Sarah Yang Zhang

Introduction: The spontaneous recanalization of an occluded extracranial internal carotid artery (ICA) is thought to be an uncommon etiology of ischemic stroke. However, a growing number of reports describe this phenomenon. We sought to perform a scoping review of the literature to assess the prevalence of spontaneous ICA recanalization and its timing in relation to occlusion, and any patterns in imaging and treatment. Methods: MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Web of Science were searched from inception to March 2024 for studies that included adults with spontaneous recanalization or transient occlusion of the extracranial internal carotid artery. Two investigators independently screened the studies and extracted data around recanalization proportion, timepoints, imaging, and treatment. These results were described qualitatively, and descriptive statistics were calculated where appropriate. Results: Of 2807 studies screened, 53 met inclusion criteria, of which 17 were cohort studies and 36 were case studies, including a total of 818 patients. The proportion of recanalization was reported in 17 cohort studies for a median of 21.2% (IQR 9.2–37.5%). Amongst the studies which reported recanalization, 46.7% of those within the cohort studies recanalized within 6 months, whereas case studies reported that 66.7% of recanalizations occurred in that same timeframe. When reported, antiplatelet treatment was the most common medical treatment pre- and post-recanalization. Doppler imaging was used to identify recanalization in 67.9% of studies, and angiography was used in 54.7%. Twenty-one studies reported a revascularization procedure following spontaneous recanalization. Conclusions: Spontaneous recanalization of an occluded extracranial carotid artery may occur, and possibly within 6 months after documented occlusion. However, clear data are lacking regarding a standard approach to imaging or treatment of patients with occluded carotid arteries.

Introduction Although previously thought to be a rare occurrence, spontaneous recanalisation is not uncommon, with a growing number of reports describing this phenomenon. However, the frequency, time course and mechanism of spontaneous recanalisation remain unknown. A better characterisation of these events is essential to ensuring adequate identification and proper future trial design for treatment. Objective To describe the current body of literature around spontaneous recanalisation following internal carotid occlusion. Methods and analysis With the assistance of an information specialist, we will search MEDLINE, Embase, Cochrane Central Register for Controlled Trials and Web of Science for studies of adults with spontaneous recanalisation or transient occlusion of the internal carotid artery. Two reviewers will independently collect data on included studies pertaining to publication data, study population information, timepoints of initial presentation, recanalisation and subsequent follow-up. Ethics and dissemination Primary data will not be collected; therefore, formal ethics is not required. The findings of this study will be disseminated through peer-reviewed publications and presentations at academic conferences.

Introduction: Spontaneous recanalization of an occluded internal carotid artery (ICA) is thought to be unlikely. However, there has been a growing number of reports describing this phenomenon. Despite this, the frequency, time course, and mechanism of spontaneous recanalization remain unknown. In this paper, we describe a patient with a symptomatic recanalization of an occluded left ICA. Case Report: A 70-year-old woman presented with transient speech arrest and right upper extremity weakness related to an occluded ICA. After 3 days, her weakness and aphasia reappeared and worsened transiently. A repeat computed tomography angiography revealed recanalization of the occluded ICA, as well as new ischemic changes in the previously hypoperfused left insular region. This finding changed the management from medical management to revascularization with a stent, after which the patient was discharged home with acetylsalicylic acid and clopidogrel. Conclusions: Although previously thought to be a rare occurrence, spontaneous recanalization is not uncommon. Further research into this phenomenon as proper identification and characterization of this phenomenon can influence follow-up and management.

There may be the potential to improve stroke recovery with mesenchymal stem cells (MSCs); however, questions about the efficacy and safety of this treatment remain. To address these issues and inform future studies, we performed a preclinical and clinical systematic review of MSC therapy for subacute and chronic ischemic stroke. MEDLINE, Embase, the Cochrane Register of Controlled Trials, and PubMed were searched. For the clinical review, interventional and observational studies of MSC therapy in ischemic stroke patients were included. For the preclinical review, interventional studies of MSC therapy using in vivo animal models of subacute or chronic stroke were included. Measures of safety and efficacy were assessed. Eleven clinical and 76 preclinical studies were included. Preclinically, MSC therapy was associated with significant benefits for multiple measures of motor and neurological function. Clinically, MSC therapy appeared to be safe, with no increase in adverse events reported (with the exception of self-limited fever immediately following injection). However, the efficacy of treatment was less apparent, with significant heterogeneity in both study design and effect size being observed. Additionally, in the only randomized phase II study to date, efficacy of MSC therapy was not observed. Preclinically, MSC therapy demonstrated considerable efficacy. Although MSC therapy demonstrated safety in the clinical setting, efficacy has yet to be determined. Future studies will need to address the discordance in the continuity of evidence as MSC therapy has been translated from “bench-to-bedside”.

