Human immunodeficiency virus-associated vasculopathy

Human immunodeficiency virus-associated vasculopathy

Human immunodeficiency virus-associated vasculopathy and opportunistic infections are common causes of HIV-related ischemic stroke. Furthermore, subtypes of HIV-associated vasculopathy may manifest as a result of an immune reconstitution-like syndrome after starting ART. A better understanding of this mechanism may point toward new treatments 1).

Human immunodeficiency virus (HIV)-associated vasculopathy can cause ischemic stroke; however, there is limited evidence on optimal management.

Mizushima et al. reported a case of acute ischemic stroke due to progressive internal carotid artery stenosis in an HIV-positive patient. Superficial temporal artery to middle cerebral artery bypass), in addition to the best medical treatments, prevented stroke progression.

A 39-year-old man with HIV infection presented with a sudden onset of aphasia and right hemiparesis. Magnetic resonance imaging revealed an ischemic lesion in the leftbasal ganglia and concentric thickening of the vessel wall in the terminal portion of the bilateral ICAs. Despite maximal medical treatments for HIV-associated vasculopathy and possible opportunistic infections, bilateral ICA stenoses progressed, leading to a second hemodynamic stroke event. Because tissue plasminogen activator treatment failed, they performed STA-MCA bypass. A significant improvement in neurological symptoms and cerebral blood flow was observed after surgery. No further stroke events occurred during the continuation of medical treatments 2).

Tat protein released from HIV-infected blood-borne leukocytes can contribute to the breakdown of the blood-brain barrier (BBB) and induction of inflammatory responses and can provide entry for HIV into the brain. To mimic this pathology, Tat was injected into the tail vein of C57BL/6 mice. Treatment with Tat markedly upregulated expression of cyclooxygenase-2 (COX-2) and decreased expression of tight junction proteins, occludin and zonula occludens-1 (ZO-1). These alterations were associated with the disruption of the BBB integrity as quantified by extravasation of Evans blue dye into the brain tissue. In addition, direct treatment of brain microvessels with prostaglandin E(2), a product of COX-2 activity, resulted in decreased expression of both occludin and ZO-1. To determine if upregulation of COX-2 is involved in the disruption of tight junction proteins and BBB integrity, mice were pretreated with rofecoxib, a specific inhibitor of COX-2, prior to Tat treatment. COX-2 inhibition attenuated Tat-induced alterations of occludin expression. However, rofecoxib was ineffective in preventing downregulation of ZO-1 expression and increased BBB permeability. These results suggest only a limited role of COX-2 overexpression in the loss of tight junction integrity and the BBB breakdown in HIV-related brain diseases 3).

Human immunodeficiency virus-associated aneurysm.


Benjamin LA, Allain TJ, Mzinganjira H, Connor MD, Smith C, Lucas S, Joekes E, Kampondeni S, Chetcuti K, Turnbull I, Hopkins M, Kamiza S, Corbett EL, Heyderman RS, Solomon T. The Role of Human Immunodeficiency Virus-Associated Vasculopathy in the Etiology of Stroke. J Infect Dis. 2017 Sep 1;216(5):545-553. doi: 10.1093/infdis/jix340. PMID: 28931222; PMCID: PMC5853476.

Mizushima M, Sugiyama T, Eguchi K, Tarisawa M, Tokairin K, Ito M, Hashimoto D, Yabe I, Fujimura M. Rescue extracranial-intracranial bypass for ischemic stroke secondary to progressive human immunodeficiency virus-associated vasculopathy. J Neurol Surg A Cent Eur Neurosurg. 2022 Feb 22. doi: 10.1055/a-1779-4142. Epub ahead of print. PMID: 35193153.

Pu H, Hayashi K, Andras IE, Eum SY, Hennig B, Toborek M. Limited role of COX-2 in HIV Tat-induced alterations of tight junction protein expression and disruption of the blood-brain barrier. Brain Res. 2007 Dec 12;1184:333-44. doi: 10.1016/j.brainres.2007.09.063. Epub 2007 Oct 2. PMID: 17976544.

Human adipose derived mesenchymal stem cell

Human adipose derived mesenchymal stem cell

Human adipose derived mesenchymal stem cells (hASCs) have a capacity to undergo adipogenic, chondrogenic, and osteogenic differentiation.

hASCs were applied to various fields including cell therapy for tissue regeneration. However, it is hard to predict the direction of differentiation of hASCs in real-time.

