Association between platelet indices and the severity of the disease and mortality in patients with COVID-19.

OBJECTIVE: The aim of the study was to determine the association between platelet indices and disease severity, and outcomes of the patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a secondary hospital. PATIENTS AND METHODS: 722 hospitalized patients who had positive rRT-PCR for SARS-CoV-2 and/or typical findings of COVID-19 at chest computed tomography (CT) were enrolled in this study. Initial platelet count (PLT) and indices, including mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), MPV/PCT, MPV/PLT, PDW/PLT, PDW/PCT on admission and the third day of hospitalization, and their relationship with disease severity and outcomes were evaluated retrospectively. RESULTS: The mean age of the patients was 57.2±15.6 years (range: 16-94) and male/female ratio was 1.22. 81.9% of the patients had moderate and 11.8% had severe disease. 1.8% of the patients had thrombocytopenia at admission. The patients transferred to the intensive care unit (ICU) had significantly lower baseline lymphocyte counts, PLT, PCT, and 3rd day lymphocyte counts when compared with the patients in wards. ICU patients also had higher baseline CRP, LDH, ferritin, MPV/PCT, MPV/PLT, PDW/PLT, PDW/PCT ratios, and 3rd day PDW, CRP, LDH, and ferritin levels than the patients in wards. Mortality was associated with lower baseline lymphocyte counts, PLT, PCT, 3rd day lymphocyte counts and PCT. Higher baseline CRP, LDH, ferritin, MPV/PCT, PDW/PLT, PDW/PCT and 3rd day CRP, LDH, ferritin, procalcitonin, PDW, MPV/PCT, PDW/PLT, and PDW/PCT ratios were also associated with poor prognosis. CONCLUSIONS: Platelet count and ratios were significantly associated with mortality in patients with COVID-19.

Frequency of bitemporal independent interictal epileptiform discharges in temporal lobe epilepsy.

PURPOSE: Bitemporal interictal epileptiform discharges (IEDs) occur in < or =42% of scalp EEGs in patients with temporal lobe epilepsy (TLE) studied with routine EEGs or partial analysis of long-term recordings. METHODS: Twenty-eight patients with TLE demonstrating exclusively unilateral temporal IEDs on routine EEGs underwent 24-h continuous recording. The entire record was visually inspected for epileptiform discharges. We used continuous EEG to assess the significance of long-term recording in detecting bilateral IEDs. RESULTS: Twenty-two patients had left temporal IEDs; 21 had right temporal IEDs. Seventeen (61%) patients had IEDs originating from both the right and left temporal lobes. The probability of detecting bilateral independent IEDs was correlated with the duration of continuous EEG recording. There was no correlation between the number of IEDs originating from one side and the probability of detecting independent IEDs on the other side. The frequencies of IEDs were not correlated with the length of time since onset of epilepsy. CONCLUSIONS: The findings suggest that when long-term recordings are performed, the incidence of bilateral discharges in TLE is higher than previously reported in the literature and supports the view that TLE is commonly a bilateral disease.

Acute optic neuritis: association with paranasal sinus inflammatory changes on magnetic resonance imaging.

The authors compared the frequency of paranasal sinus inflammatory changes (SIC) on brain magnetic resonance imaging (MRI) obtained from 23 patients with new onset acute optic neuritis (ON) and 48 control patients who underwent outpatient MRI of the brain for reasons other than ON. The authors found a higher frequency of paranasal SIC in patients with ON (83%) than in controls (54%) (p = 0.02). The distribution of paranasal SIC (in ON and in controls) was maxillary (83% and 52%), ethmoid (4% and 2%), frontal (9% and 14%), and sphenoid (4% and 10%). Frequency of the maxillary SIC was significantly higher (p = 0.02) in patients with ON than in controls. Further evaluation of maxillary paranasal SIC with a grading system showed the presence of thickened mucosal lining of the sinuses (grade I) in 17% (ON) and 23% (controls), mucous retention cysts within the sinuses (grade II) in 48% (ON) and 25% (controls), and severe mucosal thickening with complete or near-complete filling of the sinus or an air-fluid level within the sinus (grade III) in 17% (ON) and 4% (controls). Combined frequency of grade II and grade III SIC was significantly higher in the ON group than in controls (p = 0.005), as was the frequency of grade III SIC alone (p = 0.02). Grade I SIC did not significantly differ between the groups. There was a trend (p = 0.09) toward a higher prevalence of bilateral sinus inflammatory changes in patients with bilateral ON. These findings suggest that ON may be associated with sinus inflammatory changes.

