Strokes are a leading cause of death and disability in the United States, predominantly caused by ischemic events. Ischemic strokes occur when a clot or other obstruction lodges in a blood vessel of the brain, restricting the movement of blood. Subsequent rapid cell death occurs and often leads to long term neurological deficits. Pial collaterals are a well-established determinant of patient outcome due to their unique ability to remodel into conductance arteries that can reroute blood back to the ischemic tissue. During development, pial collaterals arise within the pia mater and establish connections between distant arterioles of cerebral arteries. Under healthy conditions, these vessels are exposed to bidirectional blood flow, keeping them small and dormant. Following vascular obstruction, pial collaterals are exposed to unidirectional blood flow, triggering them to expand through an adaptive process termed, arteriogenesis, allowing for retrograde perfusion into the obstructed artery and its affected tissue. However, hyperacute arteriogenesis following ischemic stroke has been poorly investigated. The following dissertation aims to address this research gap and leverage the findings to develop therapeutics that enhance arteriogenesis. Previous research has revealed EphA4 restricts arteriogenesis through the Tie2 signaling axis, therefore this work sought to evaluate the endothelial cell (EC) specific role of the EphA4/Tie2 axis in acute arteriogenesis. EC-specific EphA4 KO mice displayed increased pial collateral size from 4.5 to 24-hours post-injury, which was associated with reduced tissue damage, improved cerebral blood flow, and enhanced motor function. Additionally, pharmaceutical stimulation of the Tie2 axis using Vasculotide, an angiopoietin-1 memetic peptide, replicates these findings. Administration of 3ug/kg Vasculotide to wildtype mice immediately after permanent middle cerebral artery occlusion leads to significantly larger pial collateral diameters, correlating with reduced tissue damage and improved functional recovery. Unlike Vasculotide, device stimulation using low intensity focused ultrasound failed to increase collateral diameter, despite resulting in profound neuroprotection. Taken together, this dissertation work demonstrates that the EphA4/Tie2 signaling pathway can be pharmacologically targeted to improve arteriogenesis following ischemic stroke. / Ph.D. / Worldwide, strokes are a leading cause of death and long-term disability with many cases being ischemic strokes, where a blood clot blocks blood flow to the brain. Without the critical oxygen and nutrients that the blood provides, cells in the affected region of the brain begin to rapidly die, leading to neurological deficits. While current treatments focus on removing the clot, it does not guarantee the restoration of blood flow to the damaged area. In contrast, our research focuses on pre-existing blood vessels in the brain, called pial collaterals, that can ease the loss of blood flow after stroke. These vessels, although relatively inactive under normal conditions, can enlarge after a stroke to reroute blood flow to the injured tissue. Thus, pial collateral growth is a critical process in the initial hours after stroke when this blood flow can prevent brain cells from dying. Previous work has shown EphA4, a receptor known for its role in nervous system development, restricts pial collateral size by inhibiting the Tie2 signaling pathway. Loss of EphA4 in endothelial cells allows for Tie2 receptor activation, increased pial collateral size, and decreased tissue damage. To explore therapeutic enhancement of pial collaterals, we administered Vasculotide, a drug that activates the Tie2 receptor, to wildtype mice expressing EphA4 after a stroke. The mice treated with Vasculotide displayed significantly larger pial collateral vessels one day after the stroke, compared to control mice. Moreover, Vasculotide-treated mice exhibited reduced tissue damage and performed better on behavioral assessments. In addition to pharmaceutical stimulation with Vasculotide, we also investigated the effects of low-intensity focused ultrasound (LIFU) on collateral size. LIFU treatment resulted in decreased tissue damage compared to untreated controls; however, it did not impact collateral size. These findings suggest that inhibiting EphA4 or stimulating Tie2 could serve as novel therapeutic targets to promote the expansion of pial collateral blood vessels, thereby restoring critical blood flow to injured areas of the brain.