Chen et al. performed intracerebroventricular microinjection of human adipose mesenchymal stem cell (hADSC)-derived exosomes (hADSC-ex) in a weight-drop-induced TBI rat model.

They found that hADSC-ex promoted functional recovery, suppressed neuroinflammation, reduced neuronal apoptosis, and increased neurogenesis in TBI rats. The therapeutic effects of hADSC-ex were comparable to those of hADSC. Sequential in vivo imaging revealed increasing aggregation of DiR-labeled hADSC-ex in the lesion area. Immunofluorescent staining of coronal brain sections and primary mixed neural cell cultures revealed distinct overlap between CM-DiI-labeled hADSC-ex and microglia/macrophages, indicating that hADSC-ex were mainly taken up by microglia/macrophages. In a lipopolysaccharide-induced inflammatory model, hADSC-ex suppressed microglia/macrophage activation by inhibiting nuclear factor κB and P38 mitogen-activated protein kinase signaling. These data suggest that hADSC-ex specifically enter microglia/macrophages and suppress their activation during brain injury, thereby inhibiting inflammation and facilitating functional recovery. They also offer new insight into the cellular targeting, uptake and migration of hADSC-ex, and provide a theoretical basis for new therapeutic strategies for central nervous system diseases 1).

Three patients (two patients and one patient with 1 and 2 levels, respectively) with degenerative spondylolisthesis underwent MI-TLIF with 3D graft made of AMSCs. To obtain the AMSCs, fatty tissue was collected from the abdomen by lipoaspiration and differentiated afterwards in our Cell/Tissue bank. Clinical outcomes, including the Oswestry Disability Index (ODI) and visual analog scale (VAS) as well as fusion status were assessed preoperatively and up to 12 months postoperatively.

At 12 months, all four operated AMSC levels could be assessed (n = 4). Grade 3 fusion could be confirmed at two levels out of four. Mean VAS score improved from 8.3 to 2 and ODI also improved from 47 to 31%. No donor site complication was observed. The final AMSC osteogenic product was stable, did not rupture with forceps manipulation, and was easily implanted directly into the cage with no marked modification of operating time.

A scaffold-free 3D graft made of AMSCs can be manufactured and used as a promising alternative for spinal fusion procedures. Nevertheless, further studies of a larger series of patients are needed to confirm its effectiveness. 2).

Matrix metalloproteinases (MMPs) are one family of proteolytic enzymes that plays a pivotal role in regulating the biology of stem cells.

Matrix metalloproteinases (MMPs) secreted by hASCs are expected to show different expression patterns depending on the differentiation state of hASCs because biological functions exhibit different patterns during the differentiation of stem cells. Here, we investigated proteolytic enzyme activity, especially MMP-2 activity, in hASCs during their differentiation. The activities of proteolytic enzymes and MMP-2 were higher during chondrogenic differentiation than during adipogenic and osteogenic differentiation. During chondrogenic differentiation, mRNA expression of MMP-2 and the level of the active form of MMP-2 were increased, which also correlated with Col II. It is concluded that proteolytic enzyme activity and the level of the active form of MMP-2 were increased during chondrogenic differentiation, which was accelerated in the presence of Col II protein. According to our findings, MMP-2 could be a candidate maker for real-time detection of chondrogenic differentiation of hASCs 3).

El Bassit et al., evaluated the effect of hASC secretome on HT22 neuronal cells post injury. Protein Kinase C delta (PKCδ)1 activates survival and proliferation in neurons and is implicated in memory (1-3). We previously showed that alternatively spliced PKCδII enhances neuronal survival via Bcl2 (4) in HT22 neuronal cells. Our results demonstrate that following injury, treatment with exosomes from the hASC secretome increases expression of PKCδII in HT22 cells and increases neuronal survival and proliferation. Specifically, we demonstrate that MALAT1, a long noncoding RNA contained in the hASC exosomes mediates PKCδII splicing thereby increasing neuronal survival. Using antisense oligonucleotides for MALAT1 and RNA immunoprecipitation assays we demonstrate that MALAT1 recruits splice factor SRSF2 to promote alternative splicing of PKCδII. Finally, we evaluated the role of insulin in enhancing hASC mediated neuronal survival, and demonstrated that insulin treatment dramatically increased the association of MALAT1 and SRSF2 and substantially increases survival and proliferation after injury in HT22 cells. In conclusion, we demonstrate the mechanism of action of hASC exosomes in increasing neuronal survival. This effect of hASC exosomes to promote wound healing can be further enhanced by insulin treatment in HT22 cells 4).

human adipose tissue-derived mesenchymal stem cells (ADSCs) secrete exosomes carrying enzymatically active NEP. The NEP-specific activity level of 1 μg protein from ADSC-derived exosomes was equivalent to that of ~ 0.3 ng of recombinant human NEP. Of note, ADSC-derived exosomes were transferred into N2a cells, and were suggested to decrease both secreted and intracellular Aβ levels in the N2a cells. Importantly, these characteristics were more pronounced in ADSCs than bone marrow-derived mesenchymal stem cells, suggesting the therapeutic relevance of ADSC-derived exosomes for AD 5).



