Glucose Control and Risk of Symptomatic Intracerebral Hemorrhage Following Thrombolysis for Acute Ischemic Stroke: A SHINE Trial Analysis.

BACKGROUND AND OBJECTIVES: Baseline hyperglycemia is associated with worse outcomes in acute ischemic stroke (AIS), including higher risk of symptomatic intracerebral hemorrhage (sICH) following treatment with thrombolysis. Prospective data are lacking to inform management of post-thrombolysis hyperglycemia. In a prespecified analysis from the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial of hyperglycemic stroke management, we hypothesized that post-thrombolysis hyperglycemia is associated with a higher risk of sICH. METHODS: Hyperglycemic AIS patients <12 hours onset were randomized to intensive insulin (target range 80-130 mg/dL) vs standard sliding scale (80-179 mg/dL) over a 72-hour period, stratified by treatment with thrombolysis. Three board-certified vascular neurologists independently reviewed all sICH events occurring within 7 days, defined by neurologic deterioration of ≥4 points on the NIH Stroke Scale (NIHSS). Associations between blood glucose control and sICH were analyzed using logistic regression accounting for NIHSS, age, systolic blood pressure, onset to thrombolysis time, and endovascular therapy (odds ratios [OR], 95% CI). Additional analysis compared patients in a high-risk group (age older than 60 years and NIHSS ≥8) vs all others. Categorical variables and outcomes were compared using the χ2 test (p < 0.05). RESULTS: Of 1151 SHINE participants, 725 (63%) received thrombolysis (median age 65 years, 46% women, 29% Black, 18% Hispanic). The median NIHSS was 7, baseline blood glucose was 187 (interquartile range 153-247) mg/dL, and 80% were diabetic. Onset to thrombolysis time was 2.2 hours (1.6-2.9). Post-thrombolysis sICH occurred in 3.6% (3.0% intensive vs 4.3% standard glucose control, OR 1.10, 0.60-2.01, p = 0.697). In the first 12 hours, every 10 mg/dL higher glucose increased the odds of sICH (OR 1.08, 1.03-1.14, p = 0.004), and a greater proportion of glucose measures in the normal range (80-130 mg/dL) decreased the odds of sICH (0.89, 0.80-0.99, p = 0.030). These associations were strongest in the high-risk group (age older than 60 years and NIHSS ≥8). DISCUSSION: In this prespecified analysis from the SHINE trial, intensive insulin therapy was not associated with a reduced risk of post-thrombolysis sICH compared with standard sliding scale. However, early post-thrombolysis hyperglycemia was associated with a higher risk of sICH overall, particularly in older patients with more severe strokes. Further prospective research is warranted to address the risk of sICH in hyperglycemic stroke patients undergoing endovascular therapy. TRIAL REGISTRATION INFORMATION: NCT01369069.

Paradoxical Cerebral Air Embolism after Cardiac Ablation in Williams-Beuren Syndrome: A Clinico-Pathological Correlation.

Non-traumatic neurological deterioration is a medical emergency that may arise from diverse causes, to include cerebral infarction or intracranial hemorrhage, meningoencephalitis, seizure, hypoxic-ischemic or toxic/metabolic encephalopathy, poisoning, or drug intoxication. We describe the abrupt onset of neurological deterioration in a 53-year-old man with Williams-Beuren syndrome, a sporadically occurring genetic disorder caused by chromosomal microdeletion at 7q11.23. The clinical phenotype of Williams-Beuren syndrome is suggested by distinctive elfin facies, limited intellect, unique personality features, growth abnormalities, and endocrinopathies. The causative microdeletion of chromosomal material will frequently involve loss of the elastin gene, ELN, with resulting arteriopathy, supravalvular aortic stenosis, non-ischemic cardiopathy, and atrial fibrillation. Our patient sustained acute neurological decline within one month after undergoing a cardiac ablative procedure to convert atrial fibrillation to sinus rhythm. We present our findings in the setting of a clinico-pathological correlation, in which we reveal the cause of the abrupt neurological deterioration and discuss how our patient was affected by an uncommon stroke disorder.

