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Stem cell treatment improves post stroke neurological outcomes:a comparative study in male and female rats

Stroke & Vascular Neurology 2021年第4期6卷 519-527,I0005-I0010页

作者： Koteswara Rao Nalamolu Bharath Chelluboina Casimir A Fornal Siva Reddy Challa David M Pinson David Z Wang Jeffrey D Klopfenstein Krishna Kumar Veeravalli Cancer Biology and Pharmacology College of MedicineUniversity of IllinoisPeoriaIllinoisUSA Pharmaceutical and Biomedical Sciences California Health Sciences UniversityClovisCaliforniaUSA neurological Surgery University of Wisconsin-MadisonMadisonWisconsinUSA Health Sciences Education College of MedicineUniversity of IllinoisPeoriaIllinoisUSA Neurology College of MedicineUniversity of IllinoisPeoriaIllinoisUSA Neurology Barrow Neurological InstitutePhoenixArizonaUSA Neurosurgery College of MedicineUniversity of IllinoisPeoriaIllinoisUSA OSF HealthCare Illinois Neurological Institute PeoriaIllinoisUSA Pediatrics College of MedicineUniversity of IllinoisPeoriaIllinoisUSA

Background and purpose The therapeutic potential of different stem cells for ischaemic stroke treatment is intriguing and somewhat controversial.Recent results from our laboratory have demonstrated the potential benefits of human umbilical cord blood-derived mesenchymal stem cells(MSC)in a rodent stroke model.We hypothesised that MSC treatment would effectively promote the recovery of sensory and motor function in both males and females,despite any apparent sex differences in post stroke brain injury.Methods Transient focal cerebral ischaemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery.Following the procedure,male and female rats of the untreated group were euthanised 1 day after reperfusion and their brains were used to estimate the resulting infarct volume and tissue swelling.Additional groups of stroke-induced male and female rats were treated with MSC or vehicle and were subsequently subjected to a battery of standard neurological/neurobehavioral tests(Modified neurological Severity Score assessment,adhesive tape removal,beam walk and rotarod).The tests were administered at regular intervals(at days 1,3,5,7 and 14)after reperfusion to determine the time course of neurological and functional recovery after stroke.Results The infarct volume and extent of swelling of the ischaemic brain were similar in males and females.Despite similar pathological stroke lesions,the clinical manifestations of stroke were more pronounced in males than females,as indicated by the neurological scores and other tests.MSC treatment significantly improved the recovery of sensory and motor function in both sexes,and it demonstrated efficacy in both moderate stroke(females)and severe stroke(males).Conclusions Despite sex differences in the severity of post stroke outcomes,MSC treatment promoted the recovery of sensory and motor function in male and female rats,suggesting that it may be a promising treatment for stroke.

关键词： neurological female rats

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Poststroke seizure:optimising its management

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Stroke & Vascular Neurology 2019年第1期4卷 48-56页

作者： Michael Y Xu Department of Neurology OSF Illinois Neurological InstituteUniversity of Illinois College of MedicinePeoriaIllinoisUSA

Seizure after stroke or poststroke seizure (PSS) is a common and very important complication of stroke. It can be divided into early seizure and late seizure, depending on seizure onset time after the stroke. It has been reported that ischaemic and haemorrhagic stroke accounts for about 11% of all adult epilepsy cases and 45% of epilepsy cases over 60 years of age. However, there are no reliable guidelines in clinical practice regarding most of the fundamental issues of PSS management. In recent years there has been an increased interest in the study of PSS which may give clinical practitioners a better picture of how to optimise PSS management. Studies have indicated two peaks in PSS occurrence-the first day and 6-12 months after a stroke. Haemorrhagic stroke, cortical involvement, severity of initial neurological deficit, younger patients (<65 years of age), family history of seizures and certain genetic factors carry a higher risk of PSS. The use of continuous electroencephalogram has demonstrated significant benefits in capturing interictal or ictal abnormalities, especially in cases of non-convulsive seizures and non-convulsive status epilepticus. Current available data indicated that there was no significant difference in antiepileptic efficacy among most of the antiepileptic drugs (AEDs) in PSS. Levetiracetam and lamotrigine are the most studied newer generation AEDs and have the best drug tolerance. The purpose of this review is to summarise the recent advances in PSS research and focus on the most important practice issues of PSS management.