Impaired arterial baroreflex regulation of heart rate after blockade of P2-purinoceptors in the nucleus tractus solitarius.

Activation of P2x-purinoceptors in the nucleus tractus solitarius (NTS) via microinjection of ATP mimics baroreflex responses (bradycardia, hypotension); however, the physiological role of these receptors in cardiovascular control remains unclear. We tested whether blockade of these receptors attenuates arterial baroreflex control of heart rate (HR). Baroreflex-induced changes in HR (via graded i.v. infusion of phenylephrine and nitroprusside) were observed in seven alpha-chloralose/urethane anesthetized male Sprague-Dawley rats before and after microinjection of the purinergic P2 receptor antagonist suramin (0.5 nmol in 50 nL) into the subpostremal NTS. Before suramin, typical baroreflex changes in HR were observed (maximum gain, Gmax = 2.94 +/- 0.54 bpm/mmHg). Suramin markedly impaired baroreflex-induced changes in HR (gain = 0.02 +/- 0.08 and 0.18 +/- 0.09 bpm/mmHg for increases and decreases in mean arterial blood pressure, respectively); however, after 90-130 min, HR and baroreflex reactivity returned to control levels. Microinjections of vehicle into the same area did not alter baroreflex function. In addition, suramin did not alter the depressor responses to microinjections of glutamate into the same site of the NTS. We conclude that normal P2x-purinoceptor function in subpostremal NTS may be necessary for baroreflex regulation of HR.

Activation of purinergic receptor subtypes in the nucleus tractus solitarius elicits specific regional vascular response patterns.

The nucleus tractus solitarius (NTS) is a major integrative site in the brain stem involved in central autonomic control. Several lines of evidence indicate that ATP, acting at P2x purinoceptors, and adenosine, acting at A2a adenosine (P1) purinoceptors, play synchronous roles as transmitter substances in NTS-mediated mechanisms of cardiovascular control. The purpose of this study was to examine regional vascular response patterns elicited by selective activation of purinergic receptor subtypes in the NTS. Adult male rats were anesthetized with a mixture of alpha-chloralose and urethane. Pulsed-Doppler flow probes were placed on the iliac, renal and superior mesenteric arteries via a midline laparotomy for measurement of regional blood flow velocities. The animal was then mounted prone in a stereotaxic unit and the dorsal surface of the medulla was surgically exposed in the region of the obex. Microinjections of alpha, beta-methylene ATP (alpha,beta-MeATP), a selective P2x purinergic receptor agonist, or 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), a selective A2a adenosine (P1) receptor agonist, were made into the subpostremal region of the NTS via multibarrel glass micropipettes. Both alpha,beta-MeATP (25 and 100 pmoles/rat) and CGS 21680 (2 and 20 pmoles/rat) produced significant dose-related reductions in blood pressure and heart rate. These agonist-elicited depressor response patterns were associated with a pronounced and preferential dilation of the iliac vascular bed. However, alpha, beta-MeATP, but not CGS 21680, also caused significant dilation of the renal and superior mesenteric vascular beds, although lesser in magnitude compared to the iliac bed, whereas the hypotensive actions of CGS 21680 were considerably more prolonged compared to the very rapid and transient effects of alpha,beta-MeATP. These results support the view that extracellular ATP and adenosine via synchronous actions at specific purinergic receptor subtypes in the NTS may be functionally linked as neural signalling substances to selectively coordinate the regulation of regional vasomotor tone.

Activation of P2-purinoceptors in the nucleus tractus solitarius mediate depressor responses.

The purpose of the study was to examine the role of P2 purinergic receptors in mechanisms of cardiovascular control mediated by the nucleus tractus solitarius (NTS), a major integrative site in the brainstem involved in the reflex coordination of cardiorespiratory and visceral response patterns. Microinjections of ATP and its analogues were made into the subpostremal NTS of anesthetized, spontaneously breathing rats. ATP, alpha,beta-methylene ATP (alpha beta-meATP) and 2-methylthio-ATP (2-meSATP) produced significant dose-related reductions in arterial blood pressure. alpha beta-meATP was slightly more potent than ATP and 2-meSATP. Pretreatment with the P2 receptor antagonist, suramin (0.5 nmol/rat), into the same NTS site 10 min prior to agonist administration completely blocked pronounced depressor response pattern elicited by the highest dose of alpha beta-meATP (0.1 nmol/rat). The present findings suggest that endogenous ATP may serve as a fast transmitter substance in NTS-mediated mechanisms of cardiovascular control.