Thrombectomy for Treatment of Acute Stroke in the COVID-19 Pandemic.

This commentary will focus on the role of thrombectomy for the treatment of embolic stroke during the 2019 novel coronavirus disease (COVID-19). We will begin with review of recently promulgated guidelines for use of thrombectomy in COVID-19-associated stroke. We will then survey the reported experience of thrombectomy applied to treatment of large-vessel occlusion (LVO) stroke in COVID-19. We will conclude by discussing unusual challenges confronted by neuro-interventionalists seeking to perform thrombectomy in COVID-19 patients with acute LVO stroke.

Nerve Stimulation Enhances Task-Oriented Training for Moderate-to-Severe Hemiparesis 3-12 Months After Stroke: A Randomized Trial.

OBJECTIVE: The aim of the study was to determine whether somatosensory stimulation affects outcomes of motor training for moderate-to-severe upper limb hemiparesis less than 12 mos before stroke. DESIGN: Fifty-five adults participated in 18 intervention sessions pairing 2 hours of active (n = 33) or sham (n = 22) somatosensory stimulation with 4 hours of intensive task-oriented motor training. Wolf Motor Function Test, Action Research Arm Test, Fugl-Meyer Assessment, and Stroke Impact Scale were administered at baseline, postintervention, and 1- and 4-mo follow-up. RESULTS: Statistically significant between-groups differences favored the active condition on Wolf Motor Function Test at post (P = 0.04) and Action Research Arm Test at post (P = 0.02), 1 mo (P = 0.01), and 4 mos (P = 0.01) but favored the sham condition on Stroke Impact Scale at 1 mo (P = 0.03). There were no significant between-groups differences on Fugl-Meyer Assessment. CONCLUSIONS: Somatosensory stimulation can improve objective outcomes of motor training for moderate-to-severe hemiparesis less than 12 mos after stroke, although it needs to be determined whether the magnitude of between-groups differences in this study is clinically relevant. Future studies should investigate the intervention's impact on disability and functional recovery for this population as well as neurophysiological mechanisms underlying intervention effects.

The TNFα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss.

The cytokine, tumor necrosis factor α (TNFα), is a key regulator of neuroinflammation linked to numerous neurodegenerative conditions and diseases. The present study used transgenic rats that overexpress a murine TNFα gene, under the control of its own promoter, to investigate the impact of chronically elevated TNFα on hippocampal synaptic function. Neuronal viability and cognitive recovery in TNFα Tg rats were also determined following an ischemic insult arising from reversible middle cerebral artery occlusion (MCAO). Basal CA3-CA1 synaptic strength, recorded in acute brain slices, was not significantly different between eight-week-old TNFα Tg rats and non-Tg rats. In contrast, slices from TNFα Tg rats showed significantly greater levels of long-term potentiation (LTP) in response to 100 Hz stimulation, suggesting that synaptic networks may be hyperexcitable in the context of elevated TNFα. Cognitive and motor deficits (assessed on the Morris Water Maze and Rotarod task, respectively) were present in TNFα Tg rats in the absence of significant differences in the loss of cortical and hippocampal neurons. TNF overexpression exacerbated MCAO-dependent deficits on the rotarod, but ameliorated cortical neuron loss in response to MCAO.

C-reactive protein as a prognostic marker after lacunar stroke: levels of inflammatory markers in the treatment of stroke study.

