Acute Cerebral Insult Research Articles

WS1.11. EEG in the ICU: Status Epilepticus and the Ictal-Interictal Continuum

Epileptic seizures and nonconvulsive status (NCSE) are common in the critically ill, but non- epileptic movements and posturing are even more common. EEG can provide clarification when seizures are suspected. Different EEG patterns form a continuum of non-seizure to seizure activity, and over- interpretation of these patterns may lead to inappropriate advice and treatment. Recurrent seizures are easiest to recognise, with rhythmic discharges having spatiotemporal evolution in frequency (>4Hz), morphology and distribution. Periodic patterns are the most difficult. Generalised periodic discharges (GPDs) may or may not be ictal, and the specific EEG findings combined with the clinical context determines the approach. Severe myoclonic encephalopathy may occur after cardiac arrest, and the EEG may show burst suppression, unreactive GPDs separated by isoelectric intervals, ± electrographic seizures. The prognosis is extremely poor irrespective of treatment. Lateralised periodic discharges (i.e. PLEDs) may be an interictal finding in epilepsy and after any acute cerebral insult such as stroke or herpes encephalitis, and usually indicates a predisposition to seizures rather than ongoing seizure activity. Generalised triphasic waves are mainly seen with metabolic and toxic encephalopathies and are usually not an ictal finding. Whilst they can be sharply contoured, they are recognised by their other characteristics including morphology, state-dependent reactivity, and lag in phase and/or morphology changes from front to back. Triphasic waves (and almost all periodic patterns) are suppressed by benzodiazepines, along with consciousness and respiration. Such EEG suppression, in the absence of clinical improvement, does not diagnose NCSE. Ambiguous patterns can also be seen, with stimulus-induced rhythmic, periodic or evolving discharges. Whilst non-convulsive seizures and NCSE may be detected in comatose patients, prognosis is largely determined by the underlying aetiology and its complications. Unresolved questions include what particular EEG patterns should consistently prompt aggressive treatment. It is not always possible to be certain that an EEG pattern is ictal or non- ictal, and in the correct clinical context (especially patients presenting with seizures or with a history of epilepsy) a treatment trial may be indicated to see if temporally associated clinical improvement occurs. EEG interpretation needs to be made within the clinical context by an expert reporter.

P.1.g.020 - Effects of escitalopram and voluntary physical exercise on the firing activity of monoamine-secreting neurons in rats

Convulsive seizures (CS) are deleterious consequences of acute cerebral insults and prejudicial events in epilepsy, affecting more than 50 million people worldwide. Molecular mechanisms of depression and epilepsy include an imbalance between excitatory and inhibitory neurotransmission provoking oxidative stress (OS). OS is intimately linked to the origin and evolution of CS and is modulated by antidepressant and anticonvulsant drugs. Although newer antidepressants have exhibited a possible protective role in CS, studies analyzing serotonin and norepinephrine reuptake inhibitors merit to be further investigated. Thus, this study challenged the traditional model of pentylenetetrazol-induced CS, with only one administration of duloxetine. Male Swiss mice were treated with duloxetine (dose corresponding to the therapeutic range for human depression or greater, by allometric calculation; 10, 20 or 40 mg/kg), 30 min before pentylenetetrazol. Behavioral and electroencephalographic alterations were monitored. Lipid peroxidation, nitrites and catalase and superoxidase activities were measured in cortex. Behavioral and electroencephalographic results suggested a possible biphasic effect of duloxetine on CS, with anticonvulsant actions at therapeutic doses and a proconvulsant effect at higher doses. Duloxetine (20 mg/kg) also prevented lipid peroxidation and decreased catalase and superoxide dismutase activities in the cerebral cortex, with no influence on nitrites levels. These data demonstrated an anticonvulsant effect of duloxetine in CS for the first time. This extra anticonvulsant effect may allow the doses of anticonvulsants to be reduced, causing fewer side effects and possibly decreasing morbidity and mortality due to drug interactions in polytherapy.