Damaraland mole rats (DMRs, Fukomys damarensis) are a eusocial fossorial species that spend the majority of their life in densely populated underground burrows, in which they likely experience intermittent periods of elevated CO2 (i.e. hypercapnia). The primary physiological response to hypercapnia in most mammals is to increase depth and rate of breathing (i.e. hyperpnoea), but this response is often blunted in species that inhabit hypercapnic environments. In their natural habitat, DMRs putatively experience a gaseous environment ranging from normocapnic (0.1% CO2) to hypercapnic (6.0% CO2) conditions (Roper et al. 2001 J. Zool.254, 101–107). As such, we hypothesized that DMRs would exhibit blunted hypercapnic ventilatory and metabolic responses, relative to those of non-fossorial rodent species. To test this hypothesis, we exposed awake, freely behaving DMRs to normoxic normocapnia (21% O2, 0% CO2, balance N2) or graded normoxic hypercapnia (21% O2, 0, 2, 5, 7 and 10% CO2, balance N2), and measured ventilation and metabolism using whole-body plethysmography and indirect calorimetry, respectively. We found that ventilation and metabolism were unchanged during prolonged normocapnia, whereas during graded hypercapnia, ventilation was elevated at 2% CO2 and above. As a result, O2 extraction efficiency at the lungs decreased with increasing hyperpnoea. Conversely, metabolic rate did not increase until 10% CO2, presumably due to the metabolic cost of hyperpnoea. Taken together, our results suggest that despite their fossorial lifestyle, DMRs do not exhibit adaptations in their ventilatory or metabolic responses to environmental hypercapnia.

Damaraland and naked mole rats are the only eusocial mammalian species and live in densely populated, poorly ventilated underground burrows, within which they likely experience intermittent periods of hypoxia. Naked mole rats are the most hypoxia-tolerant mammal and do not exhibit a hypoxic ventilatory response to acute or chronic hypoxia but instead rely upon a robust hypoxic metabolic response to tolerate reduced environmental O₂. Conversely, physiological responses to hypoxia have not been explored in Damaraland mole rats but given their social and environmental similarities to naked mole rats, we hypothesized that they would exhibit similar physiological responses to hypoxia. We predicted that they would rely primarily on metabolic rate depression when O₂ is limited and would not exhibit ventilatory responses to acute or chronic hypoxia. To test this hypothesis, we exposed Damaraland mole rats to normoxia (21% O₂) or progressive hypoxia (12–5% O₂), before and after acclimation to chronic hypoxia (8–10 days at 10% O₂), and measured ventilatory, metabolic, and thermoregulatory responses. We found that ventilation increased up to fourfold with progressive hypoxia and body temperature decreased ~ 2 °C; however, a hypoxic metabolic response was absent. Following acclimation to chronic hypoxia, ventilation in 21% O₂ was ~ twofold higher than in control animals, indicating the occurrence of ventilatory plasticity to hypoxia, and body temperature and metabolic rate were elevated. However, ventilation was not further augmented in acute hypoxia following acclimation to chronic hypoxia, indicating that ventilatory acclimatization to hypoxia was atypical of other mammals. These results refute our hypothesis and we conclude that Damaraland and naked mole rats have divergent physiological responses to hypoxia.

While the mechanisms underlying the control of cutaneous vasodilation have been extensively studied, there remains a lack of understanding of the different factors that may modulate cutaneous perfusion during an exercise-induced heat stress. We evaluated the hypothesis that heat shock protein 90 (HSP90) contributes to the heat loss response of cutaneous vasodilation via the activation of nitric oxide synthase (NOS) during exercise in the heat. In 11 young males (25 ± 5 yr), cutaneous vascular conductance (CVC) was measured at four forearm skin sites that were continuously treated with 1) lactated Ringer solution (control), 2) NOS inhibition with 10 mM N^G-nitro-l-arginine methyl ester (l-NAME), 3) HSP90 inhibition with 178 μM geldanamycin, or 4) a combination of 10 mM l-NAME and 178 μM geldanamycin. Participants rested in a moderate heat stress (35°C) condition for 70 min. Thereafter, they performed a 50-min bout of moderate-intensity cycling (~52% V̇o_2peak) followed by a 30-min recovery period. We showed that NOS inhibition attenuated CVC (~40–50%) relative to the control site during pre- and postexercise rest in the heat ( P ≤ 0.05); however, no effect of HSP90 inhibition was observed ( P > 0.05). During exercise, we observed an attenuation of CVC with the separate inhibition of NOS (~40–50%) and HSP90 (~15–20%) compared with control (both P ≤ 0.05). However, the effect of HSP90 inhibition was absent in the presence of the coinhibition of NOS ( P > 0.05). We show that HSP90 contributes to cutaneous vasodilation in young men exposed to the heat albeit during exercise only. We also show that the HSP90 contribution is due to NOS-dependent mechanisms. NEW & NOTEWORTHY We show that heat shock protein 90 functionally contributes to the heat loss response of cutaneous vasodilation during exercise in the heat, and this response is mediated through the activation of nitric oxide synthase. Therefore, interventions that may activate heat shock protein 90 may facilitate an increase in heat dissipation through an augmentation of cutaneous perfusion. In turn, this may attenuate or reduce the increase in core temperature and therefore the level of heat strain.