BACKGROUND AND PURPOSE: Inflammatory biomarkers predict incident and recurrent cardiac events, but their relationship to stroke prognosis is uncertain. We hypothesized that high-sensitivity C-reactive protein (hsCRP) predicts recurrent ischemic stroke after recent lacunar stroke. METHODS: Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, prospective ancillary biomarker study nested within Secondary Prevention of Small Subcortical Strokes (SPS3), a phase III trial in patients with recent lacunar stroke. Patients were assigned in factorial design to aspirin versus aspirin plus clopidogrel, and higher versus lower blood pressure targets. Patients had blood samples collected at enrollment and hsCRP measured using nephelometry at a central laboratory. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for recurrence risks before and after adjusting for demographics, comorbidities, and statin use. RESULTS: Among 1244 patients with lacunar stroke (mean age, 63.3±10.8 years), median hsCRP was 2.16 mg/L. There were 83 recurrent ischemic strokes (including 45 lacunes) and 115 major vascular events (stroke, myocardial infarction, and vascular death). Compared with the bottom quartile, those in the top quartile (hsCRP>4.86 mg/L) were at increased risk of recurrent ischemic stroke (unadjusted HR, 2.54; 95% CI, 1.30-4.96), even after adjusting for demographics and risk factors (adjusted HR, 2.32; 95% CI, 1.15-4.68). hsCRP predicted increased risk of major vascular events (top quartile adjusted HR, 2.04; 95% CI, 1.14-3.67). There was no interaction with randomized antiplatelet treatment. CONCLUSIONS: Among recent lacunar stroke patients, hsCRP levels predict the risk of recurrent strokes and other vascular events. hsCRP did not predict the response to dual antiplatelets. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Emotion recognition and marital satisfaction in stroke.

Deficits in the comprehension of facial and prosodic expressions are commonly associated with right hemisphere stroke. However, little is known regarding the impact of these disorders on social relations. We examined facial and prosodic processing, mood, and marital satisfaction in 12 right hemisphere damaged (RHD) stroke patients and nine controls. Results revealed significant impairments in the comprehension of facial expressions and prosody among RHD stroke patients. Nonparametric correlations in the RHD group showed significant associations between marital satisfaction and facial affect discrimination and matching, and nonaffective prosody discrimination. We conclude that deficits in the recognition of nonverbal expressions are associated with reduced relationship satisfaction.

Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke.

BACKGROUND AND PURPOSE: Plasma matrix metalloproteinase-9 levels predict posttissue plasminogen activator (tPA) hemorrhage. METHODS: The authors investigated the effect of minocycline on plasma matrix metalloproteinase-9 in acute ischemic stroke in the Minocycline to Improve Neurological Outcome in Stroke (MINOS) trial and a comparison group. RESULTS: Matrix metalloproteinase-9 level decreased at 72 hours compared with baseline in MINOS (tPA, P=0.0022; non-tPA, P=0.0066) and was lower than in the non-MINOS comparison group at 24 hours (tPA, P<0.0001; non-tPA, P=0.0019). CONCLUSIONS: Lower plasma matrix metalloproteinase-9 was seen among tPA-treated subjects in the MINOS trial. Combining minocycline with tPA may prevent the adverse consequences of thrombolytic therapy through suppression of matrix metalloproteinase-9 activity.

Focal cerebral ischemia and mitochondrial dysfunction in the TNFα-transgenic rat.

Post-ischemic neurodegeneration may be accelerated by a cytokine-receptor mediated apoptotic pathway, as shown in a transgenic rat overexpressing tumor necrosis factor-alpha (TNFα) in brain. To further investigate the mechanism of ischemic cellular injury in this animal, we tested the hypothesis that increased synthesis of TNFα augments neuronal death by promoting mitochondrial dysfunction, calcium dysregulation, and oxidative stress. Adult male TNFα-transgenic (TNFα-Tg) and non-transgenic (non-Tg) littermates underwent reversible middle cerebral artery occlusion (MCAO) for 1 hour followed by 1 hour of reperfusion. Cortical mitochondria were isolated from injured (ipsilateral) and uninjured (contralateral) hemispheres of ischemic rats or from pooled hemispheres of control animals. ATP synthesis was attenuated in non-ischemic TNFα-Tg rats, demonstrated by reduction of state III and respiratory control ratio, increased production of reactive oxygen species, and earlier formation of the calcium-induced membrane permeability transition pore. After MCAO, mitochondrial dysfunction was augmented more significantly in ischemic TNFα-Tg brain mitochondria than in non-Tg rats. These results show that mitochondrial dysfunction may be caused by increased brain levels of TNFα without physiological stress but will be exacerbated after MCAO. We conclude that ischemic stress and synthesis of inflammatory cytokines synergistically augment mitochondrial dysfunction to promote neuronal death.

Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study.

BACKGROUND AND PURPOSE: Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ischemic stroke. METHODS: Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days. RESULTS: Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65±13.7 years), race (83% white), and sex (47% female) were consistent across the doses. The mean baseline National Institutes of Health Stroke Scale score was 8.5±5.8 and 60% received tissue plasminogen activator. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10-mg/kg dose. No severe hemorrhages occurred in tissue plasminogen activator-treated patients. Pharmacokinetic analysis (n=22) revealed a half-life of approximately 24 hours and linearity of parameters over doses. CONCLUSIONS: Minocycline is safe and well tolerated up to doses of 10 mg/kg intravenously alone and in combination with tissue plasminogen activator. The half-life of minocycline is approximately 24 hours, allowing every 24-hour dosing. Minocycline may be an ideal agent to use with tissue plasminogen activator.

Focal cerebral ischemia in the TNFalpha-transgenic rat.

BACKGROUND: To determine if chronic elevation of the inflammatory cytokine, tumor necrosis factor-alpha (TNFalpha), will affect infarct volume or cortical perfusion after focal cerebral ischemia. METHODS: Transgenic (TNFalpha-Tg) rats overexpressing the murine TNFalpha gene in brain were prepared by injection of mouse DNA into rat oocytes. Brain levels of TNFalpha mRNA and protein were measured and compared between TNFalpha-Tg and non-transgenic (non-Tg) littermates. Mean infarct volume was calculated 24 hours or 7 days after one hour of reversible middle cerebral artery occlusion (MCAO). Cortical perfusion was monitored by laser-Doppler flowmetry (LDF) during MCAO. Cortical vascular density was quantified by stereology. Post-ischemic cell death was assessed by immunohistochemistry and regional measurement of caspase-3 activity or DNA fragmentation. Unpaired t tests or analysis of variance with post hoc tests were used for comparison of group means. RESULTS: In TNFalpha-Tg rat brain, the aggregate mouse and rat TNFalpha mRNA level was fourfold higher than in non-Tg littermates and the corresponding TNFalpha protein level was increased fivefold (p

Telephonic guidance of systemic thrombolysis in acute ischemic stroke: safety outcome in rural hospitals.

OBJECTIVES: To determine the safety of telephonic guidance for use of intravenous recombinant tissue plasminogen activator (IV rtPA) in rural hospitals. PATIENTS AND METHODS: We performed a retrospective survey of 123 consecutive patients treated with IV rtPA for acute ischemic stroke (AIS) in rural hospitals between November 2003 and September 2006 and subsequently transferred to a tertiary medical center. Selection for treatment was performed by a stroke neurologist who conducted a structured telephone interview of the requesting physician. Primary outcome measures included symptomatic intracerebral hemorrhage (ICH) and in-hospital mortality. RESULTS: Elapsed time (ET) from stroke onset to community hospital arrival was 54+/-30 min. ET from stroke onset to tPA bolus was 133+/-37 min. Three patients (2.5%) had symptomatic ICH, 11 (9%) had asymptomatic ICH, 9 patients (7.5%) died. Mean length of stay was 4+/-3 days; 47% were discharged to their homes. Mean ET from stroke onset to rtPA dosage did not differ significantly from the active treatment group of the NINDS rtPA Stroke Study. Prevalence of symptomatic ICH and mortality were lower in our population. CONCLUSION: We conclude that telephonic guidance of rtPA treatment is safe, practical, and effective in overcoming barriers for optimal care of AIS in rural communities.