Chen Y, Li J, Ma B, Li N, Wang S, Sun Z, Xue C, Han Q, Wei J, Zhao RC. MSC-derived exosomes promote recovery from traumatic brain injury via microglia/macrophages in rat. Aging (Albany NY). 2020 Sep 23;12. doi: 10.18632/aging.103692. Epub ahead of print. PMID: 32966240.

Fomekong E, Dufrane D, Berg BV, André W, Aouassar N, Veriter S, Raftopoulos C. Application of a three-dimensional graft of autologous osteodifferentiated adipose stem cells in patients undergoing minimally invasive transforaminal lumbar interbody fusion: clinical proof of concept. Acta Neurochir (Wien). 2016 Dec 30. doi: 10.1007/s00701-016-3051-6. [Epub ahead of print] PubMed PMID: 28039550.

Arai Y, Park S, Choi B, Ko KW, Choi WC, Lee JM, Han DW, Park HK, Han I, Lee JH, Lee SH. Enhancement of Matrix Metalloproteinase-2 (MMP-2) as a Potential Chondrogenic Marker during Chondrogenic Differentiation of Human Adipose-Derived Stem Cells. Int J Mol Sci. 2016 Jun 17;17(6). pii: E963. PubMed PMID: 27322256.

El Bassit G, Patel RS, Carter G, Shibu V, Patel A, Song S, Murr M, Cooper DR, Bickford PC, Patel NA. MALAT1 in human adipose stem cells modulates survival and alternative splicing of PKCδII in HT22 cells. Endocrinology. 2016 Nov 14:en20161819. [Epub ahead of print] PubMed PMID: 27841943.

Katsuda T, Tsuchiya R, Kosaka N, Yoshioka Y, Takagaki K, Oki K, Takeshita F, Sakai Y, Kuroda M, Ochiya T. Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep. 2013;3:1197. doi: 10.1038/srep01197. Epub 2013 Feb 1. PubMed PMID: 23378928; PubMed Central PMCID: PMC3561625.

Intraarterial recombinant human tissue plasminogen activator for ischemic stroke treatment

Intraarterial recombinant human tissue plasminogen activator for ischemic stroke treatment

Mechanical thrombectomy (MT) devices have led to improved reperfusionand clinical outcomes in acute ischemic stroke patients with emergent large vessel occlusions; however, less than one-third of patients achieve complete reperfusion. Use of intraarterial thrombolysis in the context of MT may provide an opportunity to enhance these results.

Zaidi et al., evaluated the use of intraarterial rtPA (recombinant tissue-type plasminogen activator) as rescue therapy (RT) after failed MT in the North American Solitaire Stent-Retriever Acute Stroke registry.

The North American Solitaire Stent-Retriever Acute Stroke registry recruited sites within North America to submit data on acute ischemic stroke patients treated with the Solitaire device. After restricting the population of 354 patients to use of RT and anterior emergent large vessel occlusions, we compared patients who were treated with and without intraarterial rtPA after failed MT.

A total of 37 and 44 patients was in the intraarterial rtPA RT and the no intraarterial rtPA RT groups, respectively. Revascularization success (modified Thrombolysis in Cerebral Infarction ≥2b) was achieved in more intraarterial rtPA RT patients (61.2% versus 46.6%; P=0.13) with faster times to recanalization (100±85 versus 164±235 minutes; P=0.36) but was not statistically significant. The rate of symptomatic intracranial hemorrhage (13.9% versus 6.8%; P=0.29) and mortality (42.9% versus 44.7%; P=0.87) were similar between the groups. Good functional outcome (modified Rankin Scale score of ≤2) was numerically higher in intraarterial rtPA patients (22.9% versus 18.4%; P=0.64). Further restriction of the RT population to M1 occlusions only and time of onset to groin puncture ≤8 hours, resulted in significantly higher successful revascularization rates in the intraarterial rtPA RT cohort (77.8% versus 38.9%; P=0.02).

