Faculty Bibliography

Introduction: Subclavian steal syndrome (SSS) is usually due to stenosis of the Subclavian Artery (SA) proximal to the origin of the vertebral artery (VA). SSS with intact SA in patients with dialysis arterio-venous fistulas (AVF) has been occasionally reported[1-4]. We present a unique case of the same successfully treated with a covered stent. Methods: A 65-year-old male with DM, HTN, ESRD and left brachial artery- basilic vein fistula (2.27 L/min flow) had multiple admissions with vertebrobasilar symptoms in the setting of elevated BP. Repeated evaluations with CT/CTA/MRI were negative for steno-occlusive disease or infarction. Therefore, symptoms were attributed to hypertensive urgency. On his third presentation in 4 months, he had additional symptoms of left arm pain, weakness and numbness. Signs included left arm hyperemia, warmth and mild motor-sensory deficits. Results: MRA demonstrated reverse flow of blood in left VA with focal stenosis of proximal left SA. Angiogram showed a kinked LSA and rapid/ early shunting to the subcalvian vein. There was no ante-grade visualization of the LVA with reverse flow from the RVA via VB junction. However on compression of the shunt with a BP cuff, antegrade flow in LVA reappeared with disappearance of RVA-LVA steal. BP transduction revealed a 50-mmHg point difference across the kinked segment. Subsequently, proximal left SA was stented with a covered biliary stent resulting in disappearance in RVALVA & LSA-LSV shunts, reappearance of antegrade LVA flow and resolution of symptoms. Conclusions: High-flow AVF is an underdiagnosed cause of symptomatic SSS. We suggest determining AVF flow speeds in any hemodialysis patient who presents with symptoms of posterior circulation insufficiency and obtaining noninvasive vascular studies if flow exceeds 2 L/min or if there has been a recent increase in measured flow during hemodialysis. Obtaining vascular studies with and without fistula compression could be of additional diagnostic utility

Introduction: Adult onset focal dystonia often affects the upper extremities and cervical region but less often the lower extremities. Dystonia is the second most reported movement disorder post-stroke and often has a delayed presentation ranging from weeks to months. Most reports are in cases where there is permanent and substantial tissue injury. The clinical significance of Basal ganglia infarction or petechial hemorrhage following endovascular therapy for MCA occlusion is not well understood. The development of dystonia in the setting of a recanalized LMCA has never been reported before. Methods: A 39-year-old female presented with Left MCA occlusion. She had no other medical history except for an idiopathic left basal ganglia hemorrhagic stroke 6 months ago with residual mild forearm weakness. She underwent urgent mechanical thrombectomy with successful sequential recanalization of her inferior followed by superior division. The latter was complicated by a mild self-limiting subarachnoid hemorrhage in the left sylvian fissure. She had small petechial hemorrhages in the left basal ganglia on MRI. However, she recovered completely in 5 days and was discharged with a NIHSS of 1 (similar to baseline) as well as mRS of 2. Ten months later, she developed a painful, fixed right lower extremity dystonia where her ankle was inverted and plantarflexed with her toes curled. This was treated with multiple anticholinergic & GABAergic medications as well as Botox to only achieve partial success. Currently

The existence of a hyaluronic acid-rich node and duct system (HAR-NDS) within the lymphatic and blood vessels was demonstrated previously. The HAR-NDS was enriched with small (3.0-5.0 mum in diameter), adult stem cells with properties similar to those of the very small embryonic-like stem cells (VSELs). Sca-1(+)Lin(-)CD45(-) cells were enriched approximately 100-fold in the intravascular HAR-NDS compared with the bone marrow. We named these adult stem cells "node and duct stem cells (NDSCs)." NDSCs formed colonies on C2C12 feeder layers, were positive for fetal alkaline phosphatase, and could be subcultured on the feeder layers. NDSCs were Oct4(+)Nanog(+)SSEA-1(+)Sox2(+), while VSELs were Oct4(+)Nanog(+)SSEA-1(+)Sox2(-). NDSCs had higher sphere-forming efficiency and proliferative potential than VSELs, and they were found to differentiate into neuronal cells in vitro. Injection of NDSCs into mice partially repaired ischemic brain damage. Thus, we report the discovery of potential adult stem cells that may be involved in tissue regeneration. The intravascular HAR-NDS may serve as a route that delivers these stem cells to their target tissues.