Exploateringsavtal används för att fördela ansvaret för finansiering och utbyggnad av en detaljplan som upprättats på mark som inte ägs av kommunen. Avtalet upprättas mellan en kommun och en exploatör eller privat byggherre. Exploateringsavtal har tillämpats länge men blev inte angivet i lagtext förrän den 1 januari 2015. Något som fortfarande inte är angivet i lagtext är hur kommuner ska använda sig av ekonomiska säkerheter i exploateringsavtal. Avtalen reglerar finansiering och åtaganden för miljonbelopp och finansiering ska ofta ske efterhand som byggnationen färdigställs. Om en exploatör inte kan fullfölja sina åtaganden i exploateringsavtalet på grund av exempelvis konkurs, kan kommunen bli tvungen att färdigställa och finansiera exploatörens kvarstående åtagande. Har kommunen i avtalet angivit att en säkerhet måste ställas som ska täcka de belopp som motsvarar exploatörens åtaganden, kan kommunen lösa in säkerheten och på det viset säkra finansieringen om en exploatör skulle bli oförmögen att betala. Syftet med studien är att undersöka om Sveriges kommuner använder sig av säkerheter i exploateringsavtal för att säkerställa dess genomförande. Vidare är syftet med studien att kartlägga vilka säkerheter som anges i exploateringsavtal. I de fall en bankgaranti använts som säkerhet i exploateringsavtalen kommer även en fördjupning att genomföras av bankgarantin och dess bakomliggande exploateringsavtal. Exploateringsavtal och bankgarantier från Sveriges kommuner samlades in via mejl. 120kommuner valde att delta i studien vilket resulterade i en analys av 197 exploateringsavtaloch 35 bankgarantier. Resultatet av studien visar bland annat att 58 % av de 197 exploateringsavtalen innehöllsäkerhet, 37 % av avtalen saknar säkerhet och 5 % av avtalen inte har något behov av säkerhet. De vanligaste säkerheterna som kommunerna anger i exploateringsavtalen att exploatören måste ställa är valfri godtagbar säkerhet, bankgaranti, moderbolagsborgen och pantbrev i fast egendom. Resultatet visar även att 69 % av de 35 bankgarantier som studeratsär accessoriska till det bakomliggande exploateringsavtalet och 31 % av bankgarantierna är självständiga i förhållande till det bakomliggande exploateringsavtalet. Accessorisk innebär att bankgarantin är kopplad till det bakomliggande exploateringsavtalet. Självständig innebär att bankgarantin inte är kopplad till det bakomliggande exploateringsavtalet. Slutsatsen av studien är att medvetenheten och tydligheten kring säkerheter i exploateringsavtal bör förbättras och att en lagreglering av säkerheter är att föredra. / Land development agreements are used to divide responsibility for the financing and development of a detailed development plan which is arranged on land not owned by the municipality. The agreement is established between a municipality and a developer or private individual. Land development agreements were not specified in the act until a legislative change in January 1, 2015. A subject that was not specified in the act is how municipalities should use financial collateral in the land development agreement. Land development agreements involves the financing and constriction commitments for millions of crowns and the financing often take place afterwards construction is completed. If it turns out that the developer can´t perform their obligations in the land development agreement due to bankruptcy, the municipality may be required to complete and fund the developer's remaining commitments. If the municipality had stated in the agreement that the developer must perform a collateral to cover the amount corresponding to the developer's commitments, the municipality can redeem the collateral and thus secure the financing if a developer would become insolvent. The idea of the study is to examine if the Swedish municipalities are using collaterals in land development agreements. The ambition is also to identify what type of collaterals described in the land development agreements. Finally a deeper analysis will be made of the agreements for which a guarantee issued by a bank has been used as collateral. Land development agreements and guarantees from the Swedish municipalities were gathered via email. 120 municipalities did participate in the study, which resulted in ananalysis of 197 land development agreements and 35 guarantees. The result of the study shows that 58% of the 197 land development agreements contain collateral, 37% of the agreements did not contain collateral and 5% of the agreements had no need of collateral. The most commonly required collaterals by the municipality in land development agreements are any optional collateral that the municipality can accept, guarantees issued by a bank or insurance company, bail by parent company and mortgages on real estate property. The results also show that 69% of the 35 guarantees studied are ancillary to the underlying development agreement and 31% of the guarantees are independent in relation to the underlying development agreement. Ancillary means that the guarantees issued by bank is linked to the underlying land development agreement. Independent guarantee means that the guarantee is not linked to the underlying land development agreement.The final conclusion of the study is that awareness and clarity of collateral in land development agreements should be improved and that a statutory regulation of collaterals in land development agreements is preferable.

