Alcohol and drug use following traumatic brain injury: A prospective study

Primary objectives: To establish pre-morbid alcohol and drug use in persons with TBI, relative to controls, investigate how patterns of substance use change over time following TBI and identify factors associated with heavy post-injury substance use.

Methods and procedures: The Alcohol Use Disorders Identification test (AUDIT) and Drug Abuse Screening Test (DAST) was completed by 121 hospital inpatients with TBI, documenting pre-injury alcohol and drug use, and 133 demographically similar controls. Participants with TBI completed these measures and the Hospital Anxiety and Depression Scale (HADS) again 1 and 2 years post-injury and 76 also completed them at 3 years.

Results: Participants with TBI showed similar levels of drug and alcohol use to controls pre-injury, with 31.4% of the TBI group and 29.3% of controls drinking at hazardous levels. Alcohol and drug use declined in the first year post-injury, but increased by 2 years post-injury, with only 21.4% of participants with TBI reporting abstinence from alcohol and 25.4% drinking at hazardous levels. Only 9% showed a drug problem, but 24% had returned to some drug use. Those showing heavy alcohol use post-injury were young, male and heavy drinkers pre-injury. Drug and alcohol use was similar at 3 years post-injury.

Conclusions: More active intervention is needed to reduce alcohol and drug use following TBI.     

Alcohol and drug use following traumatic brain injury: a prospective study

PRIMARY OBJECTIVES: To establish pre-morbid alcohol and drug use in persons with TBI, relative to controls, investigate how patterns of substance use change over time following TBI and identify factors associated with heavy post-injury substance use. METHODS AND PROCEDURES: The Alcohol Use Disorders Identification test (AUDIT) and Drug Abuse Screening Test (DAST) was completed by 121 hospital inpatients with TBI, documenting pre-injury alcohol and drug use, and 133 demographically similar controls. Participants with TBI completed these measures and the Hospital Anxiety and Depression Scale (HADS) again 1 and 2 years post-injury and 76 also completed them at 3 years. RESULTS: Participants with TBI showed similar levels of drug and alcohol use to controls pre-injury, with 31.4% of the TBI group and 29.3% of controls drinking at hazardous levels. Alcohol and drug use declined in the first year post-injury, but increased by 2 years post-injury, with only 21.4% of participants with TBI reporting abstinence from alcohol and 25.4% drinking at hazardous levels. Only 9% showed a drug problem, but 24% had returned to some drug use. Those showing heavy alcohol use post-injury were young, male and heavy drinkers pre-injury. Drug and alcohol use was similar at 3 years post-injury. CONCLUSIONS: More active intervention is needed to reduce alcohol and drug use following TBI.     

Alcohol abuse and traumatic brain injury: quantitative magnetic resonance imaging and neuropsychological outcome

Prior or concurrent alcohol use at the time of traumatic brain injury (TBI) was examined in terms of post-injury atrophic changes measured by quantitative analysis of magnetic resonance imaging (MRI) and neuropsychological outcome. Two groups of TBI subjects were examined: those with a clinically significant blood alcohol level (BAL) present at the time of injury (TBI + BAL) and those without a significant BAL (TBI-only). To explore the potential impact of both acute and chronic alcohol use, subjects in both groups were further clustered into one of four subgroups (NONE, MILD, MODERATE or HEAVY) based upon available information regarding their pre-injury alcohol use. One-way analysis of covariance (ANCOVA) and multiple analysis of covariance (MANCOVA) were used with subject grouping as the main factor. Age, injury severity as measured by Glasgow Coma Scale (GCS) score, years of education, total intracranial volume (TICV), and the number of days post-injury were included as covariates where appropriate. Increased general atrophy was observed in patients with (a) a positive BAL and/or (b) a history of moderate to heavy pre-injury alcohol use. In addition, performance on neuropsychological outcome variables (WAIS-R and WMS-R Index scores) was generally worse in the subgroups of patients with positive BAL and a history of preinjury alcohol use, as compared to the other TBI groups though not statistically significant. Implications of alcohol use, at the time of brain injury, are discussed.     

