Basement Membrane and Repair of Injury to Peripheral Nerve: Defining a Potential Role for Macrophages, Matrix Metalloproteinases, and Tissue Inhibitor of Metalloproteinases-1

Injury to a peripheral nerve is followed by a remodeling process consisting of axonal degeneration and regeneration. It is not known how Schwann cell–derived basement membrane is preserved after injury or what role matrix metalloproteinases (MMPs) and their inhibitors play in axonal degeneration and regeneration. We showed that the MMPs gelatinase B (MMP-9), stromelysin-1 (MMP-3), and the tissue inhibitor of MMPs (TIMP)-1 were induced in crush and distal segments of mouse sciatic nerve after injury. TIMP-1 inhibitor activity was present in excess of proteinase activity in extracts of injured nerve. TIMP-1 protected basement membrane type IV collagen from degradation by exogenous gelatinase B in cryostat sections of nerve in vitro. In vivo, during the early phase (1 d after crush) and later phase (4 d after crush) after injury, induction of TNF-α and TGF-β1 mRNAs, known modulators of TIMP-1 expression, were paralleled by an upregulation of TIMP-1 and gelatinase B mRNAs. At 4 days after injury, TIMP-1, gelatinase B, and TNF-α mRNAs were localized to infiltrating macrophages and Schwann cells in the regions of nerve infiltrated by elicited macrophages. TIMP-1 and cytokine mRNA expression was upregulated in undamaged nerve explants incubated with medium conditioned by macrophages or containing the cytokines TGF-β1, TNF-α, and IL-1α. These results show that TIMP-1 may protect basement membrane from uncontrolled degradation after injury and that cytokines produced by macrophages may participate in the regulation of TIMP-1 levels during nerve repair

Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke).

BACKGROUND: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation. METHODS: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0-2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass. RESULTS: A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients ( CONCLUSIONS: In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239640

Mechanical Thrombectomy for Delayed Thrombosis of Pipeline Embolization Device

BACKGROUND: In-stent thrombosis is a potentially dangerous complication of flow diversion for cerebral aneurysms. The optimal management strategy for such thrombosis is not known. Here we present a case of acute ischemic stroke caused by occlusion of a Pipeline Embolization Device (PED) construct placed 18 months earlier for treatment of a fusiform middle cerebral artery aneurysm. This was successfully treated with mechanical thrombectomy with good neurologic outcome. CASE DESCRIPTION: A 40-year-old woman presented with acute onset of left-sided weakness and occlusion of the right middle cerebral artery harboring a PED construct. Intraarterial glycoprotein IIb/IIIa inhibitor was administered without success. Mechanical thrombectomy was then performed using a stent retriever and aspiration, and the patient was loaded with dual antiplatelet therapy. The patient showed initial neurologic improvement but several hours later demonstrated recurrent symptoms due to reocclusion of the PED construct. This was again treated with mechanical thrombectomy followed by an intravenous P2Y12 inhibitor infusion. She ultimately made an excellent neurologic recovery with persistent patency of the PED construct. CONCLUSIONS: Mechanical thrombectomy with a stent retriever and aspiration is a therapeutic option for treatment of delayed thrombosis of a flow-diverting stent

Outcomes of Mechanical Thrombectomy of Acute Basilar Artery Occlusion Due to Underlying Intracranial Atherosclerotic Disease

Background Intracranial atherosclerotic disease (ICAD) is a common cause of posterior circulation acute ischemic stroke. We aimed to compare baseline characteristics, recanalization rates, and clinical outcomes in patients with acute basilar occlusion due to underlying ICAD to patients with other causes of occlusion. Methods The Trevo Registry (ClinicalTrials.gov Identifier: NCT02040259) was a prospective open‐label mechanical thrombectomy registry that included 2008 patients from 76 sites across 12 countries. For a secondary analysis, we selected patients with isolated acute basilar occlusion. We then classified patients into 2 groups: patients with acute basilar artery occlusion due to ICAD (ICAD group) and patients with acute basilar occlusion due to another cause (non‐ICAD group). Results We identified 90 subjects with acute basilar occlusion. According to stroke mechanism, there were 9 (10.0%) patients in the ICAD group and 81 (90.0%) in the non‐ICAD group. There was a significant difference (P=0.001) in the lesion location between the 2 groups, with 60.5% of non‐ICAD occlusions located in the distal region and no ICAD occlusions there. The 2 groups showed a significant difference (P=0.003) for rescue therapy with balloon angioplasty, with 33.3% in the ICAD group and 1.2% in the non‐ICAD group, respectively. In a multivariable model adjusted for age, baseline National Institutes of Health Stroke Scale, and intravenous tissue‐type plasminogen activator (tPA), the odds of 90‐day death (odds ratio=4.6; P=0.10) were higher for atherosclerotic subjects. Conclusion Acute basilar occlusions related to ICAD showed a similar good clinical outcome (modified Rankin scale (mRS) 0–2) and a tendency for a higher rate of 90‐day mortality compared with non‐ICAD occlusions