Antidepressant drugs in convulsive seizures: Pre-clinical evaluation of duloxetine in mice

Convulsive seizures (CS) are deleterious consequences of acute cerebral insults and prejudicial events in epilepsy, affecting more than 50 million people worldwide. Molecular mechanisms of depression and epilepsy include an imbalance between excitatory and inhibitory neurotransmission provoking oxidative stress (OS). OS is intimately linked to the origin and evolution of CS and is modulated by antidepressant and anticonvulsant drugs. Although newer antidepressants have exhibited a possible protective role in CS, studies analyzing serotonin and norepinephrine reuptake inhibitors merit to be further investigated. Thus, this study challenged the traditional model of pentylenetetrazol-induced CS, with only one administration of duloxetine. Male Swiss mice were treated with duloxetine (dose corresponding to the therapeutic range for human depression or greater, by allometric calculation; 10, 20 or 40 mg/kg), 30 min before pentylenetetrazol. Behavioral and electroencephalographic alterations were monitored. Lipid peroxidation, nitrites and catalase and superoxidase activities were measured in cortex. Behavioral and electroencephalographic results suggested a possible biphasic effect of duloxetine on CS, with anticonvulsant actions at therapeutic doses and a proconvulsant effect at higher doses. Duloxetine (20 mg/kg) also prevented lipid peroxidation and decreased catalase and superoxide dismutase activities in the cerebral cortex, with no influence on nitrites levels. These data demonstrated an anticonvulsant effect of duloxetine in CS for the first time. This extra anticonvulsant effect may allow the doses of anticonvulsants to be reduced, causing fewer side effects and possibly decreasing morbidity and mortality due to drug interactions in polytherapy.

Proneurotrophin Binding to P75 Neurotrophin Receptor (P75ntr) Is Essential for Brain Lesion Formation and Functional Impairment after Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) initiates an excessive mediator release of e.g. neurotrophins, which promote neuronal survival, differentiation, and modulate synaptic plasticity. Paradoxically, mature forms of neurotrophins promote neuronal survival, whereas unprocessed forms of neurotrophins induce cell death through p75 neurotrophin receptor (p75NTR) signaling. p75NTR is widely expressed during synaptogenesis and is subsequently downregulated in adulthood. Repair mechanisms after acute cerebral insults can reactivate its expression. Therefore, the influence of p75NTR on secondary brain damage was addressed. mRNA levels of p75NTR and its ligands were quantified in brain tissue up to 7 days after experimental TBI (controlled cortical impact; CCI). Brain damage, motor function and inflammatory marker gene expression were determined in mice lacking the proneurotrophin-binding site of the p75NTR protein (NGFR(-/-)) and wild type littermates (NGFR(+/+)) 24 h and 5 days after CCI. In addition, the effect of TAT-Pep5 (pharmacological inhibitor of the intracellular p75NTR death domain) on lesion volume was evaluated 24 h after insult. p75NTR mRNA levels were induced nine-fold by TBI. In NGFR(-/-) mice, lesion volume was reduced by 29% at 24 h and by 21% 5 days after CCI. Motor coordination was significantly improved 24 h after trauma compared with the wild type. Pharmacological inhibition of the p75NTR signaling reduced lesion volume by 18%. The present study presents first time evidence that genetic mutation of the neurotrophin interaction site of p75NTR strongly limits post-traumatic cell death. In addition, we revealed pharmacological targeting of the intracellular p75NTR cell death domain as a promising approach to limit acute brain damage.

Optic nerve sheath diameter measurement using bedside ultrasound: Is it accurate?

Optic nerve sheath diameter measurement using bedside ultrasound: Is it accurate?