关键词： seizure epilepsy involvement

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Post-stroke mRNA expression profile of MMPs:effect of genetic deletion of MMP-12

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Stroke & Vascular Neurology 2018年第3期3卷 153-159页

作者： Koteswara Rao Nalamolu Bharath Chelluboina Ian B Magruder Diane N Fru Adithya Mohandass Ishwarya Venkatesh Jeffrey D Klopfenstein David M Pinson Krishna M Boini Krishna Kumar Veeravalli Department of Cancer Biology and Pharmacology University of Illinois College of MedicinePeoriaIllinoisUSA Department of Neurosurgery University of Illinois College of MedicinePeoriaIllinoisUSA Comprehensive Stroke Center Illinois Neurological InstituteOSF HealthCare SystemSaint Francis Medical CenterPeoriaIllinoisUSA Department of Pathology University of Illinois College of MedicinePeoriaIllinoisUSA Department of Pharmacological and Pharmaceutical Sciences College of PharmacyUniversity of HoustonHoustonTexasUSA Department of Neurology University of Illinois College of MedicinePeoriaIllinoisUSA

background and purpose Recent reports from our laboratory demonstrated the post-ischaemic expression profile of various matrix metalloproteinases(MMPs)in rats and the detrimental role of MMP-12 in post-stroke brain damage.We hypothesise that the post-stroke dysregulation of MMPs is similar across species and that genetic deletion of MMP-12 would not affect the post-stroke expression of other MMPs.We tested our hypothesis by determining the pre-ischaemic and post-ischaemic expression profile of MMPs in wild-type and MMP-12 knockout mice.Methods Focal cerebral ischaemia was induced in wildtype and MMP-12 knockout mice by middle cerebral artery occlusion procedure by insertion of a monofilament suture.One hour after ischaemia,reperfusion was initiated by removing the monofilament.One day after reperfusion,ischaemic brain tissues from various groups of mice were collected,and total RNA was isolated and subjected to cDNA synthesis followed by PCR analysis.results Although the post-stroke expression profile of MMPs in the ischaemic brain of mice is different from rats,there is a clear species similarity in the expression of MMP-12,which was found to be predominantly upregulated in both species.Further,the post-stroke induction or inhibition of various MMPs in MMP-12 knockout mice is different from their respective expression profile in wild-type mice.Moreover,the brain mRNA expression profile of various MMPs in MMP-12 knockout mice under normal conditions is also different to their expression in wild-type mice.Conclusions In the ischaemic brain,MMP-12 upregulates several fold higher than any other MMP.Mice derived with the genetic deletion of MMP-12 are constitutive and have altered MMP expression profile both under normal and ischaemic conditions.

关键词： MMPs removing hypothesis

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A cadaveric breast cancer tissue phantom for phase-contrast X-ray imaging applications

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Animal Models and Experimental Medicine 2023年第5期6卷 427-432页

作者： Cody C.Rounds Chengyue Li Wei Zhou Kenneth M.Tichauer Jovan G.Brankov Biomedical Engineering Illinois Institute of TechnologyChicagoIllinoisUSA Medical Imaging Research Center Illinois Institute of TechnologyChicagoIllinoisUSA Electrical and Computer Engineering Illinois Institute of TechnologyChicagoIllinoisUSA

