields more accurate results than the one-compartmental model when simulating tonic firing and oscillatory activities, and provides a useful means for the study of propagation of excitation on the dendrites.

Gamma-hydroxybutyric acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABAB receptors.

The effect of gamma-hydroxybutyric acid (GHB) on the excitatory postsynaptic potential (EPSP) evoked in thalamocortical neurones of the rat dorsal lateral geniculate nucleus and ventrobasal thalamus was investigated in vitro. GHB (0.1-5 mM) dose-dependently and reversibly decreased (36-78%) the amplitude of the sensory EPSP. This effect of GHB was blocked by the GABAB receptor antagonist CGP 35348 (1 mM). NCS 382 (1-3 mM), a putative GHB receptor antagonist, did not antagonise but weakly potentiated both the GHB- and baclofen-mediated decrease of the EPSP amplitude.

Long-lasting treatment with adenosine receptor antagonists: effects on hypoxic tolerance and vascular responsiveness.

In electrically driven myocardial preparations obtained from chronically methylxanthine-[aminophylline (APH) and 8-phenyltheophylline (8-PT)] or solvent(DMSO)-treated guinea pigs no differences were found in alteration of mechanical activity under hypoxia and reoxygenation. The vasoconstrictor effects observed after in vitro exposure of pulmonary arterial preparations (excised from either methylxanthine- or solvent-treated guinea pigs) to both noradrenaline and PGF2 alpha were also similar. In methylxanthine-treated vascular tissues, however, nitroglycerin and NO exerted more pronounced vasorelaxant effect than in specimens prepared from solvent-treated guinea pigs.

Regulation of purinoceptors in guinea pig pulmonary artery: functional evidences.

In isolated guinea pig pulmonary arteries (precontracted with 1 microM noradrenaline) N6-cyclopentyladenosine (CPA), a selective A1 adenosine receptor agonist, exerted a concentration-dependent contraction, whereas 5'-N-ethylcarboxamidoadenosine (NECA), a non-selective A1/A2 receptor agonist, in the presence of DPCPX (a highly selective A1 receptor antagonist), produced a concentration-related rapid relaxation. Pulmonary arteries obtained from guinea pigs treated with aminophylline (APH) or 8-phenyltheophylline (8-PT) for 10 consecutive days, displayed more pronounced contraction in response to CPA compared to those of solvent-treated animals. Relaxant action of NECA was, however, attenuated in arteries prepared from methylxanthine-treated guinea pigs. Opposite changes were found in vascular tissues excised from chronically dipyridamole(DP)-treated guinea pigs.

The effect of chronic diazepam treatment on hypoxia-induced alterations in functional activity of guinea pig myocardium.

The concentration-related sensitization of guinea pig left atrium to adenosine in the presence of diazepam is well established. It was found in our experiments that the cardiodepressive action of hypoxia is significantly enhanced by diazepam in the left atrial myocardium. In atrial preparations obtained from guinea pigs treated with diazepam for 10 days, the hypoxia-induced depression of myocardial contractility was not altered. These results indicate that diazepam-treatment does not impaire the hypoxic tolerance of myocardium.

Nonmutagenic activity of the nitroprusside.

The mutagenic activity of the pentacyanonitrosylferrate (II) (NP) was studied by the prophage induction and the Drosophila mosaic test. On the basis of plaque and mosaic spot induction freqauencies it is concluded that both NP and its adenine complex are nonmutagenic as for induction of chromosome breaks and point mutations. The nonmutagenic activity of the NP can be attributed to its nonpermeability through cell membranes.

[The effect of atherogenic diet on the entering of albumin into surviving segments of rabbit aortic wall]. / Atherogen diéta hatása túlélö nyúl-aorta szeletek albumin beáramlására

Damage to the endothelial cells in the early phase of atherosclerosis is of essential importance. Presence of an anhomogen layer of endothelial cells revealed in vivo, represents an early lesion of the area of vessel well influenced heavily by haemodinamics. Authors have established that entering of albumin into the aortic wall of rabbits exposed to a cholesterin-rich diet in the early phase of atherosclerosis-in vitro-increases, but later on in the advanced phase of the disease decreases, which can be explained by the slow-down of the speed of diffusion into the vessel wall. Accumulation of plasma-constituents in the vessel wall in the early phases of the vascular lesion is caused by the increase of entering of the plasma, in the advanced stages by the slow-down of the speed of diffusion.