Endogenous Protection in Subarachnoid Hemorrhage

Vasospasm-induced delayed cerebral ischemia (DCI) remains a major source of morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). Moreover, cognitive dysfunction is the primary driver of poor long-term outcome in SAH survivors; modeling such deficits preclinically is thus key for mechanistic and translational investigation. We hypothesized that activating innate neurovascular protective mechanisms by conditioning may represent a novel therapeutic approach against SAH-induced DCI, short-term, neurological deficits, and long-term neurocognitive deficits; and, secondarily, that the neurovascular protection it provides is mediated by endothelial nitric oxide synthase (eNOS) and hypoxia-inducible factor 1α (HIF-1α). In Experiment 1, wild-type C57BL/6 mice were subjected to hypoxic preconditioning (PC) or normoxia followed 24 hours later by endovascular-perforation SAH. Neurological function was analyzed daily via sensorimotor scoring; vasospasm was assessed on post-surgery day 2. Nitric oxide availability, eNOS expression, and eNOS activity were also assessed. In a separate experiment, wild-type and eNOS-null mice were subjected to hypoxic PC or normoxia followed by SAH and assessed for vasospasm and neurological deficits. All experiments were performed in a randomized and blinded fashion. PC nearly completely prevented SAH-induced vasospasm and neurological deficits. It also prevented SAH-induced reduction in nitric oxide availability and increased eNOS activity in mice with and without SAH. PC-induced protection against vasospasm and neurological deficits was lost in wild-type mice treated with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester and in eNOS-null mice. From these results, we conclude that endogenous protective mechanisms against vasospasm exist, are powerful, and can be induced by PC. eNOS-derived nitric oxide is a critical mediator of this neurovascular protection. These “proof-of-principle” results suggest that conditioning represents a promising new strategy to mitigate SAH-induced neurovascular dysfunction. In Experiment 2, we sought to determine whether these innate protective mechanisms are induced by a more clinically relevant conditioning paradigm, and whether the cerebrovascular protection extends to non-vasospasm contributors to DCI, microthrombosis and microvessel dysfunction. Adult male mice were subjected to sham surgery, SAH surgery, or SAH and subsequently postconditioned with isoflurane (2% for 1h, starting 1h after surgery). Contributors to DCI – vasospasm of the ipsilateral middle cerebral artery, cortical microthrombosis as assessed by fibrinogen immunohistochemistry, and cerebrovascular vasodilatory function was assessed in pial vessels through a closed cranial window – were measured 3 days post-SAH. Neurological outcome was assessed daily. Moreover, isoflurane-induced changes in HIF-1α-–dependent genes (glucose transporter-1, GLUT1; BNIP3) and HIF-2α-driven erythropoietin (EPO) were assessed via quantitative-PCR. HIF-1α was inhibited either pharmacologically (2-methoxyestradiol, 2ME2) or genetically in endothelial cells (EC-HIF-1-null). All experiments were performed in a randomized and blinded fashion. We found the following: first, isoflurane postconditioning markedly reduced SAH-induced DCI in wild-type mice: vasospasm was attenuated, microthrombosis was significantly reduced, and microvessel function was restored. Neurological deficits were also significantly attenuated. Second, isoflurane modulated HIF-1α- and HIF-2α-dependent genes; these changes were abolished in 2ME2-treated wild-type mice and in EC-HIF-1-null mice (HIF-1α-dependent genes only in the latter). Third, postconditioning-induced protection against vasospasm and neurological deficits was attenuated in 2ME2-treated wild-type mice and in EC-HIF-1-null mice. In Experiment 3, we sought to assess whether the protection afforded by conditioning extended to long-term neurocognitive outcomes. Whereas rat SAH causes long-term deficits in learning and memory, it remains unknown whether similar deficits are seen in the mouse, a species particularly amenable to powerful, targeted genetic manipulation. We thus subjected mice to SAH and assessed long-term cognitive outcome via the Morris water maze (MWM), the most commonly used metric for rodent neurocognition. No significant differences in MWM performance (by either of two protocols) were seen in SAH versus sham mice. Moreover, SAH caused negligible hippocampal CA1 injury. These results undercut the potential of commonly used methods (of SAH induction and assessment of long-term neurocognitive outcome) for use in targeted molecular studies of SAH-induced cognitive deficits in the mouse. From these results, we concluded that endogenous protective mechanisms against DCI exist, are powerful, and can be induced by hypoxic PC or isoflurane postconditioning. This protection depends critically on eNOS-derived nitric oxide and endothelial cell–derived HIF-1α. These studies provide strong evidence that conditioning – especially isoflurane postconditioning – represents a promising new strategy to reduce DCI after SAH. Future studies examining long-term neurocognitive deficits should utilize rat models of SAH

Crystalline optical cavity at 4 K with thermal noise limited instability and ultralow drift

Crystalline optical cavities are the foundation of today's state-of-the-art ultrastable lasers. Building on our previous silicon cavity effort, we now achieve the fundamental thermal noise-limited stability for a 6 cm long silicon cavity cooled to 4 Kelvin, reaching $6.5\times10^{-17}$ from 0.8 to 80 seconds. We also report for the first time a clear linear dependence of the cavity frequency drift on the incident optical power. The lowest fractional frequency drift of $-3\times10^{-19}$/s is attained at a transmitted power of 40 nW, with an extrapolated drift approaching zero in the absence of optical power. These demonstrations provide a promising direction to reach a new performance domain for stable lasers, with stability better than $1\times10^{-17}$ and fractional linear drift below $1\times10^{-19}$/s

Mental health of adolescents:variations by disability and borderline intellectual functioning and disability