Frequency of Hyponatremia in Central Nervous System Infections

Central nervous system infections (CNS) limited to the meninges or with brain parenchyma involvement are common causes of hospital admissions. Sodium disorders are associated with considerable morbidity and mortality. Hyponatremia is a common electrolyte disturbance and is a common finding in patients with acute cerebral insult. Current study is plan to ascertain the frequency of hyponatremia in CNS infections, to identify regular screening, as CNS infection, treatment and management is emerging as a great challenge especially in the setting of hyponatremia and its complication. In this study our aim was to determine the frequency of hyponatremia in patients with CNS infections attending tertiary health care hospital. This study was conducted in Jinnah Postgraduate Medical Centre (JPMC), Karachi, Pakistan from 6th May 2014 to 6th November 2014. Total duration of this study was six months. It was a cross sectional study and a total of 192 patients with CNS infections presenting to Hospital were included in this study. Brief history and physical examination was done. Blood sample was collected in a sterile manner for serum sodium levels and was sent to lab. Serum sodium level <130 mmol/L was considered as Hyponatremia. The findings of variables were entered in proforma. Our results showed that the average age of the patients was 43.41 ± 13.64 years. Frequency of hyponatremia in patients with CNS infections was observed in 42.71% (82/192) patients. Frequency of hyponatremia was significant among different age groups, while frequency of hyponatremia was not significant between gender and difference duration of disease Sodium disturbance is serious co morbidity in the neurosurgical population. Physicians should focus on the volume status of hyponatremic patients with neurologic disease to differentiate between Cerebral Salt Wasting (CSW) & Syndrome of Inappropriate Anti Diuretic Hormone (SIADH), because the treatment of the two conditions differs. Healthcare providers should recognize the significance of sodium dysregulation among this population and distinguish between the various therapeutic options in order to advocate safe and effective therapy.

Periodic Lateralized Epileptiform Discharges Associated With Irreversible Hyperglycemic Hemichorea–Hemiballism

Periodic lateralized epileptiform discharges (PLEDs) on electroencephlography (EEG) usually indicate an acute, diffuse, and severe cerebral insult. Although hyperglycemic hemichorea-hemiballisum (HCHB) and striatal hyperintensity on T1-weighted magnetic resonance (MR) images is an accepted clinical entity, PLEDs have not previously been reported. Herein, we report a 74-year-old man with hyperglycemic HCHB, hyperintense putamen on T1-MR images and PLEDs on EEG. Aggressive sugar control with neuroleptic treatment only slightly improved the severity of HCHB. We also tried titrated oral and intravenous haloperidol, clonazepam, and propranolol sequentially and in combination; however, the effects were poor. Unlike the generally reversibility of hyperglycemic HCHB, the condition was still present 6 months later. Hyperglycemia can cause HCHB and produce subcortical type-PLEDs, which may explain the findings in our patient. In conclusion, PLEDs can be found in patients with hyperglycemic HCHB and striatal hyperintensity on T1-weighted MR images, and the appearance of PLEDs may indicate an irreversible outcome. EEG should be considered in such circumstances.

Frequency and Prognosis of Convulsive Status Epilepticus of Different Causes

We conducted a systematic review of all studies of status epilepticus (SE) with more than 30 patients published between January 1, 1990, and December 31, 2008, to determine the frequencies of the common underlying causes and the extent to which the underlying causes affect the prognosis of an episode of SE. The frequencies of underlying causes vary among studies and show marked geographic differences, but in most studies, the most common underlying causes were cerebrovascular disease and low antiepileptic drug levels. A relatively good prognosis of SE is found when the underlying cause is associated with low antiepileptic drug levels or alcohol abuse, and a relatively poor outcome occurs when the underlying cause is cerebrovascular disease, particularly in the case of SE due to acute cerebral anoxia, but in most conditions, the reported prognosis is variable. Also, when SE occurs in the context of an acute cerebral insult, such as cerebral infection or cerebrovascular disease, the prognosis of the acute cerebral event is worsened.

EPO/POLAR—World leading trials in TBI research

Currently, two therapies with great potential to reduce neurological damage and improve outcome after a number of acute cerebral insults is the application of early prophylactic hypothermia and exogenous erythropoeitin (EPO) administration.

Effect of propofol upon brain after whole-body hyperthermia in rats

To investigate the effect of propofol upon acute cerebral insult during whole-body hyperthermia (WBH) in rats. Sixty male Wistar rats were randomly divided into 6 groups. All the animals were trained with place navigation test of Morris water maze (MWM) for 5 days pre-study. After training, some rats received anesthesia only but not WBH treatment as control, other rats were anesthetized with intraperitoneal injection of 3.0 ml/kg of chloral hydrate and 100 or 150 mg/kg of propofol followed with WBH process (keeping rat core temperature at 42 degrees C for 30 min). Space memory was checked using spatial probe test 24 h after WBH intervention. Rat brain was then removed in 24 h post-WBH to separate hippocampal regions for the detection of neuronal apoptosis with TUNEL method and ultramicrostructural changes by electron microscope. The escape latency were smaller in groups B0, C0, D0, C and D than that in group B (P < 0.05) while smaller in groups B0, C0, D0 than in groups B, C, D respectively. The amount of apoptotic neurons in hippocampus increased orderly as following with no significant differences in group B0, C0 and D0: group B0, C0, D0 < group D < group C < group B (P < 0.05). The injury degree of neuronal ultramicrostructure in hippocampus in group C after WBH were more severe than that in group D but better than that in group B. Propofol alleviates the WBH-induced acute cerebral insult by inhibiting the hippocampal neural apoptosis.

