Sex differences in clot, vessel and tissue characteristics in patients with a large vessel occlusion treated with endovascular thrombectomy.

INTRODUCTION: To improve our understanding of the relatively poor outcome after endovascular treatment (EVT) in women we assessed possible sex differences in baseline neuroimaging characteristics of acute ischemic stroke patients with large anterior vessel occlusion (LVO). PATIENTS AND METHODS: We included all consecutive patients from the MR CLEAN Registry who underwent EVT between 2014 and 2017. On baseline non-contrast CT and CT angiography, we assessed clot location and clot burden score (CBS), vessel characteristics (presence of atherosclerosis, tortuosity, size, and collateral status), and tissue characteristics with the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). Radiological outcome was assessed with the extended thrombolysis in cerebral infarction score (eTICI) and functional outcome with the modified Rankin Scale score (mRS) at 90 days. Sex-differences were assessed with multivariable regression analyses with adjustments for possible confounders. RESULTS: 3180 patients were included (median age 72 years, 48% women). Clots in women were less often located in the intracranial internal carotid artery (ICA) (25%vs 28%, odds ratio (OR) 0.85;95% confidence interval: 0.73-1.00). CBS was similar between sexes (median 6, IQR 4-8). Intracranial (aOR 0.73;95% CI:0.62-0.87) and extracranial (aOR 0.64;95% CI:0.43-0.95) atherosclerosis was less prevalent in women. Vessel tortuosity was more frequent in women in the cervical ICA (aOR 1.89;95% CI:1.39-2.57) and women more often had severe elongation of the aortic arch (aOR 1.38;95% CI:1.00-1.91). ICA radius was smaller in women (2.3vs 2.5 mm, mean difference 0.22;95% CI:0.09-0.35) while M1 radius was essentially equal (1.6vs 1.7 mm, mean difference 0.09;95% CI:-0.02-0.21). Women had better collateral status (⩾50% filling in 62%vs 53% in men, aOR 1.48;95% CI:1.29-1.70). Finally, ASPECT scores were equal between women and men (median 9 in both sexes, IQR 8-10vs 9-10). Reperfusion rates were similar between women and men (acOR 0.94;95% CI:0.83-1.07). However, women less often reached functional independence than men (34%vs 46%, aOR 0.68;95% CI:0.53-0.86). DISCUSSION AND CONCLUSION: On baseline imaging of this Dutch Registry, men and women with LVO mainly differ in vessel characteristics such as atherosclerotic burden, extracranial vessel tortuosity, and collateral status. These sex differences do not result in different reperfusion rates and are, therefore, not likely to explain the worse functional outcome in women after EVT.

Sex differences in outcomes after endovascular treatment in posterior circulation stroke: results from the MR CLEAN Registry.

BACKGROUND: Women with anterior circulation large vessel occlusion (LVO) have been reported to have worse outcomes after endovascular treatment (EVT) than men. Whether these disparities also exist in LVO of the posterior circulation is yet uncertain. We assessed sex differences in clinical, technical, and safety outcomes of EVT in posterior circulation LVO. METHODS: We used data of patients with posterior circulation LVO included in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry (2014-2018). Primary outcome was the modified Rankin Scale (mRS) score at 90 days assessed with multivariable ordinal regression analysis. Secondary outcomes included favorable functional outcome (mRS ≤3), functional independence (mRS ≤2), death within 90 days, National Institutes of Health Stroke Scale (NIHSS) score 24-48 hours postintervention, complications, successful reperfusion (extended Thrombolysis in Cerebral Ischemia 2B-3), and procedure duration analyzed with multivariable logistic and linear regression analyses. RESULTS: We included 264 patients (42% women). Compared with men, women were older (median age 68 vs 63 years), more often had prestroke disability (mRS ≥1: 37% vs 30%), and received intravenous thrombolytics less often (45% vs 56%). Clinical outcomes were similar between sexes (adjusted (common) OR (aOR) 0.82, 95% CI 0.51 to 1.34; favorable functional outcome 50% vs 43%, aOR 1.31, 95% CI 0.77 to 2.25; death 32% vs 29%, aOR 0.98, 95% CI 0.52 to 1.84). In addition, NIHSS score after 24-48 hours (median 7 vs 9), successful reperfusion (77% vs 73%), and complications did not differ between men and women. CONCLUSIONS: Outcomes in women treated with EVT for posterior circulation LVO were similar compared with men despite less favorable baseline characteristics in women. Therefore men and women may benefit equally from EVT.

Immediate Carotid Artery Stenting or Deferred Treatment in Patients With Tandem Carotid Lesions Treated Endovascularly for Acute Ischaemic Stroke.