Multi-component crystals of 4-phenylpyridine: challenging the boundaries between co-crystal and organic salt formation with insight into solid-state proton transfer

Six new multi-component crystals between 4-phenylpyridine and substituted benzoic acids (3-nitrobenzoic acid, 3,5-dinitrobenzoic acid, gallic acid, 4-aminobenozic acid, salicylic acid and 2-aminobenzoic acid) were created and characterized crystallographically to investigate the influence of chemical and structural factors on the hydrogen location between the two components. While the expected intermolecular interactions are formed between the acid and pyridine group in most cases, the gallic acid structure is anomalous forming an unexpected salt with pyridine to hydroxyl interactions. Calculations of the hydrogen bonding motifs indicate that the level of proton transfer (e.g. salt versus co-crystal formation) is not solely a function of the dimer geometry but influenced by the local crystallographic environment. Analysis of the crystal structures indicates the strength of the hydrogen bonding into this motif alters the expected protonation state from chemical considerations

Endovascular therapy in the distal neurovascular territory: results of a large prospective registry.

BACKGROUND: There is a paucity of data regarding mechanical thrombectomy (MT) in distal arterial occlusions (DAO). We aim to evaluate the safety and efficacy of MT in patients with DAO and compare their outcomes with proximal arterial occlusion (PAO) strokes. METHODS: The Trevo Registry was a prospective open-label MT registry including 2008 patients from 76 sites across 12 countries. Patients were categorized into: PAO: intracranial ICA, and MCA-M1; and DAO: MCA-M2, MCA-M3, ACA, and PCA. Baseline and outcome variables were compared across the PAO vs DAO patients with pre-morbid mRS 0-2. RESULTS: Among 407 DAOs including 350 (86.0%) M2, 25 (6.1%) M3, 10 (2.5%) ACA, and 22 (5.4%) PCA occlusions, there were 376 DAO with pre-morbid mRS 0-2 which were compared with 1268 PAO patients. The median baseline NIHSS score was lower in DAO (13 [8-18] vs 16 [12-20], P CONCLUSION: Endovascular therapy in DAO appears to result in a comparable safety and technical success profile as in PAO. The potential benefits of DAO thrombectomy should be investigated in future randomized trials

Endovascular therapy in the distal neurovascular territory: results of a large prospective registry

Background: There is a paucity of data regarding mechanical thrombectomy (MT) in distal arterial occlusions (DAO). We aim to evaluate the safety and efficacy of MT in patients with DAO and compare their outcomes with proximal arterial occlusion (PAO) strokes. Methods: The Trevo Registry was a prospective open-label MT registry including 2008 patients from 76 sites across 12 countries. Patients were categorized into: PAO: intracranial ICA, and MCA-M1; and DAO: MCA-M2, MCA-M3, ACA, and PCA. Baseline and outcome variables were compared across the PAO vs DAO patients with pre-morbid mRS 0-2. Results: Among 407 DAOs including 350 (86.0%) M2, 25 (6.1%) M3, 10 (2.5%) ACA, and 22 (5.4%) PCA occlusions, there were 376 DAO with pre-morbid mRS 0-2 which were compared with 1268 PAO patients. The median baseline NIHSS score was lower in DAO (13 [8-18] vs 16 [12-20], P\u3c0.001). There were no differences in terms of age, sex, IV-tPA use, co-morbidities, or time to treatment across DAO vs PAO. The rates of post-procedure reperfusion, symptomatic intracranial hemorrhage (sICH), and 90-mortality were comparable between both groups. DAO showed significantly higher rates of 90-day mRS 0-2 (68.3% vs 56.5%, P\u3c0.001). After adjustment for potential confounders, the level of arterial occlusion was not associated with the chances of excellent outcome (DAO for 90-day mRS 0-1: OR; 1.18, 95% CI [0.90 to 1.54], P=0.225), successful reperfusion or SICH. However, DAO patients were more likely to be functionally independent (mRS 0-2: OR; 1.45, 95% CI [1,09 to 1.92], P=0.01) or dead (OR; 1.54, 95% CI [1.06 to 2.27], P=0.02) at 90 days. Conclusion: Endovascular therapy in DAO appears to result in a comparable safety and technical success profile as in PAO. The potential benefits of DAO thrombectomy should be investigated in future randomized trials