Analysis of F response in upper motoneurone lesions

The F response can provide a measure of motoneurone excitability (MNE) and so it may be used to investigate upper motoneurone disorders. This report studies the F-wave configuration in patients with stroke to evaluate the changes of the central excitability of the motoneurones at different times after an acute cerebral insult. Various parameters of the F response, including amplitude (absolute and F%/M), duration, and persistence have been determined in 26 patients with unilateral hemiplegia and in 32 healthy subjects of both sexes in the same age range. The investigation was carried out applying a series of 20 supramaximal stimuli at 0.5 Hz on tibial and ulnar nerves bilaterally. In all patients a detailed clinical examination and a CT scan were performed. Our results indicate that an initial stage of reduced spinal motoneuron excitability evidenced by a decreased F amplitude and persistence was present in the early phases after a stroke, followed within 90 days by an enhanced MNE. Moreover, F-wave amplitude shows a positive correlation with weakness and increased tone.

Acute clinical grading in pediatric severe traumatic brain injury and its association with subsequent intracranial pressure, cerebral perfusion pressure, and brain oxygenation

The goal of this paper was to examine the relationship between methods of acute clinical assessment and measures of secondary cerebral insults in severe traumatic brain injury in children. Patients who underwent intracranial pressure (ICP), cerebral perfusion pressure (CPP), and brain oxygenation (PbtO(2)) monitoring and who had an initial Glasgow Coma Scale score, Pediatric Trauma Score, Pediatric Index of Mortality 2 score, and CT classification were evaluated. The relationship between these acute clinical scores and secondary cerebral insult measures, including ICP, CPP, PbtO(2), and systemic hypoxia were evaluated using univariate and multivariate analysis. The authors found significant associations between individual acute clinical scores and select physiological markers of secondary injury. However, there was a large amount of variability in these results, and none of the scores evaluated predicted each and every insult. Furthermore, a number of physiological measures were not predicted by any of the scores. Although they may guide initial treatment, grading systems used to classify initial injury severity appear to have a limited value in predicting who is at risk for secondary cerebral insults.

Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly.

Stroke is a major cause of both death and disability. However, there are no pharmacological treatments used in most countries other than recombinant tissue plasminogen activator, a thrombolytic, and this is only used in about 4% of patients presenting after an acute ischaemic stroke. One novel thrombolytic (desmoteplase) has just been reported to have failed in a Phase IIb/III trial, but other thrombolytics and reperfusion agents remain in development. The picture with neuroprotectant agents, that is compounds that act to preserve neurones following an acute cerebral ischaemic insult, is even more bleak. Despite the development of over 1,000 compounds, many proving effective in animal models of stroke, none has demonstrated efficacy in patients in the over 100 clinical trials conducted. This includes NXY-059, which was developed in accordance with the guidelines proposed by an academic-industry roundtable group (STAIR). This review examines the available data on compounds currently in development. It also proposes that the failure of translation between efficacy in preclinical models and patients is likely to terminate most current neuroprotective drug development. It is suggested that animal models must be made more representative of the patient condition (with other co-morbid conditions) and suggests that since stroke is primarily a cardiovascular disease with a neurological outcome, more research on the neurovascular unit would be valuable. New approaches on neuroinflammation, neurorestoration and neurorepair are also likely to gain prominence in the search for new drugs to treat this major clinical problem.