Background:As mammography X-ray imaging technologies advance and provide elevated contrast in soft tissues,a need has developed for reliable imaging phantoms for use in system design and component calibration.In advanced imaging modalities such as refraction-based methods,it is critical that developed phantoms capture the biological details seen in clinical precancerous and cancerous cases while minimizing artifacts that may be caused due to phantom production.This work presents the fabrication of a breast tissue imaging phantom from cadaveric breast tissue suitable for use in both transmission and refraction-enhanced imaging systems.Methods:Human cancer cell tumors were grown orthotopically in nude athymic mice and implanted into the fixed tissue while maintaining the native tumor/adipose tissue interface.Results:The resulting human–murine tissue hybrid phantom was mounted on a clear acrylic housing for absorption and refraction X-ray imaging.Digital breast tomosynthesis was also performed.Conclusion:Both attenuation-based imaging and refraction-based imaging of the phantom are presented to confirm the suitability of this phantom's use in both imaging modalities.

关键词： breast tumors digital mammography imaging phantoms orthotopic animal models phasecontrast X-ray imaging

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Sodium and water perturbations in patients who had an acute stroke:clinical relevance and management strategies for the neurologist

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Stroke & Vascular Neurology 2022年第3期7卷 258-266页

作者： Kevin C J Yuen Valerie Sharf Elizabeth Smith Minhwan Kim Alissya S M Yuen Paul R MacDonald Departments of Neuroendocrinology and Neurosurgery Barrow Neurological InstitutePhoenixArizonaUSA University of Arizona College of Medicine and Creighton School of Medicine PhoenixArizonaUSA Department of Neurology Barrow Neurological InstitutePhoenixArizonaUSA Midwestern University GlendaleIllinoisUSA Creighton University School of Medicine PhoenixArizonaUSA University of California Davis DavisCaliforniaUSA

Sodium and water perturbations,manifesting as hyponatraemia and hypernatraemia,are common in patients who had an acute stroke,and are associated with worse outcomes and increased mortality.Other non-stroke related causes of sodium and water perturbations in these patients include underlying comorbidities and concomitant medications.Additionally,hospitalised patients who had an acute stroke may receive excessive intravenous hypotonic solutions,have poor fluid intake due to impaired neurocognition and consciousness,may develop sepsis or are administered drugs(eg,mannitol);factors that can further alter serum sodium levels.Sodium and water perturbations can also be exacerbated by the development of endocrine consequences after an acute stroke,including secondary adrenal insufficiency,syndrome of inappropriate antidiuretic hormone secretion and diabetes insipidus.Recently,COVID-19 infection has been reported to increase the risk of development of sodium and water perturbations that may further worsen the outcomes of patients who had an acute stroke.Because there are currently no accepted consensus guidelines on the management of sodium and water perturbations in patients who had an acute stroke,we conducted a systematic review of the literature published in English and in peer-reviewed journals between January 2000 and December 2020,according to PRISMA guidelines,to assess on the current knowledge and clinical practices of this condition.In this review,we discuss the signs and symptoms of hyponatraemia and hypernatraemia,the pathogenesis of hyponatraemia and hypernatraemia,their clinical relevance,and we provide our recommendations for effective treatment strategies for the neurologist in the management of sodium and water perturbations in commonly encountered aetiologies of patients who had an acute stroke.

关键词： patients impaired consequences

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Opening already occluded middle cerebral artery,internal carotid artery or other cerebral arteries:when,where,how and why?

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Stroke & Vascular Neurology 2017年第3期2卷 106-107页

作者： David Wang Yongjun Wang osf/INI Stroke Network and Comprehensive Stroke Center OSF Saint Francis Medical CenterPeoriaIllinoisUSA Department of Neurology University of Illinois College of Medicine at PeoriaPeoriaIllinoisUSA China National Clinical Research Center for neurological Diseases BeijingChina Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina

Time is of essence in saving brain cells in patients with acute ischaemic stroke,the faster the treatment,the better the outcome.The time window for intravenous tissue plasminogen activator(tPA)treatment is<3 hours.With the recent success of multiple bridging trials,the treatment time window has been opened up to 6-8 hours.In fact,both Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset and Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times trials have treated patients between 8 and 12 hours from the onset.12 We know that the number needed to treat(NNT)to have the benefit for intrave-nous tPA is 1 in 3.In bridging therapy,intra-venous tPA plus intra-arterial thrombectomy within 6 hours of onset,the NNT is 1 in 2-4.