Intraarterial rtPA as RT demonstrated a similar safety and clinical outcome profile, with higher reperfusion rates achieved in patients with M1 occlusions. Prospective studies are needed to delineate the role of intraarterial thrombolysis in MT 1).

Intraarterial recombinant human tissue plasminogen activator for ischemic stroke treatment may be the simplest endovascular technique to undertake, when compared to Stent retriever or Penumbra aspiration. However, on its own, while the recanalization rates may be better than IV tPA, they are inferior to o Stent retriever or Penumbra aspiration 2) 3).

Currently,i.a.tPA is used in conjunction with other techniques in ischemic stroke.

Intraarterial recombinant human tissue plasminogen activator may be indicated for the following situations:

● Persistent symptoms of stroke despite Intravenous recombinant human tissue plasminogen activator and adequate medical management

● Where angiography may be performed and treatment administered within 3 and 6 hours after symptom onset with an NIHSS score greater than 4, or those with an NIHSS score of greater than 20 and the ability to be treated within 6 hours

● Posterior circulation strokes may be treated endovascularly for up to 24 hrs (due to a lesser likelihood of hemorrhagic conversion of infarct)

● CTA or MRA demonstrating a diffusion-perfusion mismatch.In face of significant penumbra, it may be worthwhile to perform endovascular intervention even outside the therapeutic window. Conversely, intervention may be abandoned even within the therapeutic window, if the stroke is complete. Centers are relying more and more on neuroimaging rather than the therapeutic window

● When Intravenous recombinant human tissue plasminogen activator is contraindicated e.g., recent surgery

Contraindications to intervention

Most contraindications are relative and have to be weighed against the risk of not intervening. These contraindications include:

● Hemorrhagic infarct or,ICH

● CT demonstrating hypodensity or mass effect consistent with evolving infarct of more than one-third of middle cerebral artery territory

● Recent major surgery

● Pregnancy

● When considering stenting, contraindication to anticoagulants and/or thrombolytics

Preprocedural management

This may be under the supervision of a stroke neurologist, or the neurosurgeon. Ensure the following:

● Rapid transfer of patient to a stroke center/facility with endovascular capabilities.

● ABC’s take precedence.

● Ensure patient has two intravenous lines, preferably 18G or larger. Start monitoring BPpulse oximetry, ECG, O2 saturation, heart rate and rhythm, respiratory rate. Insert a Foley catheter.

● Verify laboratory values including Platelet countBUNCRAPTT, PT/INR. ß-HCG for females of reproductive age group.

● Maintain MAP ≥ 90mmHg.

● CT scan head: To rule out ICH.

● CTA: To assess location of the clot (hyperdense artery sign and vascular tortuosity.

● MRI head (select cases).

● If available and can be done without delay, then perfusion studies e.g., CTP or MRP. These perfusion studies will demonstrate viable brain (penumbra) vs completed stroke.

● In centers where available, CT, CTA and CTP all a reperformed during the same session on CT scanner.

● Be cognizant of renal insufficiency, diabetes, congestive heart failure etc., in which case consider diluted non-ionic contrast agent and carefully pre-plan, to maintain contrast load to minimum.

● If the patient is not responding to IV tPA or it if is contraindicated, then endovascular intervention is considered.

● The goal of intervention is to re-establish circulation, as soon as possible.



Zaidi SF, Castonguay AC, Jumaa MA, Malisch TW, Linfante I, Marden FA, Abraham MG, Chebl AB, Novakovic R, Taqi MA, Nogueira RG, Martin CO, Holloway WE, Mueller-Kronast N, English JD, Dabus G, Bozorgchami H, Xavier A, Rai AT, Froehler MT, Badruddin A, Nguyen TN, Yoo AJ, Shaltoni H, Janardhan V, Chen PR, Britz GW, Kaushal R, Nanda A, Gupta R, Zaidat OO. Intraarterial Thrombolysis as Rescue Therapy for Large Vessel Occlusions. Stroke. 2019 Apr;50(4):1003-1006. doi: 10.1161/STROKEAHA.118.024442. PubMed PMID: 30791829.

Ernst R, Pancioli A, Tomsick T, Kissela B, Woo D, Kanter D, Jauch E, Carrozzella J, Spilker J, Broderick J. Combined intravenous and intra-arterial recombinant tissue plasminogen activator in acute ischemic stroke. Stroke. 2000; 31:2552–2557

Intra-arterial thrombolysis. AJNR Am J Neuroradiol. 2001; 22:S18–S21
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