Mobilization of CD34+ hematopoietic cells, colony-forming cells and long-term culture-initiating cells into the peripheral blood of patients with an acute cerebral ischemic insult

In vitro and in vivo data indicate that stem cells found in the bone marrow (BM) are capable of differentiating into neural cells. The aim of this study was to investigate whether potentially pluripotent hematopoietic stem and progenitor cells are recruited from the BM into the peripheral blood as a reaction to ischemic damage of neural tissues. The number of CD34+ cells, colony-forming cells (CFC) and long-term culture-initiating cells (LTC-IC) was measured within 24 h and on day 7 after stroke onset by flow cytometry, or in functional assays in the peripheral blood of 10 patients with acute middle cerebral artery infarct. The National Institute of Health stroke scale, Barthel index and modified Rankin scale were used to monitor the clinical outcome. In four patients receiving intravenous thrombolytic therapy (tissue plasminogen activator; TPA), no significant increase of CD34+ cells, CFC or LTC-IC was detected. In six patients without thrombolytic treatment, the mean number of CD34+ cells/mL increased significantly from 1181+/-248 at day 1 to 3001+/-881 at day 7. Accordingly, the numbers of CFC and LTC-IC increased 2.7- and 1.7-fold. Granulocyte colony-stimulating factor and neutrophil elastase were monitored by ELISA and remained unchanged during the study period. Our results showed a recruitment of hematopoietic progenitor cells from the BM into the peripheral blood after acute ischemic stroke when no thrombolytic treatment was given. Increased progenitor cell recruitment might be caused by so far unknown signaling stimuli of the ischemic penumbra for stem cell mobilization.

Neurogenic pulmonary edema

Neurogenic pulmonary edema (NPE) is usually defined as an acute pulmonary edema occurring shortly after a central neurologic insult. It has been reported regularly for a long time in numerous and various injuries of the central nervous system in both adults and children, but remains poorly understood because of the complexity of its pathophysiologic mechanisms involving hemodynamic and inflammatory aspects. NPE seems to be under-diagnosed in acute neurologic injuries, partly because the prevention and detection of non-neurologic complications of acute cerebral insults are not at the forefront of the strategy of physicians. The presence of NPE should be high on the list of diagnoses when patients with central neurologic injury suddenly become dyspneic or present with a decreased P(a)o(2)/F(i)o(2) ratio. The associated mortality rate is high, but recovery is usually rapid with early and appropriate management. The treatment of NPE should aim to meet the oxygenation needs without impairing cerebral hemodynamics, to avoid pulmonary worsening and to treat possible associated myocardial dysfunction. During brain death, NPE may worsen myocardial dysfunction, preventing heart harvesting.

The articles of Babinski on his sign and the paper of 1898

In 1896 Joseph François Felix Babinski described for the first time the phenomenon of the toes; nevertheless in this first paper he simply described extension of all toes with pricking of the sole of the foot. It was not until the second paper of 1898 that he specifically described the extension of the hallux with strong tactile stimulation (stroking) of the lateral border of the sole. Babinski probably discovered his sign by a combination of chance observation and careful re-observation and replication. He also had in mind practical applications of the sign, particularly in the differential diagnosis with hysteria and in medico-legal areas. Several of the observations and physiopathological mechanisms proposed by Babinski are still valid today, e.g, he realized since 1896 that the reflex was part of the flexor reflex synergy and observed that several patients during the first hours of an acute cerebral or spinal insult had absent extensor responses. He also found that most patients with the abnormal reflex had weakness of dorsiflexion of the toes and ankles and observed a lack of correlation between hyperactive myotatic reflexes and the presence of an upgoing hallux. He discovered that not all patients with hemiplegia or paraplegia had the sign but thought erroneously that some normal subjects could have an upgoing toe. Between 1896 and 1903 Babinski continued to think on the sign that bears his name and enrich its semiological and physiopathological value.

Optimizing therapy of seizures in neurosurgery

The use of antiepileptic drugs (AEDs) in the neurosurgical setting has a number of implications, including their possible role in the prevention of seizures after acute cerebral insults or brain tumors and the potential for toxicity and interactions when these agents are administered in association with radiotherapy or chemotherapy. This review discusses these controversial issues and draws the following conclusions. 1) AEDs should be prescribed on a short-term basis to prevent seizures occurring within the first week after a cerebral insult (trauma, neurosurgical procedure) but are ineffective to avoid true post-traumatic epilepsy or first seizures in patients with primary or secondary cerebral neoplasms. 2) The use of phenytoin and, to a lesser extent, phenobarbital and carbamazepine during cranial irradiation is associated with an increased risk for severe, potentially fatal, mucocutaneous reactions. In this context, new AEDs with a very low potential for allergic cutaneous reactions should be preferred. 3) Enzyme-inducing AEDs, such as phenytoin, phenobarbital, and carbamazepine, may increase the clearance and reduce the clinical efficacy of corticosteroids and anticancer agents that are also metabolized by the cytochrome P450 system. The newly developed AEDs that are devoid of hepatic metabolism, such as levetiracetam and gabapentin, are now recommended because of good results in preliminary studies and because they do not show interactions with anticancer agents.