Hereditary hemorrhagic telangectasia and spinal cord infarct: case report with a review of the neurological complications of HHT.

Hereditary hemorrhagic telangectasia (HHT), also known as Osler-Weber-Rendu disease, is an autosomal dominant vascular dysplasia with high penetrance and variable expressivity. A wide variety of neurological complications have been reported in association with this condition. We report the first case of spinal cord infarction likely due to paradoxical embolization with HHT and review the literature on the neurological complications of this disorder. MEDLINE was employed to identify all published reports of HHT with neurological complications. We identified 44 references with a total of 436 cases of neurological complications of HHT. The most common complication was ischemic stroke and the main etiology for the vascular neurological complications in patients with HHT was pulmonary arteriovenous malformation. HHT should be considered in the differential diagnosis of any patient with cutaneous or mucosal telangiectasia or a history of unexplained epistaxis. HHT is associated with a diverse array of neurological disorders; most commonly ischemic and hemorrhagic stroke, transient ischemic attack, and brain abscess. While myelopathy secondary to arteriovenous malformation with HHT has been previously reported, this is the first instance of spinal cord infarction due to paradoxical embolization in this disorder.

The effects of stroke disability on spousal caregivers.

OBJECTIVE: To examine the effects of unilateral stroke patients' neurobehavioral characteristics on spousal psychosocial function. PARTICIPANTS: The sample consisted of twenty unilateral stroke patients and their spousal caregivers. METHODS: Patient assessments included mood, affect perception, sensorimotor and cognitive function, marital satisfaction, and activities of daily living. Spousal assessments included mood, marital satisfaction, and perceived stress. RESULTS: To avoid the risk of committing a type I error, the alpha-level of 0.05 was corrected for multiple comparisons involving the three outcome measures, resulting in an adjusted alpha of 0.017 (0.05/3). Using this criterion, the negative correlation between patient depression and spousal marital satisfaction was statistically significant (rs=-0.585, p=0.007). There was also a trend for hemispheric side of stroke to correlate with spousal stress (rs=0.498, p=0.025), such that strokes in the left hemisphere were associated with greater stress, whereas strokes in the right hemisphere were associated with less stress. CONCLUSION: These results show that patient depression in particular constitutes a risk factor for marital dissatisfaction in the first few months following stroke. Given that spousal partners provide a large portion of informal support to stroke patients, successful treatment of patient depression may have benefits at the level of the individual, family, and community.

Protective effects of NIM811 in transient focal cerebral ischemia suggest involvement of the mitochondrial permeability transition.

Cerebral ischemia followed by reperfusion activates numerous pathways that lead to cell death. One such pathway involves the release of large quantities of the excitatory amino acid glutamate into the synapse and activation of N-methyl-D-aspartate receptors. This causes an increase in mitochondrial calcium levels ([Ca(2+)](m)) and a production of reactive oxygen species (ROS), both of which may induce the mitochondrial permeability transition (MPT). As a consequence, there is eventual mitochondrial failure culminating in either apoptotic or necrotic cell death. Thus, agents that inhibit MPT might prove useful as therapeutic interventions in cerebral ischemia. In this study, we have investigated the neuroprotective efficacy of the novel compound NIM811. Similar in structure of its parent compound cyclosporin A, NIM811 is a potent inhibitor of the MPT. Unlike cyclosporin A, however, it is essentially void of immunosuppressive actions, allowing the role of MPT to be clarified in ischemia/reperfusion injury. The results of these studies demonstrate that NIM811 provides almost 40% protection in a model of transient focal cerebral ischemia. This was associated with a nearly 10% reduction in mitochondrial reactive species formation and 34% and 38% reduction of cytochrome c release in core and penumbra, respectively. Treatment with NIM811 also increased calcium retention capacity by approximately 20%. Interestingly, NIM811 failed to improve ischemia-induced impairment of bioenergetics. The neuroprotective effects of NIM811 were not due to drug-induced alterations in cerebral perfusion after ischemia. Activation of MPT appears to be an important process in ischemia/reperfusion injury and may be a therapeutic target.