New Findings: What is the central question of this study? Protease‐activated receptor 2 (PAR2) is located in the endothelial cells of skin vessels and eccrine sweat glands. However, a functional role of PAR2 in the control of cutaneous blood flow and sweating remains to be assessed in humans in vivo. What is the main finding and its importance? Our results demonstrate that in normothermic resting humans in vivo, activation of PAR2 elicits cutaneous vasodilatation partly through nitric oxide synthase‐dependent mechanisms, but does not mediate sweating. These results provide important new insights into the physiological significance of PAR2 in human skin. Protease‐activated receptor 2 (PAR2) is present in human skin, including keratinocytes, endothelial cells of skin microvessels and eccrine sweat glands. However, whether PAR2 contributes functionally to the regulation of cutaneous blood flow and sweating remains entirely unclear in humans in vivo. We hypothesized that activation of PAR2 directly stimulates cutaneous vasodilatation and sweating via actions of nitric oxide synthase (NOS) and cyclo‐oxygenase (COX). In 12 physically active young men (29 ± 5 years old), cutaneous vascular conductance (CVC) and sweat rate were measured at four intradermal microdialysis forearm skin sites that were treated with the following: (i) lactated Ringer's solution (control); (ii) 10 mm N^G‐nitro‐l‐arginine (NOS inhibitor); (iii) 10 mm ketorolac (COX inhibitor); or (iv) a combination of both inhibitors. At all sites, a PAR2 agonist (SLIGKV‐NH₂) was co‐administered in a dose‐dependent fashion (0.06, 0.18, 0.55, 1.66 and 5 mm, each for 25 min). The highest dose of SLIGKV‐NH₂ (5 mm) increased CVC from baseline at the control site (P ≤ 0.05). This increase in CVC associated with PAR2 activation was attenuated by NOS inhibition regardless of the presence or absence of simultaneous COX inhibition (both P ≤ 0.05). However, COX inhibition alone did not affect the PAR2‐mediated increase in CVC (P > 0.05). No increase in sweat rate was measured at any administered dose of SLIGKV‐NH₂ (all P > 0.05). We show that in normothermic resting humans in vivo, PAR2 activation does not increase sweat rate, whereas it does modulate cutaneous vasodilatation through NOS‐dependent mechanisms.

We recently showed that intradermal administration of endothelin-1 diminished endothelium-dependent and -independent cutaneous vasodilation. We evaluated the hypothesis that Rho kinase may be a mediator of this response. We also sought to evaluate if endothelin-1 increases sweating. In 12 adults (25 ± 6 yr), we measured cutaneous vascular conductance (CVC) and sweating during 1) endothelium-dependent vasodilation induced via administration of incremental doses of methacholine (0.25, 5, 100, and 2,000 mM each for 25 min) and 2) endothelium-independent vasodilation induced via administration of 50 mM sodium nitroprusside (20–25 min). Responses were evaluated at four skin sites treated with either 1) lactated Ringer solution (Control), 2) 400 nM endothelin-1, 3) 3 mM HA-1077 (Rho kinase inhibitor), or 4) endothelin-1+HA-1077. Pharmacological agents were intradermally administered via microdialysis. Relative to the Control site, endothelin-1 attenuated endothelium-dependent vasodilation (CVC at 2,000 mM methacholine, 80 ± 10 vs. 56 ± 15%max, P < 0.01); however, this response was not detected when the Rho kinase inhibitor was simultaneously administered (CVC at 2,000 mM methacholine for Rho kinase inhibitor vs. endothelin-1 + Rho kinase inhibitor sites: 73 ± 9 vs. 72 ± 11%max, P > 0.05). Endothelium-independent vasodilation was attenuated by endothelin-1 compared with the Control site (CVC, 92 ± 13 vs. 70 ± 14%max, P < 0.01). However, in the presence of Rho kinase inhibition, endothelin-1 did not affect endothelium-independent vasodilation (CVC at Rho kinase inhibitor vs. endothelin-1+Rho kinase inhibitor sites: 81 ± 9 vs. 86 ± 10%max, P > 0.05). There was no between-site difference in sweating throughout (P > 0.05). We show that in young adults, Rho kinase is an important mediator of the endothelin-1-mediated attenuation of endothelium-dependent and -independent cutaneous vasodilation, and that endothelin-1 does not increase sweating.