Alcohol consumption in traumatic brain injury: attenuation of TBI-induced hyperthermia and neurocognitive deficits

Clinical and animal studies indicate that hyperthermia during or after traumatic brain injury (TBI) is associated with poor outcome. Alcohol intoxication, a complicating risk factor in many cases of head injury, has been found to both worsen or attenuate posttraumatic neural damage and outcome. The purpose of the present study was to determine whether chronic ethanol consumption would affect TBI-induced hyperthermia and deficits in spatial learning. TBI was produced by cortical contusion injury in adult male rats. We first characterized the TBI-induced febrile response using probes implanted intraperitoneally (ip) or intracerebroventricularly for continuous biotelemetric recording of core body and brain temperatures and locomotor activity. In another experiment, rats, implanted with ip probes, were fed a liquid diet containing ethanol (5% w/v, 35% ethanol-derived calories); control rats were pair-fed the isocaloric liquid diet (P-P). At 14 days after commencement of diet feeding, TBI or sham surgery was performed, and the ethanol-fed rats were divided into two groups: half were transferred to the isocaloric diet (E-P) and the other half remained on the ethanol-containing diet (E-E). TBI produced a significant febrile response in all rats, that persisted for at least 6 days in the E-P and P-P groups but lasted for only 2 days in the E-E group. When tested at 3-4 weeks after TBI, E-E rats required significantly fewer trials than E-P rats to reach criterion in the Morris water maze. In sum, continuous consumption of ethanol before and after TBI attenuated TBI-induced hyperthermia and deficits in spatial learning. Whereas the results suggest that this ethanol regimen may be neuroprotective, a causal relationship between the two outcomes remains to be determined.     

Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury

Previous studies from our laboratory indicate that traumatic brain injury (TBI) in humans results in proteolysis of neuronally-localized, intracellular microtubule associated protein (MAP)-tau to produce cleaved tau (C-tau). The present study evaluated the utility of C-tau to function as a biomarker of neuronal injury and as a biomarker for evaluating neuroprotectant drug efficacy in a controlled cortical impact model of rat TBI. Brain C-tau was determined in rats subjected to controlled cortical impact-induced mild, moderate or severe levels of TBI. A significant severity-dependent increase in C-tau levels was observed in the cortex and hippocampus (1.5-8-fold) of TBI rats compared to shams 72 h after impact. C-tau rat brain and serum time course was determined by measuring levels at 0.25, 6, 24, 48, 72 and 168 h after TBI. A significant time-dependent increase in C-tau levels was observed in ipsilateral cortex (5-16-fold) and hippocampus (2-40-fold) compared to sham animals. C-tau levels increased as early as 6 h after TBI with peak C-tau levels observed 168 h after injury. Elevated brain C-tau levels were associated with TBI-induced tissue loss, which was histologically determined. The effect of cyclosporin-A (CsA), previously demonstrated to be neuroprotective in rat TBI, on brain C-tau levels was examined. CsA (20 mg/kg i.p., 15 min and 24 h after TBI) significantly attenuated the TBI-induced increase in hippocampal C-tau levels observed in vehicle-treated animals confirming CsA's neuroprotectant effect. CsA treatment also lowered ipsilateral cortical C-tau levels, although it did not reach statistical significance. CsA's neuroprotectant effect was confirmed utilizing histologic measures of TBI-induced tissue loss. In addition, serum C-tau levels were significantly increased 6 h after TBI but not at later time points. These results suggest that C-tau is a reliable, quantitative biomarker for evaluating TBI-induced neuronal injury and a potential biomarker of neuroprotectant drug efficacy in the rat TBI model. Serum data suggests that C-tau levels are dependent both on a compromised blood-brain barrier as well as release of TBI biomarkers from the brain, which has implications for the study of human serum TBI biomarkers.     

Citalopram treatment of traumatic brain damage in a 6-year-old boy

Traumatic brain damage may cause acute emotional symptoms such as uncontrolled crying, apathy, and sleep problems. Rehabilitation may be less effective in patients afflicted by these symptoms. Citalopram, a selective serotonin reuptake inhibitor (SSRI), has a documented immediate and dramatic effect on pathological crying in stroke patients. The present case history of a 6-year-old boy with a traumatic right-sided hemorrhage in the basal ganglia indicates that early SSRI treatment has a dramatic effect on pathological crying and in addition may have a concomitant beneficial effect on motor paresis, sleep disturbance, and neurobehavioral problems.     