Effects of harmane (1-methyl-beta-carboline) on neurons in the nucleus accumbens of the rat.

Harmane, a beta-carboline alkaloid reported to exert locomotor and psychoactive effects, is found in certain plants and also has been shown to exist in the mammalian brain as an endogenous substance. In this study, the effects of locally perfused harmane were examined on spontaneous neuronal activity in the nucleus accumbens of urethane-anesthetized rats. Extracellular single-unit recording, coupled with push-pull perfusion, enabled the discrimination of specific, dose-related effects of harmane across a wide concentration range. At lower concentrations (10(-9)-10(-11) M), excitation prevailed, while at higher concentrations (10(-8)-10(-6) M) depression was most pronounced. These findings suggest a neuromodulatory role for harmane in the forebrain reward system.

Visceroendocrine responses elicited by neuropeptide Y in the nucleus tractus solitarius.

Neuropeptide Y (NPY) has been shown to be localized in a number of CNS regions, including the nucleus tractus solitarius (NTS). In this meeting report, a brief overview is presented of recent studies from our laboratory examining the role of NPY in NTS-mediated mechanisms of cardiorespiratory and visceroendocrine regulation. Microinjections of NPY, NPY analogs, or C-terminal NPY fragments were made into the subpostremal NTS of anesthetized spontaneously breathing rats. NPY elicited pronounced dose-related depressor responses, bradycardia, and reductions in respiratory minute volume. The overall cardiorespiratory response pattern elicited by NPY was mimicked by NPY, a fragment of NPY exhibiting selective agonist properties at presynaptic Y2 receptors, whereas the Y1 receptor-selective analog, [Leu31,Pro34]NPY, and the C-terminal inactive fragment, NPY, were found to be ineffective. In an effort to further characterize intrinsic NTS mechanisms mediating the NPY-evoked response pattern, NPY microinjections were similarly made in a group of rats with bilateral glossopharyngeovagotomy (G-vagotomy) and in a group of rats decerebrated at the supracollicular level. The results showed that whereas decerebration did not appreciably affect the NTS-mediated cardiorespiratory responses elicited by NPY, G-vagotomy enhanced the NPY-evoked hypotension while at the same time abolishing the NPY-evoked bradycardia and reductions in tidal volume. Taken together, these observations with G-vagotomized animals, along with the results from microinjection studies using selective ligands for NPY receptors, suggest that NPY may modulate primary visceral afferent information via activation of Y2 receptors distributed at presynaptic sites in the subpostremal NTS.(ABSTRACT TRUNCATED AT 250 WORDS)

An atlas of the rat subpostremal nucleus tractus solitarius.

The nucleus tractus solitarius (NTS) in the dorsal medulla is the principal visceral sensory relay nucleus in the brain. In the rat, numerous lines of evidence indicate that the caudal NTS at the level of the area postrema serves as a major integrating site for coordinating cardiorespiratory reflexes and viscerobehavioral responses. This region of the caudal NTS not only exhibits high densities of binding sites for an impressive array of transmitters and modulators but microinjections of many of these same neuroactive substances into the rat subpostremal NTS elicit pronounced cardiorespiratory and visceral response patterns. This report provides an abbreviated atlas of the rat subpostremal NTS consisting of a series of transverse, sagittal, and horizontal plates. Photomicrographs, together with their corresponding schematic drawings, are provided for the serial sections generated from each reference plane.

Decreased cardiorespiratory effects of neuropeptide Y in the nucleus tractus solitarius in diabetes.