Stroke is a leading cause of morbidity and long-term neurological disability in the U.S. Ischemic stroke, which accounts for approximately 90% of all strokes, is the result of an occlusion in the arteriole cerebrovascular network. No effective treatment options exist to provide neuroprotection from occlusion, and limited success has been seen clinically when attempting to restore blood flow to vulnerable neural tissue regions. Enhancement of pial collateral remodeling (Arteriogenesis) has recently been shown to improve blood flow and mitigate neural tissue damage following stroke (1-3). Arteriogenesis is the remodeling of pre-existing arteriole vessel which are able to re-route blood to blood-deprived regions of tissue. Arteriogenesis requires endothelial cell (EC) and smooth muscle cell proliferation, extracellular matrix degradation and recruitment of circulating bone marrow-derived cells (4-6). Unlike spouting angiogenesis, which requires weeks following occlusion to develop, arteriogenesis begins as early as 24-48hrs post-stroke (7, 8) and can expeditiously enhance blood flow to ischemic regions, making it an attractive target for therapeutic intervention. Our preliminary studies, in an EphA4 global knockout mouse model, indicated that EphA4 receptor tyrosine kinase severely limits pial arteriole collateral formation. The preliminary work also showed that activation of EC EphA4 receptor in vitro inhibited vascular formation. Additionally, ECs lining the collateral vessel have been shown to play a role in collateral remodeling (9). Taken together, the objective of this dissertation was to elucidate the cell autonomous role of the EphA4 receptor and given the central role of the EC in collateral remodeling, we postulated that EphA4 receptor on ECs the limits pial collateral formations. Using a cell-specific loss-of-function approach, we tested the hypothesis that EC-specific EphA4 plays an important role in pial collateral development and remodeling after induced stroke. The results from this dissertation show that (1) EphA4 expression on ECs suppress the formation of pial collaterals during development and limits EC growth via suppression of p-Akt in vitro (2) EC-specific EphA4 ablation leads to increased collateral remodeling, enhanced blood flow recovery, tissue protection and improved neurological behavioral outcomes after stroke and (3) Mechanistically, EphA4 limits pial collateral remodeling via attenuation of the Tie2/Angiopoietin-2 signaling pathway. The work presented in this dissertation demonstrate that EphA4 can be targeted therapeutically to increase pial collateral remodeling to alleviate neurological deficits after ischemic stroke. / Doctor of Philosophy / Stroke is the fifth leading cause of death in the United States. Ischemic stroke is the most common type of stroke and occurs when blood flow to part of the brain is impeded. Lack of blood results in cell death and tissue damage in the brain. In an effort to restore blood flow, specialized blood vessels in the brain called collaterals remodel and become larger to allow re-routed blood to the blood-deprived region of the brain. The duration it takes to remodel these remarkable blood vessels and re-route blood varies in humans, and sometimes is not able to prevent adequate tissue damage. The current work explores novel therapeutic targets to accelerate collateral remodeling in an effort to reduce tissue loss after stroke. We present studies which show that a protein called EphA4, found on endothelial cells restricts remodeling, and when inhibited in the brain can increase collateral remodeling and reduced adverse effects after ischemic stroke.

Basel II initially focused on the banking sector; it hit bank clients significantly too. The core of the banking sector became the risk management. The internal rating is expressing the stability of client's economic situation and is the core stone of the business relationship between the bank and its client.

Peripheral arterial occlusive disease (PAOD) often presents as intermittent claudication, which may be caused by impaired vasodilation. Impairment of resistance vessels may contribute to the pathogenesis of PAOD, and explain the poor correlation between resting blood flow and limb function. Collateral function following arterial occlusion is not well defined, however collaterals and arterialized collateral capillaries (ACCs) in male and female animal models exhibit impaired vasodilation following arterial occlusion, which can potentially be improved with exercise training. Furthermore, resistance vessels in the ischemic tree and stem are likely involved in the pathogenesis of PAOD, however the relative importance of each is unknown. Therefore, we measured functional vasodilation in pre-existing collaterals, ACCs, the ischemic tree, and the stem region, 7 and 21-days following spinotrapezius feed artery ligation in male and female BALB/c mice, and with exercise therapy. Vasodilation in ACCs was more impaired in female mice than in males. Generally, vasodilation was impaired at day-7, likely due to impaired endothelium-dependent and smooth muscle-dependent vasodilation in maturing collaterals, and recovered by day-21. Exercise training appears to enhance collateral reactivity, more in ACCs in males than in females, suggesting that its therapeutic benefits are linked not only to structural adaptation but also to vessel functionality. Therefore, future research is required to determine the cause of sex differences in exercise therapy to treat peripheral arterial occlusive disease.