Impact of traumatic brain damage on family dynamics and functioning: A review

The purpose of this paper is to review the dynamics and functioning of families with a severely head-injured member. In order to stress the unique problems faced by persons with brain damage and their families, a comparison with spinal cord-injured persons is presented. The review's major conclusion is that a head injury exposes the family to a complex of problems that are unique to this disability and, therefore, necessitates the delivery of special family support services focused on the family, rather than on the head-injured person.     

Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice

OBJECT: This study was designed to investigate the beneficial effects of recombinant human erythropoietin (rhEPO) treatment of traumatic brain injury (TBI) in mice. METHODS: Adult male C57BL/6 mice were divided into 3 groups: 1) the saline group (TBI and saline [13 mice]); 2) EPO group (TBI and rhEPO [12]); and 3) sham group (sham and rhEPO [8]). Traumatic brain injury was induced by controlled cortical impact. Bromodeoxyuridine (100 mg/kg) was injected daily for 10 days, starting 1 day after injury, for labeling proliferating cells. Recombinant human erythropoietin was administered intraperitoneally at 6 hours and at 3 and 7 days post-TBI (5000 U/kg body weight, total dosage 15,000 U/kg). Neurological function was assessed using the Morris water maze and footfault tests. Animals were killed 35 days after injury, and brain sections were stained for immunohistochemical evaluation. RESULTS: Traumatic brain injury caused tissue loss in the cortex and cell loss in the dentate gyrus (DG) as well as impairment of sensorimotor function (footfault testing) and spatial learning (Morris water maze). Traumatic brain injury alone stimulated cell proliferation and angiogenesis. Compared with saline treatment, rhEPO significantly reduced lesion volume in the cortex and cell loss in the DG after TBI and substantially improved recovery of sensorimotor function and spatial learning performance. It enhanced neurogenesis in the injured cortex and the DG. CONCLUSIONS: Recombinant human erythropoietin initiated 6 hours post-TBI provided neuroprotection by decreasing lesion volume and cell loss as well as neurorestoration by enhancing neurogenesis, subsequently improving sensorimotor and spatial learning function. It is a promising neuroprotective and neurorestorative agent for TBI and warrants further investigation.     

Intensity- and interval-specific repetitive traumatic brain injury can evoke both axonal and microvascular damage

Abstract In the experimental setting several investigators have recently reported exacerbations of the burden of axonal damage and other neuropathological changes following repetitive traumatic brain injuries (TBI) that were sustained at intervals from hours to days following the initial insult. These same studies also revealed that prolonging the interval between the first and second insult led to a reduction in the burden of neuropathological changes and/or their complete elimination. Although demonstrating the capability of repetitive TBI to evoke increased axonal and other neuropathological changes, these studies did not address the potential for concomitant microvascular dysfunction or damage, although vascular dysfunction has been implicated in the second-impact syndrome. In this study we revisit the issue of repetitive injury in a well-controlled animal model in which the TBI intensity was bracketed from subthreshold to threshold insults, while the duration of the intervals between the injuries varied. Employing cranial windows to assess vascular reactivity and post-mortem amyloid precursor protein (APP) analysis to determine the burden of axonal change, we recognized that subthreshold injuries, even when administered in repeated fashion over a short time frame, evoked neither axonal nor vascular change. However, with an elevation of insult intensity, repetitive injuries administered within 3-h time frames caused dramatic axonal damage and significant vascular dysfunction bordering on a complete loss of vasoreactivity. If, however, the interval between the repetitive injury was extended to 5?h, the burden of axonal change was reduced, as was the overall magnitude of the ensuing vascular dysfunction. With the extension of the interval between injuries to 10?h, neither axonal nor vascular changes were found. Collectively, these studies reaffirm the existence of significant axonal damage following repetitive TBI administered within a relatively short time frame. Additionally, they also demonstrate that these axonal changes parallel changes in the cerebral microcirculation, which also may have adverse consequences for the injured brain.     

