Biomedical subjects

David A Hovda

Publications and source records attributed to David A Hovda.

32 records · Page 2Linked to original sources

PubMed2004

Acute changes in regional cerebral (18)F-FDG kinetics in patients with traumatic brain injury.

UNLABELLED: During the acute phase after traumatic brain injury (TBI), the metabolic state is regionally heterogeneous. The purpose of this study was to characterize contusional, pericontusional, and remote regions of TBI by estimating glucose transporter and hexokinase activities on the basis of (18)F-FDG kinetic modeling. METHODS: A standard 2-compartment model was used to measure (18)F-FDG kinetic parameters in 21 TBI patients with cerebral contusions studied during the acute phase (3.1 +/- 2.1 [mean +/- SD] d after injury). Nineteen patients also underwent (15)O-water PET to measure regional cerebral blood flow (CBF). A control study ((18)F-FDG and (15)O-water) was done with 18 healthy volunteers. The rate constants K(i), K(1), and k(3) were assumed to represent the uptake, transport, and hexokinase activity of (18)F-FDG, respectively; K(i) was calculated as K(1) x [k(3)/(k(2) + k(3))]. RESULTS: The areas of contusional and pericontusional tissues located 4.5, 13.5, and 22.5 mm away from the contusion (PC(4.5), PC(13.5), and PC(22.5), respectively) demonstrated significantly reduced K(1) values, whereas the K(1) values for remote areas remained normal. The k(3) values were significantly reduced regardless of the distance from the contusion. Pericontusional areas with CT- or MRI-evidenced tissue damage showed significantly lower K(i) (P < 0.001), CBF (P < 0.01), and K(1) (P < 0.0001) values than did areas without such damage, whereas the k(3) values did not differ significantly. Seven patients showed regionally increased (18)F-FDG uptake (hot spots) in pericontusional areas. The k(3) value for the hot spots (0.086 +/- 0.024/min) was significantly higher than that for the remote cortex (P < 0.01), whereas the K(i), CBF, and K(1) values did not show significant differences. Patients with hot spots showed significantly higher K(i) and k(3) values in PC(4.5) (P < 0.05) and higher k(3) values in PC(22.5) (P < 0.05) than did patients without hot spots, whereas the K(1) and CBF values did not differ significantly. CONCLUSION: Brain tissue (18)F-FDG kinetics in TBI patients were consistent with reduced hexokinase activity in the whole brain (including apparently uninjured cortex), whereas glucose transport was impaired only in the area immediately around the contusion. Pericontusional high levels of (18)F-FDG uptake observed in a subgroup of patients could have been the result of regionally increased hexokinase activity.

Acute Disease↗

PubMed2003

Developing experimental models to address traumatic brain injury in children.

Traumatic brain injury (TBI) is the leading cause of injury-related death and disability among children under the age of 15 years in the United States. Epidemiological studies have revealed that even within the pediatric population there are differences in incidence, gender differences, causes, types of injuries sustained, and mortality within age subdivisions. This heterogeneity must be taken into account when developing appropriate models to address TBI in children. This review explores the current developmental TBI models, including fluid percussion, weight drop, and controlled cortical impact. It also addresses unique considerations to modeling pediatric brain injury that require special attention when modeling and designing studies: age appropriateness, injury severity, evaluation of recovery, plasticity, and anesthesia.

Animals↗

PubMed2003

Increased hippocampal CA3 vulnerability to low-level kainic acid following lateral fluid percussion injury.

This study was designed to determine whether a secondary increase in neuronal activity induced by a low dose of kainic acid (KA), a glutamate analogue, exacerbates the anatomical damage in hippocampal regions following a mild lateral fluid percussion (LFP) brain injury. KA (9 mg/kg) was injected intraperitoneally in LFP-injured rats (n = 16) 1 h post-trauma. The neuronal loss in the CA3, CA4, and hilar regions at 7 days was quantified by two-dimensional cell counts. Hippocampal activation 15 min following KA injection was assessed by measuring local glucose metabolic rates (lCMR(glc)). Following LFP + KA, the ipsilateral side exhibited a 62.7%, 75.7%, and 52.1% decrease in the number of CA3, CA4 and hilar neurons, respectively, compared to naive rats (n = 3). These CA3 and CA4 neuronal counts were also significantly decreased compared to LFP + saline (n = 5) and sham + KA (n = 9) groups. The median Racine Score, used to rate the severity of behavioral seizures, was 4 in LFP + KA and 2 in sham + KA groups (p < 0.015), suggesting a reduction in seizure threshold following injury. lCMRglc in CA3 following LFP + KA was 121.8 +/- 2.0 (mean +/- SE) ipsilaterally and 71.5 +/- 5.4 contralaterally (p < 0.0012). No changes were found in the BBB permeability as measured by [(14)C]aminoisobutyric acid in CA3, CA4, and hilar regions. We conclude that the presence of low-level KA 1 h after LFP dramatically increases the extent of hippocampal activation and induces a striking loss of ipsilateral CA3 and CA4 pyramidal neurons. Neuronal excitation during a time of cellular vulnerability may trigger or amplify the cycle of secondary damage in functionally impaired, but potentially viable, tissue.