Background The Circle of Willis (CoW) is an arterial anastomotic circle located at the skull base thatmaintains collateral circulation in the brain. Variations in CoW anatomy are commonly presentin the general population. Absent or hypoplastic segments of the CoW have been linked to anincreased stroke risk. Aim To determine whether CoW completeness is related to future ischemic stroke in the elderlypopulation after adjustment for relevant clinical risk factors. Methods Consecutive patients that underwent computed tomography angiography (CTA) of the headbetween 2014-2015 (60 years or older) were included. CoW-integrity was determined on CTAimages. Patient journals were retrospectively examined for ischemic stroke events followingthe CTA. Cox proportional hazard regression analysis was performed to determine hazard forischemic stroke in patients with incomplete CoW. Results 147 patients were included. The median follow-up time was 6.4 years (interquartile range 3.0years). 17 ischemic stroke events occurred during the follow-up period. Age (hazard ratio, HR1.10, p=0.03) and gender (HR 0.25, p=0.04) were statistically significant risk factors forischemic stroke. Complete anterior and posterior CoW was associated with lower strokehazards, however, the association was not statistically significant (HR 0.36, p=0.34 and HR0.67, p=0.45, respectively). Conclusions No significant risk reduction could be observed for either complete posterior or anterior CoW.Sex and age were significant risk factors for ischemic stroke. Further research is necessary toinvestigate how CoW integrity influences stroke risk after adjustment for other risk factors.

Cholinergic input to, and cholinergic mechanisms within the lower lumbar (L6) and upper sacral (S1) spinal cord of rat may influence neuronal excitability and afferent transmission (Thor et al, 2000) and may provide the environment necessary for appropriate central nervous system control of bladder and bowel function. It is unclear, however, if cholinergic terminals and receptors are present in the L6 & S1 spinal segments of rat and when this may develop. Cholinergic mechanisms have been shown to alter sensory afferent transmission, enhance motoneuron excitability, induce plateau potentials via non-linear membrane properties in motoneurons and reveal oscillations in locomotor-related interneurons. The enhanced activity of sphincter motoneurons was attributed to non-linear properties during the continence phase of distention-evoked voiding in the decerebrate cat (Paroschy & Shefchyk, 2000). Candidate neurotransmitters inducing non-linear properties in cat sphincter motoneurons are 5-HT (Paroschy & Shefchyk, 2000) and acetylcholine via motoneuron axon collaterals (Sasaki, 1994) and other spinal sources. We have established using the antibody to the vesicular acetylcholine transporter (VAChT) that cholinergic terminals are present on ventrolateral Onuf (VLO), dorsomedial Onuf (DMO) motoneurons and parasympathetic preganglionic motoneurons (PGN) in the L6 and S1 rat spinal cord segments. Muscarinic receptor (M2), nicotinic-α4 and α7 receptor subunit immunoreactivity was also present on Onuf motoneurons and in regions dorsal to the PGN. One source of the cholinergic puncta on Onuf motoneurons may be from motoneuron axon collaterals which we observed on a postnatal day 15 VLO motoneuron. Cholinergic terminals were observed on vasoactive intestinal polypeptide-immunoreactive (VIP) afferents, interneurons in the intermediolateral (IML) region and perhaps on other afferents in the lateral and medial collateral pathway of L6 and S1 spinal segments. In the ventral horn, the cholinergic puncta and receptors appear to have a mature distribution around two weeks postnatal and the cholinergic terminals appeared to have a mature distribution in the IML region by three weeks postnatal. Using whole cell patch clamp recording techniques and thick slices of the L6 and S1 rat spinal cord, we observed excitatory responses of ventral horn neurons and motoneurons to carbachol (10-50 μM), a non-specific cholinergic agonist. Ventral horn neurons (postnatal day 8- 16) exhibited prolonged firing and prolonged depolarizations (plateau potentials) beyond the duration of the applied excitatory input from cholinergic (n=6/33) and other (n= 4/37) neurotransmitter