Cell-free DNA as a marker for prediction of brain damage in traumatic brain injury in rats

Traumatic brain injury (TBI) is a major cause of morbidity and mortality, and early predictors of neurological outcomes are of great clinical importance. Cell free DNA (CFD), a biomarker used for the diagnosis and monitoring of several diseases, has been implicated as a possible prognostic indicator after TBI. The purpose of this study was to determine the pattern and timing of CFD levels after TBI, and whether a relationship exists between the level of CFD and brain edema and neurological outcomes. Thirty-nine Sprague-Dawley rats were randomly assigned to two groups: rats in group 1 (sham group) were anesthetized and had a scalp incision without TBI, and rats in group 2 were anesthetized and had a scalp incision with TBI, which was induced by using a weight drop model that causes diffuse brain injury. A neurological severity score (NSS) was assessed at 1, 24, and 48?h after TBI. CFD was measured via blood samples drawn at t=0 (baseline), 12, 24, 48, 72, and 120?h after TBI. At 48?h after TBI, brain edema was determined in a subgroup of 11 rats by calculating the difference between rats' wet and dry brain weight. The significance of comparisons between and within groups (CFD levels, brain water content, and NSS) were determined using the Kruskal-Wallis, Mann-Whitney and Student t test. The correlation between CFD levels and the NSS, as well as between CFD levels and the extent of brain edema, was calculated using the Spearman and Pearson tests, respectively. Compared with baseline levels, the CFD levels in rats subjected to TBI were significantly increased at 24 and 48 h after TBI (p<0.01 and p<0.05, respectively). A positive correlation was demonstrated between CFD levels 24?h following TBI and the extent of brain edema (r=0.63, p<0.05), as well as between CFD levels and the NSS (r=0.79, p<0.005). In this study, we demonstrated an increase in CFD levels after TBI, as well as a correlation between CFD levels and brain edema and NSS. CFD levels may provide a quick, reliable, and simple prognostic indicator of neurological outcome in animals after TBI. Its role in humans has not been clearly elucidated, but has potentially significant clinical implications.     

Postinjury cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury.

Recent observations concerning presumed calcium-induced mitochondrial damage and focal intraaxonal proteolysis in the pathogenesis of traumatic axonal injury (TAI) have opened new perspectives for therapeutic intervention. Studies from our laboratory demonstrated that cyclosporin A (CsA), a potent inhibitor of Ca2+-induced mitochondrial damage, administered 30 min prior to traumatic brain injury preserved mitochondrial integrity in those axonal foci destined to undergo delayed disconnection. We attributed this neuroprotection to the inhibition by CsA of mitochondrial permeability transition (MPT). Additional experiments proved that CsA pretreatment also significantly reduced calcium-induced, calpain-mediated spectrin proteolysis (CMSP) and neurofilament compaction (NFC), pivotal events in the pathogenesis of axonal failure and disconnection. Given these provocative findings the goal of the current study was to evaluate the potential of CsA to inhibit calcium-induced axonal damage in a more clinically relevant postinjury treatment paradigm. To this end, cyclosporin A was administered intrathecally to Sprague Dawley rats 30 min following impact acceleration traumatic brain injury. The first group of animals were sacrificed 120 min postinjury and the density of CMSP and NFC immunoreactive damaged axonal segments of CsA-treated and vehicle-treated injured animals were quantitatively analyzed. A second group of CsA- versus vehicle-treated rats was sacrificed at 24 h postinjury to compare the density of damaged axons displaying beta amyloid precursor protein (APP) immunoreactivity, a signature protein of axonal perturbation and disconnection. Postinjury CsA administration resulted in a significant decrease (>60%) in CMSP/NFC immunoreactivity in corticospinal tracts and medial longitudinal fasciculi. A similar decrease was detected in the density of APP immunoreactive damaged axons, indicating an attenuation of axonal disconnection at 24 h postinjury in CsA-treated animals. These results once again suggest that the maintenance of the functional integrity of the mitochondria can prevent TAI, presumably via the preservation of the local energy homeostasis of the axon. Moreover and perhaps more importantly, these studies also demonstrate the efficacy of CsA administration when given in the early posttraumatic period. Collectively, our findings suggest that a therapeutic window exists for the use of drugs targeting mitochondria and energy regulation in traumatic brain injury.     