Adolescence is a period of elevated stress for many young people, and it is possible that the challenges of adolescence are different for vulnerable groups. We aimed to document the mental health, emotional and behavioral difficulties and suicidal/self-harming behaviors among adolescents with borderline intellectual functioning (BIF) or a disability, compared to those with neither disability nor BIF. Data was drawn from the Longitudinal Study of Australian Children, a nationally representative Australian study. Participants were 2950 adolescents with complete data for Waves 3-6 (years 2008-2014), aged 14-15 years in 2014. Mental health items and self-harming/suicidal thought/behaviors were self-reported. Emotional-behavioral difficulties items came from the Strengths and Difficulties Questionnaire, and were parent-, and adolescent-reported. Results of logistic regression analyses indicate that the emotional-behavioral difficulties of adolescents with either a disability or BIF, was worse than for those with neither disability nor BIF. Additionally, adolescents with a disability reported more symptoms of anxiety and depression, and were more likely to report self-harming/suicidal thoughts and behaviors. Adolescents with BIF or a disability are at higher risk of emotional-behavioral difficulties than those with neither disability nor BIF. There is some evidence that adolescents with a disability are at higher risk of anxiety, self-harming/suicidal thoughts and behaviors than adolescents without a disability

Laser treatment of cutaneous vascular lesions

Methods for treating maladies such as cutaneous vascular lesions. A patient in need of vascular lesion treatment is identified. A hyperosmotic agent is administered to a region adjacent the lesion. Blood flow velocity is slowed within the region using the hyperosmotic agent, and the lesion is exposed to laser radiation.Board of Regents, University of Texas Syste

HIF-1α mediates isoflurane-induced vascular protection in subarachnoid hemorrhage

OBJECTIVE: Outcome after aneurysmal subarachnoid hemorrhage (SAH) depends critically on delayed cerebral ischemia (DCI) – a process driven primarily by vascular events including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction. This study sought to determine the impact of postconditioning – the phenomenon whereby endogenous protection against severe injury is enhanced by subsequent exposure to a mild stressor – on SAH-induced DCI. METHODS: Adult male C57BL/6 mice were subjected to sham, SAH, or SAH plus isoflurane postconditioning. Neurological outcome was assessed daily via sensorimotor scoring. Contributors to DCI including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction were measured 3 days later. Isoflurane-induced changes in hypoxia-inducible factor 1alpha (HIF-1α)-dependent genes were assessed via quantitative polymerase chain reaction. HIF-1α was inhibited pharmacologically via 2-methoxyestradiol (2ME2) or genetically via endothelial cell HIF-1α-null mice (EC-HIF-1α-null). All experiments were performed in a randomized and blinded fashion. RESULTS: Isoflurane postconditioning initiated at clinically relevant time points after SAH significantly reduced cerebral vasospasm, microvessel thrombosis, microvascular dysfunction, and neurological deficits in wild-type (WT) mice. Isoflurane modulated HIF-1α-dependent genes – changes that were abolished in 2ME2-treated WT mice and EC-HIF-1α-null mice. Isoflurane-induced DCI protection was attenuated in 2ME2-treated WT mice and EC-HIF-1α-null mice. INTERPRETATION: Isoflurane postconditioning provides strong HIF-1α-mediated macro- and microvascular protection in SAH, leading to improved neurological outcome. These results implicate cerebral vessels as a key target for the brain protection afforded by isoflurane postconditioning, and HIF-1α as a critical mediator of this vascular protection. They also identify isoflurane postconditioning as a promising novel therapeutic for SAH

Biomechanics associated with tibial stress fracture in runners: A systematic review and meta-analysis

Background Tibial stress fracture (TSF) is an overuse running injury with a long recovery period. While many running studies refer to biomechanical risk factors for TSF, only a few have compared biomechanics in runners with TSF to controls. The aim of this systematic review and meta-analysis was to evaluate biomechanics in runners with TSF compared to controls. Methods Electronic databases PubMed, Web of Science, SPORTDiscus, Scopus, Cochrane, and CINAHL were searched. Risk of bias was assessed and meta-analysis conducted for variables reported in 3 or more studies. Results The search retrieved 359 unique records, but only the 14 that compared runners with TSF to controls were included in the review. Most studies were retrospective, 2 were prospective, and most had a small sample size (5–30 per group). Many variables were not significantly different between groups. Meta-analysis of peak impact, active, and braking ground reaction forces found no significant differences between groups. Individual studies found larger tibial peak anterior tensile stress, peak posterior compressive stress, peak axial acceleration, peak rearfoot eversion and hip adduction in the TSF group. Conclusion Meta-analysis indicated that discrete ground reaction force variables were not statistically significantly different in runners with TSF compared to controls. In individual included studies, many biomechanical variables were not statistically significantly different between groups. However, many were reported by only a single study, and sample sizes were small. We encourage additional studies with larger sample sizes of runners with TSF and controls and adequate statistical power to confirm or refute these findings

Crystalline optical cavity at 4 K with thermal-noise-limited instability and ultralow drift

Crystalline optical cavities are the foundation of today’s state-of-the-art ultrastable lasers. Building on our previous silicon cavity effort, we now achieve the fundamental thermal-noise-limited stability for a 6 cm long silicon cavity cooled to 4 K, reaching 6.5×10−17 from 0.8 s to 80 s. We also report for the first time, to the best of our knowledge, a clear linear dependence of the cavity frequency drift on incident optical power. The lowest fractional frequency drift of −3×10−19/s is attained at a transmitted power of 40 nW, with an extrapolated drift approaching zero in the absence of optical power. These demonstrations provide a promising direction to reach a new performance domain for stable lasers, with stability better than 1×10−17 and fractional linear drift below 1×10−19/s