systems. In a selection of the neurons with plateau potentials, the L-type calcium current played a role in the plateau production (n=5/5) and low frequency oscillations (n=2/2) as revealed by nifedipine. Postnatally, the voiding reflex changes from a perineal-evoked reflex, to the adult bladder-bladder reflex. Cholinergic input may be responsible in part for the bursting activity of the external urethral sphincter and the activation of the bladder, which is required for complete voiding reflexes in the adult rat. Plateau potentials and enhanced excitability due to cholinergic mechanisms could render inessential a constant excitatory drive that is required in the perineal-evoked voiding reflex in the neonatal rat and may underlie changes in the voiding reflexes that occur during postnatal development. / February 2006

Cholinergic input to, and cholinergic mechanisms within the lower lumbar (L6) and upper sacral (S1) spinal cord of rat may influence neuronal excitability and afferent transmission (Thor et al, 2000) and may provide the environment necessary for appropriate central nervous system control of bladder and bowel function. It is unclear, however, if cholinergic terminals and receptors are present in the L6 & S1 spinal segments of rat and when this may develop. Cholinergic mechanisms have been shown to alter sensory afferent transmission, enhance motoneuron excitability, induce plateau potentials via non-linear membrane properties in motoneurons and reveal oscillations in locomotor-related interneurons. The enhanced activity of sphincter motoneurons was attributed to non-linear properties during the continence phase of distention-evoked voiding in the decerebrate cat (Paroschy & Shefchyk, 2000). Candidate neurotransmitters inducing non-linear properties in cat sphincter motoneurons are 5-HT (Paroschy & Shefchyk, 2000) and acetylcholine via motoneuron axon collaterals (Sasaki, 1994) and other spinal sources. We have established using the antibody to the vesicular acetylcholine transporter (VAChT) that cholinergic terminals are present on ventrolateral Onuf (VLO), dorsomedial Onuf (DMO) motoneurons and parasympathetic preganglionic motoneurons (PGN) in the L6 and S1 rat spinal cord segments. Muscarinic receptor (M2), nicotinic-α4 and α7 receptor subunit immunoreactivity was also present on Onuf motoneurons and in regions dorsal to the PGN. One source of the cholinergic puncta on Onuf motoneurons may be from motoneuron axon collaterals which we observed on a postnatal day 15 VLO motoneuron. Cholinergic terminals were observed on vasoactive intestinal polypeptide-immunoreactive (VIP) afferents, interneurons in the intermediolateral (IML) region and perhaps on other afferents in the lateral and medial collateral pathway of L6 and S1 spinal segments. In the ventral horn, the cholinergic puncta and receptors appear to have a mature distribution around two weeks postnatal and the cholinergic terminals appeared to have a mature distribution in the IML region by three weeks postnatal. Using whole cell patch clamp recording techniques and thick slices of the L6 and S1 rat spinal cord, we observed excitatory responses of ventral horn neurons and motoneurons to carbachol (10-50 μM), a non-specific cholinergic agonist. Ventral horn neurons (postnatal day 8- 16) exhibited prolonged firing and prolonged depolarizations (plateau potentials) beyond the duration of the applied excitatory input from cholinergic (n=6/33) and other (n= 4/37) neurotransmitter systems. In a selection of the neurons with plateau potentials, the L-type calcium current played a role in the plateau production (n=5/5) and low frequency oscillations (n=2/2) as revealed by nifedipine. Postnatally, the voiding reflex changes from a perineal-evoked reflex, to the adult bladder-bladder reflex. Cholinergic input may be responsible in part for the bursting activity of the external urethral sphincter and the activation of the bladder, which is required for complete voiding reflexes in the adult rat. Plateau potentials and enhanced excitability due to cholinergic mechanisms could render inessential a constant excitatory drive that is required in the perineal-evoked voiding reflex in the neonatal rat and may underlie changes in the voiding reflexes that occur during postnatal development.