Animals↗

PubMed2003

Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysis study.

Disturbed glucose brain metabolism after brain trauma is reflected by changes in extracellular glucose levels. The authors hypothesized that posttraumatic reductions in extracellular glucose levels are not due to ischemia and are associated with poor outcome. Intracerebral microdialysis, electroencephalography, and measurements of brain tissue oxygen levels and jugular venous oxygen saturation were performed in 30 patients with traumatic brain injury. Levels of glucose, lactate, pyruvate, glutamate, and urea were analyzed hourly. The 6-month Glasgow Outcome Scale extended (GOSe6) score was assessed for each patient. In regions of increased glucose utilization defined by positron emission tomography, the extracellular glucose concentration was less than 0.2 mmol/l. Extracellular glucose values were less than 0.2 mmol during postinjury days 0 to 7 in 19% to 30% of hourly samples on each day. Transient decreases in glucose levels occurred with electrographic seizures and nonischemic reductions in cerebral perfusion pressure and jugular venous oxygen saturation. Glutamate levels were elevated in the majority of low-glucose samples, but the lactate/pyruvate ratio did not indicate focal ischemia. Terminal herniation resulted in reductions in glucose with increases in the lactate/pyruvate ratio but not in lactate concentration alone. GOSe6 scores correlated with persistently low glucose levels, combined early low glucose levels and low lactate/glucose ratio, and with the overall lactate/glucose ratio. These results suggest that the level of extracellular glucose is typically reduced after traumatic brain injury and associated with poor outcome, but is not associated with ischemia.

Adult↗

PubMed2003

Metabolic, neurochemical, and histologic responses to vibrissa motor cortex stimulation after traumatic brain injury.

During the prolonged metabolic depression after traumatic brain injury (TBI), neurons are less able to respond metabolically to peripheral stimulation. Because this decreased responsiveness has been attributed to circuit dysfunction, the present study examined the metabolic, neurochemical, and histologic responses to direct cortical stimulation after lateral fluid percussion injury (LFPI). This study addressed three specific hypotheses: that neurons, if activated after LFPI, will increase their utilization of glucose even during a period of posttraumatic metabolic depression; that this secondary activation results in an increase in the production of lactate and a depletion of extracellular glucose; and that because cells are known to be in a state of energy crisis after traumatic brain injury, additional energy demands resulting from activation can result in their death. The results indicate that stimulating to levels eliciting a vibrissa twitch resulted in an increase in the cerebral metabolic rate for glucose (CMR(glc); micromol.100 g(-1).min(-1)) of 34% to 61% in the sham-operated, 1-hour LFPI, and 7-day LFPI groups. However, in the 1-day LFPI group, stimulation induced a 161% increase in CMR(glc) and a 35% decrease in metabolic activation volume. Extracellular lactate concentrations during stimulation significantly increased from 23% in the sham-injured group to 55% to 63% in the 1-day and 7-day LFPI groups. Extracellular glucose concentrations during stimulation remained unchanged in the sham-injured and 7-day LFPI groups, but decreased 17% in the 1-day LFPI group. The extent of cortical degeneration around the stimulating electrode in the 1-day LFPI group nearly doubled when compared with controls. These results indicate that at 1 day after LFPI, the cortex can respond to stimulation with an increase in anaerobic glycolysis; however, this metabolic response to levels eliciting a vibrissa response via direct cortical stimulation appears to constitute a secondary injury in the TBI brain.

Animals↗

PubMed2003

Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism.