It has been observed that diabetes results in increased neuropeptide Y (NPY) in various brain regions, especially the paraventricular nucleus, which projects to the nucleus of the solitary tract (NTS). Because previous studies indicated a pathophysiological relationship between diabetes and NPY, we investigated the effect of diabetes on the sensitivity of NTS-mediated responses to NPY administration. Rats were made diabetic using streptozocin (55 mg/kg iv) and maintained for 48 to 50 days. Normal and streptozocin-diabetic rats were anesthetized with urethan and alpha-chloralose, instrumented for cardiovascular and respiratory monitoring, and positioned in a stereotaxic apparatus. The brain stem was exposed surgically. NPY (0.15 nmol/kg) was microinjected into the NTS and the cardiovascular and respiratory parameters were monitored for 60 min. Diabetes increased systolic (SAP), diastolic (DAP), and mean (Pa) blood pressure but not pulse pressure (PP) and heart rate (HR). Respiratory parameters were not altered. NPY significantly decreased SAP, DAP, Pa, PP, HR, respiratory rate, and minute volume in normal animals. In diabetic animals, NPY also decreased SAP, DAP, and Pa but pronouncedly increased PP. Although NPY decreased the SAP and Pa in diabetic animals, the response was attenuated compared with normal animals. The respiratory parameters and HR of diabetic animals, unlike normal animals, did not respond to NPY administration. We conclude that chronic diabetes results in a decreased sensitivity to NTS-mediated responses and that the hyporesponsiveness of the NTS to NPY modulation may be important in the tendency toward elevated blood pressure and hypertension in diabetes.

Neuropeptide-Y stimulation of insulin secretion is mediated via the nucleus tractus solitarius.

Neuropeptide-Y (NPY) is widely distributed in nervous tissue. In the central nervous system, NPY has been shown to be densely located in specific brain regions wherein it may mediate specific functions. Previous data have indicated that NPY may act at a selective site in the brain to modulate insulin secretion. In this study, we investigated the effect of NPY on NTS-mediated insulin secretion. A limited occipital craniotomy was performed on anesthetized rats to expose the caudal medulla in the region of the obex. NPY was microinjected into the NTS and blood samples were subsequently collected from the femoral vein. NPY microinjection resulted in a significant increase in insulin secretion within 5 minutes that returned to baseline at 30 minutes. However, microinjections of NPY did not significantly alter the plasma glucose in this model system. We conclude that NPY can act directly on the NTS to increase circulating insulin levels. Thus, the NTS may be a major brainstem site that directly mediates the central action of NPY on nutrient homeostasis.

Y2 receptors for neuropeptide Y in the nucleus of the solitary tract mediate depressor responses.

In anesthetized, spontaneously breathing rats, microinjections of selective agonists of neuropeptide Y (NPY) receptor subtypes were made into the medial region of the caudal nucleus of the solitary tract (NTS) at the level of the area postrema. This region of the rat NTS exhibits very high densities of NPY binding sites. Microinjections of the long C-terminal NPY fragment, NPY(13-36), a selective agonist at Y2 receptors, into the caudal NTS elicited pronounced, dose-related reductions in blood pressure and respiratory minute volume. Moreover, the specific pattern of cardiorespiratory responses elicited by NPY(13-36) was remarkably similar, over approximately the same dosage range, with the cardiorespiratory response pattern elicited by intact NPY. In contrast to the potent NTS-mediated responses evoked by NPY(13-36), similar microinjections conducted with either NPY(26-36), an inactive C-terminal NPY fragment, or [Leu31,Pro34]NPY, a NPY analog with specific agonist properties at Y1 receptors, into the same caudal NTS sites did not appreciably affect cardiorespiratory parameters even at 10-20-fold higher dosages. The present results with selective agonists for NPY receptor subtypes suggest that the depressor responses and reductions in minute volume elicited by microinjections of intact NPY and NPY(13-36) were mediated by Y2 receptors in the caudal NTS, likely distributed at presynaptic sites in the medial region of the subpostremal NTS.

Adenosine receptor subtypes in the brainstem mediate distinct cardiovascular response patterns.