Fifteen to 20% of patients with an acute ischaemic stroke have a tandem lesion defined by the combination of an intracranial large vessel thrombo-embolic occlusion and a high grade stenosis or occlusion of the ipsilateral internal carotid artery. These patients tend to have worse outcomes than patients with isolated intracranial occlusions, with higher rates of disability and death. The introduction of endovascular thrombectomy to treat the intracranial lesion clearly improved the outcome compared with treatment with intravenous thrombolysis alone. However, the best treatment strategy for managing the extracranial carotid artery lesion in patients with tandem lesions remains unknown. Current guidelines recommend carotid endarterectomy for patients with transient ischaemic attack or non-disabling stroke and moderate or severe stenosis of the internal carotid artery, within two weeks of the initial event, to prevent major stroke recurrence and death. Alternatively, the symptomatic carotid artery could be treated by endovascular placement of a stent during endovascular thrombectomy (EVT). This would negate the need for a second procedure, immediately reduce the risk of stroke recurrence, increase patient satisfaction, and could be cost effective. However, the administration of dual antiplatelet therapy could potentially increase the risk of symptomatic intracranial haemorrhage in patients with acute ischaemic stroke. Randomised controlled trials evaluating the efficacy and safety of immediate carotid artery stenting during EVT in acute stroke patients with tandem lesions are currently ongoing and will impact the current guidelines regarding the treatment of patients with acute ischaemic stroke due to these tandem lesions.

The plant stress hormone jasmonic acid evokes defensive responses in streptomycetes.

IMPORTANCE: Microorganisms that live on or inside plants can influence plant growth and health. Among the plant-associated bacteria, streptomycetes play an important role in defense against plant diseases, but the underlying mechanisms are not well understood. Here, we demonstrate that the plant hormones jasmonic acid (JA) and methyl jasmonate directly affect the life cycle of streptomycetes by modulating antibiotic synthesis and promoting faster development. Moreover, the plant hormones specifically stimulate the synthesis of the polyketide antibiotic actinorhodin in Streptomyces coelicolor. JA is then modified in the cell by amino acid conjugation, thereby quenching toxicity. Collectively, these results provide new insight into the impact of a key plant hormone on diverse phenotypic responses of streptomycetes.

Sex differences in onset to hospital arrival time, prestroke disability, and clinical symptoms in patients with a large vessel occlusion: a MR CLEAN Registry substudy.

BACKGROUND: Women have been reported to have worse outcomes after endovascular treatment (EVT), despite a similar treatment effect in non-clinical trial populations. We aimed to assess sex differences at hospital presentation with respect to workflow metrics, prestroke disability, and presenting clinical symptoms. METHODS: We included consecutive patients from the Multicentre Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in The Netherlands (MR CLEAN) Registry (2014-2018) who received EVT for anterior circulation large vessel occlusion (LVO). We assessed sex differences in workflow metrics, prestroke disability (modified Rankin Scale (mRS) score ≥1), and stroke severity and symptoms according to the National Institutes of Health Stroke Scale (NIHSS) score on hospital admission with logistic and linear regression analyses and calculated the adjusted OR (aOR). RESULTS: We included 4872 patients (47.6% women). Compared with men, women were older (median age 76 vs 70 years) and less often achieved good functional outcome at 90 days (mRS ≤2: 35.2% vs 46.4%, aOR 0.70, 95% CI 0.60 to 0.82). Mean onset-to-door time was longer in women (2 hours 16 min vs 2 hours 7 min, adjusted delay 9 min, 95% CI 4 to 13). This delay contributed to longer onset-to-groin times (3 hours 26 min in women vs 3 hours 13 min in men, adjusted delay 13 min, 95% CI 9 to 17). Women more often had prestroke disability (mRS ≥1: 41.1% vs 29.1%, aOR 1.57, 95% CI 1.36 to 1.82). NIHSS on admission was essentially similar in men and women (mean 15±6 vs 15±6, NIHSS <10 vs ≥10, aOR 0.91, 95% CI 0.78 to 1.06). There were no clear sex differences in the occurrence of specific stroke symptoms. CONCLUSION: Women with LVO had longer onset-to-door times and more often prestroke disability than men. Raising awareness of these differences at hospital presentation and investigating underlying causes may help to improve outcome after EVT in women.

NOn-invasive Vagus nerve stimulation in acute Ischemic Stroke (NOVIS): a study protocol for a randomized clinical trial.

BACKGROUND: Secondary damage due to neurochemical and inflammatory changes in the penumbra in the first days after ischemic stroke contributes substantially to poor clinical outcome. In animal models, vagus nerve stimulation (VNS) inhibits these detrimental changes and thereby reduces tissue injury. The aim of this study is to investigate whether non-invasive cervical VNS (nVNS) in addition to the current standard treatment can improve penumbral recovery and limit final infarct volume. METHODS: NOVIS is a single-center prospective randomized clinical trial with blinded outcome assessment. One hundred fifty patients will be randomly allocated (1:1) within 12 h from clinical stroke onset to nVNS for 5 days in addition to standard treatment versus standard treatment alone. The primary endpoint is the final infarct volume on day 5 assessed with MRI. DISCUSSION: We hypothesize that nVNS will result in smaller final infarct volumes as compared to standard treatment due to improved penumbral recovery. The results of this study will be used to assess the viability and approach to power a larger trial to more definitively assess the clinical efficacy of nVNS after stroke. TRIAL REGISTRATION: ClinicalTrials.gov NCT04050501 . Registered on 8 August 2019.