UNLABELLED: The purpose of this study was to determine if the relationship between abnormalities in glucose, lactate, and oxygen metabolism were predictive of neurologic outcome after moderate or severe head injury, relative to other known prognostic factors. Serial assessments of the cerebral metabolic rates for glucose, lactate, and oxygen were performed using a modified Kety-Schmidt method. In total, 31 normal control subjects were studied once, and 49 TBI patients (mean age 36+/-16 years, median GCS 7) were studied five times median per patient from postinjury days 0 to 9. Univariate and multivariate analyses were performed. Univariate analysis showed that the 6-month postinjury Glasgow Outcome Scale (GOS) was most strongly associated with the mean cerebral metabolic rate of oxygen (CMRO2) (P = 0.0001), mean arterial lactate level (P = 0.0001), mean arterial glucose (P = 0.0008), mean cerebral blood flow (CBF), (P = 0.002), postresuscitation GCS (P = 0.003), and pupillary status (P = 0.004). Brain lactate uptake was observed in 44% of all metabolic studies, and 76% of patients had at least one episode of brain lactate uptake. By dichotomized GOS, patients achieving a favorable outcome (GOS 4-5) were distinguished from those with an unfavorable outcome (GOS1-3) by having a higher CMRO2 (P = 0.003), a higher rate of abnormal brain lactate uptake relative to arterial lactate levels (P = 0.04), and lesser degrees of blood-brain barrier damage based on CT findings (P = 0.03). CONCLUSIONS: During the first 6 days after moderate or severe TBI, CMRO2 and arterial lactate levels are the strongest predictors of neurologic outcome. However, the frequent occurrence of abnormal brain lactate uptake despite only moderate elevations in arterial lactate levels in the favorable outcome patients suggests the brain's ability to use lactate as a fuel may be another key outcome predictor. Future studies are needed to determine to what degree nonglycolytic energy production from alternative fuels such as lactate occurs after TBI and whether alternative fuel administration is a viable therapy for TBI patients.

Adult↗

PubMed2003

Correlation of regional metabolic rates of glucose with glasgow coma scale after traumatic brain injury.

UNLABELLED: After traumatic brain injury (TBI), subcortical white matter damage may induce a functional disconnection leading to a dissociation of regional cerebral metabolic rate of glucose (CMRglc) between the cerebral cortex and deeper brain regions. Therefore, thalamic and brain stem CMRglc may have a closer correlation than does the cerebral cortex with depth of coma after TBI. METHODS: Eleven adult healthy volunteers and 23 adult patients with TBI (median initial Glasgow Coma Scale score [GCSini], 8) underwent (18)F-FDG PET within 5 d after injury. The CMRglc of cortical areas (remote from hemorrhagic lesions), striatum, thalamus, brain stem, cerebellar cortex, and whole brain was compared with severity of injury and the level of consciousness evaluated using GCSini and the Glasgow Coma Scale score at the time of PET (GCSpet). RESULTS: The regional CMRglc of the brain stem is relatively unaffected by the TBI. Compared with healthy volunteers, TBI patients exhibited significantly depressed CMRglc in the striatum (3.9 +/- 1.3 vs. 5.1 +/- 0.9 mg/100 g/min, P < 0.05) and thalamus (3.1 +/- 1.0 vs. 4.3 +/- 0.9 mg/100 g/min, P < 0.05). CMRglc levels were not statistically lower in the cerebellum (2.9 +/- 0.8 vs. 3.5 +/- 0.8 mg/100 g/min, P = NS) and brain stem (2.5 +/- 0.5 vs. 2.6 +/- 0.5 mg/100 g/min, P = NS). However, compared between comatose and noncomatose patients, CMRglc values in the thalamus (2.7 +/- 0.7 vs. 3.6 +/- 1.2 mg/100 g/min, P < 0.05), brain stem (2.2 +/- 0.4 vs. 2.8 +/- 0.5 mg/100 g/min, P < 0.01), and cerebellar cortex (2.6 +/- 0.5 vs. 3.4 +/- 1.0 mg/100 g/min, P < 0.05) were significantly lower in comatose patients. When individual values of regional CMRglc were plotted against posttraumatic level of consciousness, CMRglc values for the thalamus, brain stem, and cerebellum significantly correlated with the level of consciousness at the time of PET (r = 0.58, P < 0.01; r = 0.66, P < 0.01; r = 0.64, P < 0.01, respectively). CT or MRI findings were normal for the analyzed structures except for 3 patients with diffuse axonal injury of the brain stem. The presence of shear injury was associated with poor GCSini (P < 0.05.) but was not related to GCSpet and brain stem CMRglc. CONCLUSION: A PET investigation using (18)F FDG demonstrated a significant difference in glucose metabolism in the thalamus, brain stem, and cerebellum between comatose and noncomatose patients acutely after TBI. The metabolic rate of glucose in these regions significantly correlated with the level of consciousness at the time of PET.