A limited occipital craniotomy was conducted on urethane-chloralose anesthetized, spontaneously breathing rats to expose the caudal medulla in the region of the obex. Microinjections of highly selective agonists for adenosine receptor subtypes were made into the medial region of the caudal nucleus tractus solitarius (NTS) at the level of the posterior portion of the area postrema. Cardiorespiratory parameters were subsequently recorded for a 60-min test period following microinjection of drug or vehicle solutions. The following selective adenosine receptor agonists were used: the A1 agonist, N6-cyclopentyladenosine (CPA), which is 480-fold selective for A1 receptors in rat brain binding assays, and the A2 agonist, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), which is 170-fold selective for A2 receptors in rat brain binding studies and over 1500-fold selective in functional assays. The results showed that distinct and converse cardiovascular response patterns were elicited by these selective agonists for adenosine receptor subtypes following microinjections into the caudal NTS. Specifically, CGS 21680 selectively elicited potent dose-related decreases in mean arterial blood pressure (ED50 = 0.064 nmol/kg) and dose-related decreases in pulse pressure (ED50= 0.058 nmol/kg). Conversely, CPA selectively elicited potent dose-related increases in mean arterial blood pressure (ED50 = 0.62 nmol/kg) and dose-related increases in pulse pressure (ED50 = 0.70 nmol/kg). Additionally, the overall agonist-mediated response patterns were dramatically different wherein the CGS agonist exhibited a considerably more rapid time course in eliciting its hypotensive responses whereas CPA exhibited a more delayed and substantially longer time course to exert its hypertensive responses. Additionally, these distinct and converse cardiovascular response patterns were further shown to be receptor-selective since the depressor responses elicited by the A2 receptor agonist, CGS 21680, and the pressor responses elicited by the A1 receptor agonist, CPA, were completely and selectively blocked, respectively, by the selective A2 receptor antagonist, CGS 15943A, and the selective A1 receptor antagonist, DPCPX. Taken together, these findings provide persuasive in vivo evidence showing that pharmacologic activation of adenosine receptor subtypes in the caudal NTS of rats elicits specific response patterns with selective and opposite actions on cardiorespiratory behavior. These data also indicate that separate physiologic responses are specifically mediated by A2 receptors in the intact nervous system and thereby lend additional support to the case for using in vivo models to assess the functional role of adenosine A2 receptors in brain function.

Cardiorespiratory response patterns elicited by microinjections of neuropeptide Y in the nucleus tractus solitarius.

A limited occipital craniotomy was conducted on anesthetized, spontaneously breathing rats to expose the caudal medulla in the region of the obex. Microinjections of neuropeptide Y (NPY), a putative neuromodulator associated with catecholaminergic (CA) synapses, were made into the medial region of the caudal nucleus tractus solitarius (NTS) at the level of the posterior portion of the area postrema, an area of the NTS in which there is known to be a functional coexistence of cardiovascular and respiratory-related neuronal elements. This region of the caudal NTS in the rat is not only the principal site of termination of baro- and chemoreceptor afferents, but it also has profuse reciprocal connections with NPY-containing cardiorespiratory control regions in the hypothalamus and with other brainstem regulatory nuclei. Moreover, this same region of the rat NTS also shows very high densities of NPY binding sites. Cardiorespiratory responses were subsequently recorded for a 60-min test period following NPY administration. Microinjections of NPY, in the dose range of 10-100 pmol/rat, into the caudal NTS of intact rats produced significant dose-related reductions in mean arterial blood pressure, pulse pressure and minute volume. To a lesser extent, NPY microinjections also produced significant reductions in heart rate, respiratory rate and tidal volume. In a series of separate experiments, in an effort to ascertain the modulatory influences of rostral brain regions on these NPY-evoked, NTS-mediated cardiorespiratory response patterns, microinjections of NPY were made under identical anesthetic and experimental conditions in a group of rats wherein reciprocal connections between the NTS and rostral brain regions had been disrupted via supracollicular decerebration. In addition, since NPY microinjections were made into specific loci wherein afferent inputs from cardiopulmonary receptors are known to converge in the rat NTS, the effects of bilateral vagotomy on NPY-evoked, NTS-mediated cardiorespiratory response patterns were also examined in otherwise intact rats and under the same experimental conditions. The effects of NPY microinjections at the same dosage on NTS-mediated cardiorespiratory response patterns were subsequently compared among the intact, decerebrate and vagotomized rats. The results showed that whereas the hypotensive actions of NPY were not affected by decerebration, vagotomy significantly increased the magnitude of the hypotension elicited by NPY microinjections in comparison to the intact and decerebrate groups of rats. On the other hand, vagotomy abolished the NPY-evoked bradycardia which had a similar magnitude in both intact and decerebrate rats.(ABSTRACT TRUNCATED AT 400 WORDS)