关键词： cerebral Acute acute

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Simultaneous determination of LY3214996,abemaciclib,and M2 and M20 metabolites in human plasma,cerebrospinal fluid,and brain tumor by LC-MS/MS

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Journal of Pharmaceutical Analysis 2022年第4期12卷 601-609页

作者： Tigran Margaryan Mackenna Elliott Nader Sanai Artak Tovmasyan Ivy Brain Tumor Center Barrow Neurological InstitutePhoenixAZ85013USA

A sensitive and rapid liquid chromatography tandem mass spectrometry(LC-MS/MS)method was established for the quantification of total and unbound concentrations of LY3214996,an extracellular signal-regulated kinase inhibitor;abemaciclib,a cyclin-dependent kinase 4/6 inhibitor;and abemaciclib active metabolites,M2 and M20,in human plasma,brain tumor,and cerebrospinal fluid samples.The method was validated over a concentration range of 0.2e500 nM within a total run time of 3.8 min using isocratic elution on a Kinetex^(TM) F_(5) column.Detection was performed on a Sciex QTRAP 6500t mass spectrometer employing multiple reaction monitoring mode under positive electrospray ionization.The intra-and inter-batch accuracy as well as the precision of the method for all matrices was within ±20% and ≤20% at the lower limit of quantification,and within ±15% and ≤15% for other quality control levels for all analytes.The unbound fractions of drugs and metabolites in spiked and patient samples were determined using an optimized equilibrium dialysis.The validated method was successfully applied in a phase 0/2 clinical trial to assess the central nervous system penetration of LY3214996 and abemaciclib.

关键词： LC-MS/MS LY3214996 Abemaciclib Brain tumor penetration Equilibrium dialysis

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Mindscape and Its Effect on Cities' Sustainability:A Case Study of Bronzeville Neighborhood—Chicago

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Chinese Journal of Urban and Environmental Studies 2023年第3期11卷 88-116页

作者： Ali MOAZZENI KHORASGANI Maria H.VILLALOBOS Landscape Architecture + Urbanism Program illinois institute of Technology illinois institute of Technology

Neighborhoods and urban contexts are full of potential hidden inside them in an intangible form and can be used for their development and sustainability. Therefore, studying, discovering, and using them can help revive worn and historical textures. These mental factors include things not in the city’s outward appearance but in its heart and memory. The mindscape of the city includes everything that has meaning for its residents. Collective memories lead to strengthening their sense of belonging. The sense of belonging and collective memory is one factor that promotes social participation in the neighborhood and urban contexts. Social involvement is an efficient factor in facilitating neighborhood management, attracting investment, and helping environmental issues. Finally, it plays an influential role in sustaining life in urban contexts. Despite the plans that have been made to promote the sense of collective memory and increase the sense of belonging to the place, Chicago’s Bronzeville neighborhood has yet to achieve its growth and prosperity as in the past. Therefore, this paper focuses on studying how mindscape can help the sustainability and development of cities. The research method in this paper is based on document study, the review of documents related to prominent research in the fields of objective landscape,place identity, sense of place, and surface, and was carried out by descriptive-analytical research method. The method of collecting information is in two forms: documentary and field. Field information will be collected through two questionnaires(see Appendices A and B) from residents and experts. In this research, after reviewing and studying the documents and analyzing the field data, we present the proposed model of the influential factors of the mental landscape in the sustainability of urban contexts and draw the following conclusions: The concept of the mindscape holds significant importance in the context of creating sustainable cities and communities. It encompasses belonging, collective m

关键词： Mindscape sustaining regeneration Bronzeville collective memory social participation