4-1BB (CD137) is expressed on dendritic cells (DCs) and its biological function has remained largely unresolved. By comparing 4-1BB-intact (4-1BB(+/+)) and 4-1BB-deficient (4-1BB(-/-)) DCs, we found that 4-1BB was strongly induced on DCs during the maturation and that DC maturation was normal in the absence of 4-1BB. However, DC survival rate was low in the absence of 4-1BB, which was due to the decreased Bcl-2 and Bcl-x(L) in 4-1BB(-/-) DCs compared with 4-1BB(+/+) DCs after DC maturation. Consistent with these results, 4-1BB(-/-) DCs showed an increased turnover rate in steady state and more severely decreased in spleen by injecting LPS compared with 4-1BB(+/+) DCs. When OVA-pulsed DCs were adoptively transferred to recipient mice along with OVA-specific CD4(+) T cells, 4-1BB(-/-) DCs did not properly migrate to the T cell zone in lymph nodes and poorly induced proliferation of CD4(+) T cells, although both DCs comparably expressed functional CCR7. Eventually, 4-1BB(-/-) DCs generated a reduced number of OVA-specific memory CD4(+) T cells compared with 4-1BB(+/+) DCs. To further assess the role of 4-1BB on DC longevity in vivo, 4-1BB(+/+) and 4-1BB(-/-) C57BL/6 were administrated with Propionibacterium acnes that develop liver granuloma by recruiting DCs. Number and size of granuloma were reduced in the absence of 4-1BB, but the inflammatory cytokine level was comparable between the mice, which implied that the granuloma might be reduced due to the decreased longevity of DCs. These results demonstrate that 4-1BB on DCs controls the duration, DC-T interaction, and, therefore, immunogenicity.

To explore the roles of 4-1BB (CD137) and CD28 in corneal transplantation, we examined the effect of 4-1BB/4-1BB ligand (4-1BBL) and/or CD28/CD80/CD86 blockade on corneal allograft survival in mice. Allogeneic corneal transplantation was performed between two strains of wild-type (WT) mice, BALB/c and C57BL/6 (B6), and between BALB/c and B6 WT donors and various gene knockout (KO) recipients. Some of the WT graft recipients were treated intraperitoneally with agonistic anti-4-1BB or blocking anti-4-1BBL monoclonal antibody (mAb) on days 0, 2, 4 and 6 after transplantation. Transplanted eyes were observed over a 13-week period. Allogeneic grafts in control WT B6 and BALB/c mice treated with rat immunoglobulin G showed median survival times (MST) of 12 and 14 days, respectively. Allogeneic grafts in B6 WT recipients treated with anti-4-1BB mAb showed accelerated rejection, with an MST of 8 days. In contrast, allogeneic grafts in BALB/c 4-1BB/CD28 KO and B6 CD80/CD86 KO recipients had significantly prolonged graft survival times (MST, 52.5 days and 36 days, respectively). Treatment of WT recipients with anti-4-1BB mAb resulted in enhanced cellular proliferation in the mixed lymphocyte reaction and increased the numbers of CD4(+) CD8(+) T cells, and macrophages in the grafts, which correlated with decreased graft survival time, whereas transplant recipients with costimulatory receptor deletion showed longer graft survival times. These results suggest that the absence of receptors for the 4-1BB/4-1BBL and/or CD28/CD80/CD86 costimulatory pathways promotes corneal allograft survival, whereas triggering 4-1BB with an agonistic mAb enhances the rejection of corneal allografts.

4-1BB (CD137) triggering typically induces Th1 response by increasing IFN-gamma from T cells upon TCR ligation. We found recently that 4-1BB costimulation increased the expression of IL-13 from CD4(+) T cells, as well as CD8(+) T cells. The enhanced IL-13 expression by agonistic anti-4-1BB treatment was mediated via MAPK1/2, PI-3K, JNK, mammalian target of rapamycin, NF-AT, and NF-kappaB signaling pathways. The signaling for IL-13 induction was similar to that of IFN-gamma production by anti-4-1BB treatment in T cells. When the anti-4-1BB-mediated IL-13 expression was tested in an in vivo viral infection model such as HSV-1 and vesicular stomatitis virus, 4-1BB stimulation enhanced IL-13 expression of CD4(+) T, rather than CD8(+) T cells. Although IL-13 was enhanced by anti-4-1BB treatment, the increased IL-13 did not significantly alter the anti-4-1BB-induced Th1 polarization of T cells--increase of T-bet and decrease of GATA-3. Nevertheless, anti-4-1BB treatment polarized T cells excessively in the absence of IL-13 and even became detrimental to the mice by causing liver inflammation. Therefore, we concluded that IL-13 was coinduced following 4-1BB triggering to maintain the Th1/2 balance of immune response.