Adolescent↗

PubMed2002

Genes preferentially induced by depolarization after concussive brain injury: effects of age and injury severity.

Fluid percussion (FP) brain injury leads to immediate indiscriminate depolarization and massive potassium efflux from neurons. Using Northern blotting, we examined the post-FP expression of primary response/immediate early genes previously described as induced by depolarization in brain. RNA from ipsilateral and contralateral hippocampus was harvested from immature and adult rats 1 h following mild, moderate, or severe lateral fluid percussion injury and compared against age-matched sham animals. C-fos gene expression was used as a positive control and showed marked induction in both pups (6-25-fold with increasing severity) and adults (9.7-17.1-fold). Kinase-induced-by-depolarization-1 (KID-1) and salt-inducible kinase (SIK) gene expression was increased in adult (KID-1 1.5-1.6-fold; SIK 1.3-3.9-fold) but not developing rats. NGFI-b RNA was elevated after injury in both ages (pups 1.8-6.1-fold; adults 3.5-5-fold), in a pattern similar to that seen for c-fos. Secretogranin I (sec I) demonstrated no significant changes. Synaptotagmin IV (syt IV) was induced only following severe injury in the immature rats (1.4-fold). Our results reveal specific severity- and age-dependent patterns of hippocampal immediate early gene expression for these depolarization-induced genes following traumatic brain injury. Differential expression of these genes may be an important determinant of the distinct molecular responses of the brain to varying severities of trauma experienced at different ages.

Age Factors↗

PubMed2002

Subarachnoid hemorrhage induces dynamic changes in regional cerebral metabolism in rats.

Following a subarachnoid hemorrhage (SAH), adult rats exhibit dynamic regional changes in cerebral glucose metabolism characterized by an increase in metabolic rates and a subsequent upregulation of cytochrome oxidase (CO). We evaluated both local cerebral metabolic rates for glucose (ICMRglc: (mol/100 g/min) and CO in 23 brain regions of interest (ROI). Sham animals underwent anesthesia and superficial surgery; saline-controls received an injection of 0.9% saline into the cisterna magna; and SAH rats received an injection of autologous blood into the cisterna magna. This blood, measured by albumin labeled with radioactive carbon 14, distributed throughout the brain but predominated ventrally. After experimental animals were sacrificed at day 0 (3 h), 1, 3, and 7 days postinjection, ROI were analyzed using [14C]2-deoxy-D-glucose autoradiography and CO histochemistry. ICMRglc in SAH rats increased in many regions (ranging from 0.7% to 32.2% above sham levels). Cytochrome oxidase also increased from 1% to 9% above sham levels, peaking on day 3. Conversely, saline-controls exhibited prolonged depression of ICMRglc (ranging from 11% to 35% below sham levels) and CO (ranging from 4% to 11% below sham levels) from day 0 through day 7. All saline-control ROI for all time points showed this metabolic depression, and between 91% and 95% of saline-control ROI presented lower CO levels as compared to sham. Overall, ICMRglc and CO levels were greater in SAH than in saline-control ROI. However, when considering the influence of subarachnoid blood on metabolic changes in SAH animals, both CO and 2DG levels did not correlate well with the amount of 14C-albumin binding. While previous studies have measured both metabolic rates of glucose and CO soon after SAH, this is the first to simultaneously conduct these measurements in the same SAH rat model.

Animals↗

PubMed2002

Clinical trials in head injury.

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate significant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.

Brain Injuries↗

PubMed2002

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.

Alcohol Drinking↗

PubMed2002

Early and persistent impaired percent alpha variability on continuous electroencephalography monitoring as predictive of poor outcome after traumatic brain injury.

OBJECT: Early prediction of outcomes in patients after they suffer traumatic brain injury (TBI) is often nonspecific and based on initial imaging and clinical findings alone, without direct physiological testing. Improved outcome prediction is desirable for ethical, social, and financial reasons. The goal of this study was to determine the usefulness of continuous electroencephalography (EEG) monitoring in determining prognosis early after TBI, while the patient is in the intensive care unit. METHODS: The authors hypothesized that the reduced percentage of alpha variability (PAV) in continuous EEG tracings indicates a poor prognosis. Prospective continuous EEG monitoring was performed in 89 consecutive patients with moderate to severe TBI (Glasgow Coma Scale [GCS] Scores 3-12) from 0 to 10 days after injury. The PAV was calculated daily, and the time course and trends of the PAV were analyzed in comparison with the patient's Glasgow Outcome Scale (GOS) score at the time of discharge. In patients with GCS scores of 8 or lower, a PAV value of 0.1 or lower is highly predictive of a poor outcome or death (positive predictive value 86%). The determinant PAV value was obtained by Day 3 after injury. Persistent PAV values of 0.1 or lower over several days or worsening of the PAV to a value of 0.1 or lower indicated a high likelihood of poor outcome (GOS Scores 1 and 2). In comparison with the combination of traditional initial clinical indicators of outcome (GCS score, pupillary response to light, patient age, results of computerized tomography scanning, and early hypotension or hypoxemia), the early PAV value during the initial 3 days after injury independently improved prognostic ability (p < 0.01). CONCLUSIONS: Continuous EEG monitoring performed with particular attention paid to the PAV is a sensitive and specific method of prognosis that can indicate outcomes in patients with moderate to severe TBI within 3 days postinjury.