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PET imaging in ischemic cerebrovascular disease:current status and future directions

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Neuroscience Bulletin 2014年第5期30卷 713-732页

作者： Wolf-Dieter Heiss Max Planck institute for neurological Research

Cerebrovascular diseases are caused by interruption or significant impairment of the blood supply to the brain, which leads to a cascade of metabolic and molecular alterations resulting in functional disturbance and morphological damage. These pathophysiological changes can be assessed by positron emission tomography （PET）, which permits the regional measurement of physiological parameters and imaging of the distribution of molecular markers. PET has broadened our understanding of the flow and metabolic thresholds critical for the maintenance of brain function and morphology： in this application, PET has been essential in the transfer of the concept of the penumbra （tissue with perfusion below the functional threshold but above the threshold for the preservation of morphology） to clinical stroke and thereby has had great impact on developing treatment strategies. Radioligands for receptors can be used as early markers of irreversible neuronal damage and thereby can predict the size of the final infarcts; this is also important for decisions concerning invasive therapy in large （＂malignant＂） infarctions. With PET investigations, the reserve capacity of blood supply to the brain can be tested in obstructive arteriosclerosis of the supplying arteries, and this again is essential for planning interventions. The effect of a stroke on the surrounding and contralateral primarily unaffected tissue can be investigated, and these results help to understand the symptoms caused by disturbances in functional networks. Chronic cerebrovascular disease causes vascular cognitive disorders, including vascular dementia. PET permits the detection of the metabolic disturbances responsible for cognitive impairment and dementia, and can differentiate vascular dementia from degenerative diseases. It may also help to understand the importance of neuroinflammation after stroke and its interaction with amyloid deposition in the development of dementia. Although the clinical application of PET investigations is limited, this technology had

关键词： stroke dementia PET brain metabolism brain ischemia

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Differentiation and functional connectivity of fetal tectal transplants

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Neural Regeneration Research 2023年第11期18卷 2325-2331页

作者： Alan R.Harvey School of Human Sciences The University of Western AustraliaLions Eye Instituteand Perron Institute for Neurological and Translational ScienceNedlandsWAAustralia

Data from studies analyzing the differentiation and functional connectivity of embryo nic neural tissue grafted into the mammalian nervous system has led to the clinical testing of the fetal graft approach in patients with neurodegenerative disease.While some success has been achieved,ethical concerns have led to a search for alternative therapeutic strategies,mostly exploring the use of neural precursors or neurons derived from pluripotent stem cells to replace damaged host neurons and restore lost circuitries.These more recent studies address questions of graft viability,differentiation,and connectivity similar to those posed by researchers in earlier fetal transplant work,thus reviews of the fetal graft literature may inform and help guide ongoing research in the stem cell/organoid field.This brief review describes some key observations from research into the transplantation of neural tissue into the rat visual syste m,focusing on grafts of the fetal supe rior colliculus(tectal grafts) into neonatal or adult hosts.In neonate hosts,grafts quickly develop connections with the underlying host mid b rain and attain a morphology typical of mature grafts by about 2 weeks.G rafts consistently contain numerous localized regions which,based on neurofibrillar staining,neuronal morphology(Golgi),neurochemistry,receptor expression,and glial architecture,are homologous to the stratum griseum supe rficiale of normal superior colliculus.These localized "patches" are also seen after explant culture and when donor tectal tissue is dissociated and reaggregated prior to transplantation.In almost all circumstances,host retinal innervation is restricted to these localized patches,but only those that are located adjacent to the graft surfa ce.Synapses are formed and there is evidence of functional drive.The only exception occurs when Schwann cells are added to dissociated tecta prior to reaggregation.In these co-grafts,the peripheral glia appear to compete with local target fa ctors and host retinal ingrowth is more widespread.Othe

关键词： axon regeneration differentiation embyronic grafts fetal tissue neural precursors retinotectal stem cells superior colliculus synaptogenesis transplantation

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