Pharmacokinetics of arundic acid, an astrocyte modulating agent, in acute ischemic stroke.

Arundic acid is an astrocyte modulating agent that improves neurological outcome in experimental acute stroke models. The pharmacokinetics of arundic acid in patients with acute ischemic stroke was investigated in a randomized, double-blind study. Six groups of 8 to 9 patients each received 2, 4, 6, 8, 10, or 12 mg/kg/h of arundic acid for a daily 1-hour infusion until completion of 7 doses. Maximum plasma concentrations of arundic acid increased with increasing dose; however, the systemic exposure was less than dose proportional at higher doses. The mean terminal half-life was approximately 2 to 3 hours. There was no excessive accumulation in plasma. Although systemic exposure in elderly patients was 30% greater than that in younger patients, the plasma concentration returned to nearly or below the limit of quantification prior to next administration. The pharmacokinetics of arundic acid in acute stroke patients assessed in this study were similar to that in healthy adults.

Safety and tolerability of arundic acid in acute ischemic stroke.

Arundic acid (AA; ONO-2506), a novel modulator of astrocyte activation, may improve neuronal survival after stroke. We conducted a multicenter, dose-escalating, randomized, double-blind Phase I trial of AA in acute ischemic stroke. Subjects were randomized to treatment with AA or placebo in sequential dose tiers of 2-12 mg/kg/h (10-16 patients/group) within 24 h of stroke onset. Study drug was infused for 1 h daily over 7 days, and follow-up terminated at 40 days. Neurological and functional outcomes were evaluated through Day 40 as exploratory endpoints. A total of 92 subjects were enrolled with no dose-related pattern of serious adverse events (AEs). Premature terminations caused by AEs occurred in four (8.2%) patients treated with AA and five (11.6%) treated with placebo. Two subjects treated with AA (4.1%) and four given placebo (9.3%) died. Exploratory efficacy analysis showed a trend toward improvement in the change from baseline National Institutes of Health Stroke Scale (NIHSS) in the 8 mg/kg/h AA group on Days 3 (p=0.023 vs. placebo), 7 (p=0.002), 10 (p=0.003), and 40 (p=0.018). A dose of 8 mg/kg/h AA produced a favorable trend in reduction of NIHSS that should be confirmed in a future clinical trial.

Effect of arundic acid on serum S-100beta in ischemic stroke.

We prospectively examined the effect of arundic acid (AA; ONO-2506) on S-100beta, an astrocyte-derived protein, in a phase I acute stroke study. Subjects with acute ischemic stroke were randomized to daily infusion of AA or placebo for 7 days. Serum S-100beta levels were assayed pre-infusion on Days 1-7 and post-infusion on Days 1, 3, and 7, and correlated with National Institutes of Health Stroke Scale (NIHSS). Samples were obtained from 86 subjects (46 AA, 40 placebo). Increase in S-100beta protein level from baseline was less in the AA cohort than in the placebo cohort at 7 (p=0.0471; t-test) and 12 (p=0.0095)-hours post-infusion on Day 3. Baseline NIHSS correlated with maximal S-100beta levels between Days 1 and 3 in the AA (r=0.51; p=0.0003) and placebo (r=0.41; p=0.0084) cohorts and in the pooled aggregate (n=86; r=0.46; p<0.0001). The same correlations were observed between Day 10 NIHSS and Day 1-3 maximum serum S-100beta levels. Treatment with AA was associated with lower serum levels of S-100beta after acute ischemic stroke. Our results showing correlation between S-100beta and NIHSS indicate that this protein is a clinically relevant marker of neurological deficit in acute stroke.

The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia.

Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable 'upstream' targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia-reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function.