Stress-induced formation of cell wall-deficient cells in filamentous actinomycetes.

The cell wall is a shape-defining structure that envelopes almost all bacteria and protects them from environmental stresses. Bacteria can be forced to grow without a cell wall under certain conditions that interfere with cell wall synthesis, but the relevance of these wall-less cells (known as L-forms) is unclear. Here, we show that several species of filamentous actinomycetes have a natural ability to generate wall-deficient cells in response to hyperosmotic stress, which we call S-cells. This wall-deficient state is transient, as S-cells are able to switch to the normal mycelial mode of growth. However, prolonged exposure of S-cells to hyperosmotic stress yields variants that are able to proliferate indefinitely without their cell wall, similarly to L-forms. We propose that formation of wall-deficient cells in actinomycetes may serve as an adaptation to osmotic stress.

Inter- and intracellular colonization of Arabidopsis roots by endophytic actinobacteria and the impact of plant hormones on their antimicrobial activity.

Many actinobacteria live in close association with eukaryotes such as fungi, insects, animals and plants. Plant-associated actinobacteria display (endo)symbiotic, saprophytic or pathogenic life styles, and can make up a substantial part of the endophytic community. Here, we characterised endophytic actinobacteria isolated from root tissue of Arabidopsis thaliana (Arabidopsis) plants grown in soil from a natural ecosystem. Many of these actinobacteria belong to the family of Streptomycetaceae with Streptomyces olivochromogenes and Streptomyces clavifer as well represented species. When seeds of Arabidopsis were inoculated with spores of Streptomyces strain coa1, which shows high similarity to S. olivochromogenes, roots were colonised intercellularly and, unexpectedly, also intracellularly. Subsequent exposure of endophytic isolates to plant hormones typically found in root and shoot tissues of Arabidopsis led to altered antibiotic production against Escherichia coli and Bacillus subtilis. Taken together, our work reveals remarkable colonization patterns of endophytic streptomycetes with specific traits that may allow a competitive advantage inside root tissue.

Chemical ecology of antibiotic production by actinomycetes.

Actinomycetes are a diverse family of filamentous bacteria that produce a plethora of natural products relevant for agriculture, biotechnology and medicine, including the majority of the antibiotics we use in the clinic. Rather than as free-living bacteria, many actinomycetes have evolved to live in symbiosis with among others plants, fungi, insects and sponges. As a common theme, these organisms profit from the natural products and enzymes produced by the actinomycetes, for example, for protection against pathogenic microbes, for growth promotion or for the degradation of complex natural polymers such as lignocellulose. At the same time, the actinomycetes benefit from the resources of the hosts they interact with. Evidence is accumulating that these interactions control the expression of biosynthetic gene clusters and have played a major role in the evolution of the high chemical diversity of actinomycete-produced secondary metabolites. Many of the biosynthetic gene clusters for antibiotics are poorly expressed under laboratory conditions, but they are likely expressed in response to host-specific demands. Here, we review the environmental triggers and cues that control natural product formation by actinomycetes and provide pointers as to how these insights may be harnessed for drug discovery.

Effect of histamine H2 receptor antagonism on levodopa-induced dyskinesia in the MPTP-macaque model of Parkinson's disease.

Levodopa-induced motor complications, including dyskinesia and wearing off, are troublesome side effects of treatment and impair quality of life in Parkinson's disease (PD) patients. The use of nondopaminergic agents as adjuncts to levodopa are potential options for managing these problems. Here, we asses the ability of the clinically available, selective histamine H(2) antagonist, famotidine (1, 3, and 30 mg/kg) to treat levodopa-induced dyskinesia and wearing off in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-macaque model of PD. Famotidine (3 mg/kg) increased peak activity, enhanced peak anti-parkinsonian action (1 and 3 mg/kg), and extended duration of action (3 mg/kg, by 38%) of a low dose of levodopa (compared to low dose levodopa alone). Enhancement of anti-parkinsonian actions of low dose levodopa by famotidine (3 mg/kg) was associated with only mild, nondisabling dystonia. Famotidine had no effect on the anti-parkinsonian actions of high dose levodopa (compared to high dose levodopa alone). However, famotidine (1, 3, and 30 mg/kg) had a significant effect on chorea, but not dystonia, induced by high dose levodopa (compared to high dose levodopa alone). Famotidine increased high dose levodopa-induced "good quality" on time, i.e., on time not associated with disabling dyskinesia, by up to 28% (compared to high dose levodopa alone). In conclusion, famotidine, a drug currently available for use in the clinic, can enhance the peak-dose anti-parkinsonian actions and extend total duration of action of a low dose of levodopa, without producing disabling dyskinesia. Furthermore, in combination with a higher dose of levodopa, famotidine can reduce peak-dose levodopa-induced chorea and improve the quality of on-time.