GFAP versus S100B in serum after traumatic brain injury: relationship to brain damage and outcome

Research indicates that glial fibrillary acidic protein (GFAP), part of the astroglial skeleton, could be a marker of traumatic brain injury (TBI). S100B, an astroglial protein, is an acknowledged marker of TBI. Our goal was to analyze the relationship of GFAP/S100B to brain damage and outcome, and to compare the accuracy of GFAP/S100B for prediction of mortality after TBI. Our prospective study included 92 patients admitted <12 h after TBI (median injury severity score 25, median Glasgow Coma Scale 6). TBI was verfied by computerized tomography. GFAP/S100B were measured immunoluminometrically at admission and daily in the intensive care unit (average 10 days, range 1-21 days). We compared GFAP/S100B in non-survivors versus survivors, accuracy for mortality prediction according to receiver operated characteristic curve analysis, correlation between GFAP and S100B, relationship of GFAP/S100B to computerized tomography, cerebral perfusion pressure (CPP), mean arterial pressure (MAP) and 3-month Glasgow Outcome Score (GOS). GFAP (p < 0.005) and S100B (p < 0.0005) were higher in non-survivors than survivors. Both GFAP and S100B were accurate for mortality prediction (area under curve 0.84 versus 0.78 at <12 h after TBI). GFAP and S100B release correlated better later than 36 h after TBI (r = 0.75) than earlier (r = 0.58). GFAP was lower in focal lesions of <25 mL than in shifts of >0.5 cm (p < 0.0005) and non-evacuated mass lesions of >25 mL (p < 0.005). S100B was lower in focal lesions of <25 mL than in non-evacuated mass lesions (p < 0.0005) and lower in swelling than in shifts of >0.5 cm (p < 0.005). GFAP and S100B were lower in ICP < 25 than ICP > or = 25 (p < 0.0005), in CPP > or = 60 than CPP < 60 (p < 0.0005), in MAP > 70 than MAP < or = 70 mm Hg, and in GOS 4-5 than GOS 1 (p < 0.0005). Both measurement of GFAP and S100B is a useful non-invasive means of identifying brain damage with some differences based on the pattern of TBI and accompanying multiple trauma and/or shock.     

Investigation of cavitation as a possible damage mechanism in blast-induced traumatic brain injury

Cavitation was investigated as a possible damage mechanism for war-related traumatic brain injury (TBI) due to an improvised explosive device (IED) blast. When a frontal blast wave encounters the head, a shock wave is transmitted through the skull, cerebrospinal fluid (CSF), and tissue, causing negative pressure at the contrecoup that may result in cavitation. Numerical simulations and shock tube experiments were conducted to determine the possibility of cranial cavitation from realistic IED non-impact blast loading. Simplified surrogate models of the head consisted of a transparent polycarbonate ellipsoid. The first series of tests in the 18-inch-diameter shock tube were conducted on an ellipsoid filled with degassed water to simulate CSF and tissue. In the second series, Sylgard gel, surrounded by a layer of degassed water, was used to represent the tissue and CSF, respectively. Simulated blast overpressure in the shock tube tests ranged from a nominal 10-25 pounds per square inch gauge (psig; 69-170?kPa). Pressure in the simulated CSF was determined by Kulite thin line pressure sensors at the coup, center, and contrecoup positions. Using video taken at 10,000 frames/sec, we verified the presence of cavitation bubbles at the contrecoup in both ellipsoid models. In all tests, cavitation at the contrecoup was observed to coincide temporally with periods of negative pressure. Collapse of the cavitation bubbles caused by the surrounding pressure and elastic rebound of the skull resulted in significant pressure spikes in the simulated CSF. Numerical simulations using the DYSMAS hydrocode to predict onset of cavitation and pressure spikes during cavity collapse were in good agreement with the tests. The numerical simulations and experiments indicate that skull deformation is a significant factor causing cavitation. These results suggest that cavitation may be a damage mechanism contributing to TBI that requires future study.     

The influence of victim characteristics on potential jurors' perceptions of brain damage in mild traumatic brain injury

PRIMARY OBJECTIVE: To determine the influence of victim/plaintiff sex, occupation and intoxication status at the time of injury on potential jurors' judgement about the presence of brain damage in mild traumatic brain injury (MTBI). RESEARCH DESIGN: Survey. METHODS AND PROCEDURES: One of eight scenarios describing a MTBI from a motor vehicle accident was presented to 460 participants at a Department of Motor Vehicles. Victim sex, occupation (accountant or cafeteria worker) and alcohol intoxication status at the time of injury (sober or intoxicated) were manipulated across eight scenarios. Participants rated whether the victim's complaints at 6 months post-injury were the result of brain damage. MAIN OUTCOMES AND RESULTS: Ratings were influenced by victim occupation and intoxication status (chi2>5.3, p<0.03), but not the sex of the victim. CONCLUSIONS: The occupational and intoxication status of MTBI victims may influence potential jurors' decision about the presence of brain damage.     

Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction

OBJECTIVE: Caspase-1 plays an important functional role mediating neuronal cell death and dysfunction after experimental traumatic brain injury (TBI) in mice. Minocycline, a derivative of the antibiotic tetracycline, inhibits caspase-1 expression. This study investigates whether minocycline can ameliorate TBI-mediated injury in mice. METHODS: Brains from mice subjected to traumatic brain injury underwent immunohistochemical analyses for caspase-1, caspase-3, and a neuronal specific marker (NeuN). Minocycline- and saline-treated mice subjected to traumatic brain injury were compared with respect to neurological function, lesion volume, and interleukin-1beta production. RESULTS: Immunohistochemical analysis revealed that activated caspase-1 and caspase-3 are present in neurons 24 hours after TBI. Intraperitoneal administration of minocycline 12 hours before or 30 minutes after TBI in mice resulted in improved neurological function when compared with mice given saline control, as assessed by Rotarod performance 1 to 4 days after TBI. The lesion volume, assessed 4 days after trauma, was significantly decreased in mice treated with minocycline before or after trauma when compared with saline-treated mice. Caspase-1 activity, quantified by measuring mature interleukin-1beta production by enzyme-linked immunosorbent assay, was considerably increased in mice that underwent TBI, and this increase was significantly diminished in minocycline-treated mice. CONCLUSION: We show for the first time that caspase-1 and caspase-3 activities localize specifically within neurons after experimental brain trauma. Further, these results indicate that minocycline is an effective pharmacological agent for reducing tissue injury and neurological deficits that result from experimental TBI, likely through a caspase-1-dependent mechanism. These results provide an experimental rationale for the evaluation of minocycline in human trauma patients.     

Obesity and traumatic brain injury

BACKGROUND: As obesity continues to run rampant in our society, an understanding of its adverse effect after traumatic injury is starting to unfold. We hypothesize that obesity negatively impacts head-injured patients, and the current study intends to compare obese and lean patients with traumatic brain injury (TBI). METHODS: This is a retrospective study evaluating all blunt trauma patients with TBI admitted to the intensive care unit (ICU) in our urban, Level I trauma center from 1998 until 2003. Body mass index (BMI) was used to categorize patients as either lean (BMI <30 kg/m2) or obese (BMI > or =30 kg/m2). Admission demographics, type and severity of head injury, and associated injuries were recorded for each patient. Primary outcome was mortality, while secondary outcomes were cause of death, complications, and for survivors, days of mechanical ventilation, ICU length of stay, and hospital length of stay. Obese and lean patients were compared using univariate analysis and multivariate stepwise logistic regression. In addition, a subgroup analysis of patients with isolated head injury was performed. RESULTS: There were 690 patients with TBI admitted to the ICU during the study period, with 129 (19%) obese patients (BMI = 34 +/- 5 kg/m2) and 561 (81%) lean patients (BMI = 24 +/- 4 kg/m2). The two groups were similar with the exceptions that obese patients were older (46 +/- 20 years versus 39 +/- years, p < 0.01), had lower admission systolic blood pressure (125 +/- 38 mm Hg versus 134 +/- 30 mm Hg, p = 0.01), and more often sustained an associated chest injury (46% versus 35%, p = 0.03). Obese patients with TBI had a trend toward more complications (34% versus 28%, p = 0.17) and a higher mortality (36% versus 25%, p = 0.02). However, stepwise logistic regression failed to identify obesity as an independent risk factor for either morbidity or mortality. In addition, obese patients with isolated head injury had no increase in complications or death. CONCLUSIONS: Although obese patients suffer more complications and higher mortality than lean patients after TBI, this adverse effect seems to be due to age, lower admission blood pressure, and more associated chest injury, rather than a direct result of the obese state.