Cholinergic input to, and cholinergic mechanisms within the lower lumbar (L6) and upper sacral (S1) spinal cord of rat may influence neuronal excitability and afferent transmission (Thor et al, 2000) and may provide the environment necessary for appropriate central nervous system control of bladder and bowel function. It is unclear, however, if cholinergic terminals and receptors are present in the L6 & S1 spinal segments of rat and when this may develop. Cholinergic mechanisms have been shown to alter sensory afferent transmission, enhance motoneuron excitability, induce plateau potentials via non-linear membrane properties in motoneurons and reveal oscillations in locomotor-related interneurons. The enhanced activity of sphincter motoneurons was attributed to non-linear properties during the continence phase of distention-evoked voiding in the decerebrate cat (Paroschy & Shefchyk, 2000). Candidate neurotransmitters inducing non-linear properties in cat sphincter motoneurons are 5-HT (Paroschy & Shefchyk, 2000) and acetylcholine via motoneuron axon collaterals (Sasaki, 1994) and other spinal sources. We have established using the antibody to the vesicular acetylcholine transporter (VAChT) that cholinergic terminals are present on ventrolateral Onuf (VLO), dorsomedial Onuf (DMO) motoneurons and parasympathetic preganglionic motoneurons (PGN) in the L6 and S1 rat spinal cord segments. Muscarinic receptor (M2), nicotinic-α4 and α7 receptor subunit immunoreactivity was also present on Onuf motoneurons and in regions dorsal to the PGN. One source of the cholinergic puncta on Onuf motoneurons may be from motoneuron axon collaterals which we observed on a postnatal day 15 VLO motoneuron. Cholinergic terminals were observed on vasoactive intestinal polypeptide-immunoreactive (VIP) afferents, interneurons in the intermediolateral (IML) region and perhaps on other afferents in the lateral and medial collateral pathway of L6 and S1 spinal segments. In the ventral horn, the cholinergic puncta and receptors appear to have a mature distribution around two weeks postnatal and the cholinergic terminals appeared to have a mature distribution in the IML region by three weeks postnatal. Using whole cell patch clamp recording techniques and thick slices of the L6 and S1 rat spinal cord, we observed excitatory responses of ventral horn neurons and motoneurons to carbachol (10-50 μM), a non-specific cholinergic agonist. Ventral horn neurons (postnatal day 8- 16) exhibited prolonged firing and prolonged depolarizations (plateau potentials) beyond the duration of the applied excitatory input from cholinergic (n=6/33) and other (n= 4/37) neurotransmitter systems. In a selection of the neurons with plateau potentials, the L-type calcium current played a role in the plateau production (n=5/5) and low frequency oscillations (n=2/2) as revealed by nifedipine. Postnatally, the voiding reflex changes from a perineal-evoked reflex, to the adult bladder-bladder reflex. Cholinergic input may be responsible in part for the bursting activity of the external urethral sphincter and the activation of the bladder, which is required for complete voiding reflexes in the adult rat. Plateau potentials and enhanced excitability due to cholinergic mechanisms could render inessential a constant excitatory drive that is required in the perineal-evoked voiding reflex in the neonatal rat and may underlie changes in the voiding reflexes that occur during postnatal development.

Credit is an asset of the creditor that can be transferred, allowing event the constitutionof a security on it. Now, despite the fact that the remuneration the worker perceives is also a credit, the Law of Movable Collaterals has expressly excluded security possibilities on it, limiting the property right of the worker and economically damaging him. Is this right?In this article, the author develops the answer to this question, through a systematic interpretation of Peruvian legislation and the credit figure as an object of movable collateral. / El crédito es un activo del acreedor que puede ser transferido, permitiéndose, incluso, que se constituya garantía sobre el mismo. Ahora bien, pese a que la remuneración quepercibe el trabajador también es un crédito, la Ley de Garantía Mobiliaria la ha excluido expresamente de las posibilidades de garantía, limitando el derecho de propiedad del trabajador y perjudicándolo económicamente. ¿Es esto correcto?En el presente artículo, el autor desarrolla la respuesta a dicha interrogante, mediante una interpretación sistemática de la normativa peruana y la figura del crédito como objeto de garantía mobiliaria.