Adult↗

PubMed2002

Efficacy of hyperventilation, blood pressure elevation, and metabolic suppression therapy in controlling intracranial pressure after head injury.

OBJECT: Hyperventilation therapy, blood pressure augmentation, and metabolic suppression therapy are often used to reduce intracranial pressure (ICP) and improve cerebral perfusion pressure (CPP) in intubated head-injured patients. In this study, as part of routine vasoreactivity testing, these three therapies were assessed in their effectiveness in reducing ICP. METHODS: Thirty-three patients with a mean age of 33 +/- 13 years and a median Glasgow Coma Scale (GCS) score of 7 underwent a total of 70 vasoreactivity testing sessions from postinjury Days 0 to 13. After an initial 133Xe cerebral blood flow (CBF) assessment, transcranial Doppler ultrasonography recordings of the middle cerebral arteries were obtained to assess blood flow velocity changes resulting from transient hyperventilation (57 studies in 27 patients), phenylephrine-induced hypertension (55 studies in 26 patients), and propofol-induced metabolic suppression (43 studies in 21 patients). Changes in ICP, mean arterial blood pressure (MABP), CPP, PaCO2, and jugular venous oxygen saturation (SjvO2) were recorded. With hyperventilation therapy, patients experienced a mean decrease in PaCO2 from 35 +/- 5 to 27 +/- 5 mm Hg and in ICP from 20 +/- 11 to 13 +/- 8 mm Hg (p < 0.001). In no patient who underwent hyperventilation therapy did SjvO2 fall below 55%. With induced hypertension, MABP in patients increased by 14 +/- 5 mm Hg and ICP increased from 16 +/- 9 to 19 +/- 9 mm Hg (p = 0.001). With the aid of metabolic suppression, MABP remained stable and ICP decreased from 20 +/- 10 to 16 +/- 11 mm Hg (p < 0.001). A decrease in ICP of more than 20% below the baseline value was observed in 77.2, 5.5, and 48.8% of hyperventilation, induced-hypertension, and metabolic suppression tests, respectively (p < 0.001 for all comparisons). Predictors of an effective reduction in ICP included a high PaCO2 for hyperventilation, a high study GCS score for induced hypertension, and a high PaCO2 and a high CBF for metabolic suppression. CONCLUSIONS: Of the three modalities tested to reduce ICP, hyperventilation therapy was the most consistently effective, metabolic suppression therapy was variably effective, and induced hypertension was generally ineffective and in some instances significantly raised ICP. The results of this study suggest that hyperventilation may be used more aggressively to control ICP in head-injured patients, provided it is performed in conjunction with monitoring of SjvO2.

Adult↗

PubMedDate not supplied

Measurement of the global lumped constant for 2-deoxy-2-[18F]fluoro-D-glucose in normal human brain using [15O]water and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography imaging. A method with validation based on multiple methodologies.

PURPOSE: This study aims to determine a lumped constant (LC) value that can be applied to the 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography (FDG-PET) study to yield a physiological value of cerebral metabolic rate of glucose (CMR(glc)) in normal brain. PROCEDURES: We developed a more robust method for determining the global FDG LC. Dynamic FDG and H(2)(15)O PET studied were acquired in 18 normal subjects. Arterial-venous difference of blood glucose level was measured. RESULTS: A global LC of 0.65 +/- 0.15 was obtained if a 3-microparameter FDG model (k*(4)=0)was assumed. Assumption of a 4-microparameter FDG model (k*(4) not equal 0) in analyzing the FDG data resulted in a higher LC value of 0.81 +/- 0.18. CONCLUSION: The value of LC used for quantitating CMR(glc) should match the assumption inherent to the method of data analysis. The LC results in this study agree well with recent findings in the literature.

Adult↗