Ultrasound thrombolysis

Cardiovascular diseases are a major cause of mortality in the developed world. Efficacy of thrombolysis plays an important role in the management of acute myocardial infarction and cerebral insult both in the acute event and in the long-term outcome of these patients. New adjunctive strategies have been tested, therefore, to make thrombolytic therapies more effective and safer. Ultrasound Thrombolysis is a technique which showed promising results under in vitro conditions and in animal studies. Now clinical trials have to prove if it is also feasible for clinical application. This report gives an overview on different technical approaches and their current performances in the clinical setting. All original articles are chronologically ordered in tables providing detailed information on each study concerning experimental design, acoustical parameters and thrombolysis outcome.

Aquaporins in brain: distribution, physiology, and pathophysiology.

Water homeostasis in the brain is of central physiologic and clinical importance. Neuronal activity and ion water homeostasis are inextricably coupled. For example, the clearance of K+ from areas of high neuronal activity is associated with a concomitant water flux. Furthermore, cerebral edema, a final common pathway of numerous neurologic diseases, including stroke, may rapidly become life threatening because of the rigid encasement of the brain. A water channel family, the aquaporins, facilitates water flux through the plasma membrane of many cell types. In rodent brain, several recent studies have demonstrated the presence of different types of aquaporins. Aquaporin 1 (AQP1) was detected on epithelial cells in the choroid plexus whereas AQP4, AQP5 and AQP9 were localized on astrocytes and ependymal cells. In rodent brain, AQP4 is present on astrocytic end-feet in contact with brain vessels, and AQP9 is found on astrocytic processes and cell bodies. In basal physiologic conditions, AQP4 and AQP9 appear to be implicated in brain homeostasis and in central plasma osmolarity regulation. Aquaporin 4 may also play a role in pathophysiologic conditions, as shown by the reduced edema formation observed after water intoxication and focal cerebral ischemia in AQP4-knockout mice. Furthermore, pathophysiologic conditions may modulate AQP4 and AQP9 expression. For example, AQP4 and AQP9 were shown to be upregulated after ischemia or after traumatic injuries. Taken together, these recent reports suggest that water homeostasis in the brain is maintained by regulatory processes that, by control of aquaporin expression and distribution, induce and organize water movements. Facilitation of these movements may contribute to the development of edema formation after acute cerebral insults such as ischemia or traumatic injury.

Inhibition of nNOS activity in rat brain by synthetic kynurenines: structure-activity dependence.

The overstimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is involved in excitotoxicity, a process participating in neurodegeneration that characterizes some neurological disorders and acute cerebral insults. In looking for compounds with neuroprotective properties, a series of kynurenine derivatives were synthesized, and their effects on both the NMDA and nNOS activity in rat striatum were evaluated. Two compounds, 15a (2-acetamido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid) and 15c (2-butyramido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid), displayed more potent activities than the other synthetic compounds tested for the inhibition of NMDA excitability and nNOS activity. Two other compounds, 18a (2-acetamido-4-(3-methoxyphenyl)-4-oxobutyric acid) and 18c (2-butyramido-4-(3-methoxyphenyl)-4-oxobutyric acid), that have the same structure as 15a and 15c, except the amino group in R(1), showed different effects. Whereas compound 18a showed lower electrophysiological potency than compounds 15a and 15c in the inhibition of the NMDA-dependent excitability, compound 18c showed the opposite effect. Moreover, compounds 18a and 18c were unable to modify nNOS activity. The remaining kynurenines tested behave like compound 18a. These results suggest that a structure-related activity of these synthetic kynurenines and a N-H bond in a specific direction is necessary for some kynurenine analogues to inhibit nNOS activity.