Tissue plasminogen activator-mediated PDGF signaling and neurovascular coupling in stroke.

The use of tissue plasminogen activator (tPA) as a thrombolytic treatment in ischemic stroke is limited largely due to concerns for hemorrhagic complications. The underlying mechanisms are still unknown, but evidence is beginning to emerge that tPA interacts with key regulators of the neurovascular unit (NVU), and that these interactions may contribute to the undesirable side effects associated with the use of tPA in ischemic stroke. Understanding these connections and tPA's normal function within the NVU may offer new insights into future therapeutic approaches.

Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of transforming growth factor beta-mediated cardiac fibrosis in experimental autoimmune myocarditis.

Rationale: Myocardial fibrosis is a hallmark of inflammation-triggered end-stage heart disease, a common cause of heart failure in young patients.

Objective: We used CD4(+) T-cell-mediated experimental autoimmune myocarditis model to determine the parameters regulating cardiac fibrosis in inflammatory heart disease.

Methods And Results: alpha-Myosin heavy chain peptide/complete Freund's adjuvant immunization was used to induce experimental autoimmune myocarditis in BALB/c mice.

A survey of ABCA1 sequence variation confirms association with dementia.

We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1,567 Swedish dementia cases (including 1,275 with Alzheimer disease) and 2,203 controls, providing evidence of association with maximum significance at marker rs2230805 (odds ratio [OR]=1.39; 95% confidence interval [CI] 1.

Angiogenesis inhibition causes hypertension and placental dysfunction in a rat model of preeclampsia.

Background: Preeclampsia is a serious pregnancy complication, accompanied by increased maternal and fetal morbidity. Different models have been used to study preeclampsia, but none of these display all the key features of the disease.

Method: We investigated the effects on maternal blood pressure and fetal outcome exerted by the angiogenesis inhibitor Suramin (100 mg/kg i.

Optical coherence tomography is helpful in the diagnosis of foveal hypoplasia.

Purpose: To investigate whether optical coherence tomography (OCT) is helpful in the diagnosis of foveal hypoplasia in children.

Methods: Children with albinism and aniridia were examined with Stratus OCT 3 software 4.0.

SOD1 deficiency causes salt sensitivity and aggravates hypertension in hydronephrosis.

Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with nitric oxide deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt sensitivity and for hypertension in hydronephrosis. Hydronephrosis was induced in superoxide dismutase 1-transgenic (SOD1-tg), SOD1-deficient (SOD1-ko), and wild-type mice and in rats.

PDGF-C and -D and their receptors PDGFR-alpha and PDGFR-beta in atherosclerotic human arteries.

Background: Platelet derived growth factors (PDGFs) are mitogens for fibroblasts and smooth muscle cells. This growth factor family contains four members PDGF-A, PDGF-B, PDGF-C and PDGF-D. Biology of recently discovered PDGF-C and PDGF-D is not well-established.

Prominin-1/CD133+ lung epithelial progenitors protect from bleomycin-induced pulmonary fibrosis.

Rationale: The mouse model of bleomycin-induced lung injury offers an approach to study idiopathic pulmonary fibrosis, a progressive interstitial lung disease with poor prognosis. Progenitor cell-based treatment strategies might combine antiinflammatory effects and the capacity for tissue repair.

Objectives: To expand progenitor cells with reparative and regenerative capacities and to evaluate their protective effects on pulmonary fibrosis in vivo.

SPG11 mutations cause Kjellin syndrome, a hereditary spastic paraplegia with thin corpus callosum and central retinal degeneration.

Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is genetically heterogenous and approximately 35% of patients carry mutations in either of the SPG11 or SPG15 genes. Disease onset is during the first three decades of life with spastic paraplegia and mental impairment. Peripheral neuropathy and amyotrophy may occur.

Vascular endothelial growth factor-B induces myocardium-specific angiogenesis and arteriogenesis via vascular endothelial growth factor receptor-1- and neuropilin receptor-1-dependent mechanisms.

Background: New revascularization therapies are urgently needed for patients with severe coronary heart disease who lack conventional treatment options.

Methods And Results: We describe a new proangiogenic approach for these no-option patients using adenoviral (Ad) intramyocardial vascular endothelial growth factor (VEGF)-B186 gene transfer, which induces myocardium-specific angiogenesis and arteriogenesis in pigs and rabbits. After acute infarction, AdVEGF-B186 increased blood vessel area, perfusion, ejection fraction, and collateral artery formation and induced changes toward an ischemia-resistant myocardial phenotype.

Specific local cardiovascular changes of Nepsilon-(carboxymethyl)lysine, vascular endothelial growth factor, and Smad2 in the developing embryos coincide with maternal diabetes-induced congenital heart defects.

Objective: Embryos exposed to a diabetic environment in utero have an increased risk to develop congenital heart malformations. The mechanism behind the teratogenicity of diabetes still remains enigmatic. Detrimental effects of glycation products in diabetic patients have been well documented.

Congenital anomalies in diabetic pregnancy.

Congenital malformations are more common in infants of diabetic women than in children of non-diabetic women. The etiology, pathogenesis and prevention of the diabetes-induced malformations have spurred considerable clinical and basic research efforts. The ultimate aim of these studies has been to obtain an understanding of the teratogenic process, which may enable precise preventive therapeutic measures in diabetic pregnancies.

Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts.

Cancer results from the concerted performance of malignant cells and stromal cells. Cell types populating the microenvironment are enlisted by the tumor to secrete a host of growth-promoting cues, thus upholding tumor initiation and progression. Platelet-derived growth factors (PDGF) support the formation of a prominent tumor stromal compartment by as of yet unidentified molecular effectors.

Future therapeutic strategies in inflammatory cardiomyopathy: insights from the experimental autoimmune myocarditis model.

Inflammatory cardiomyopathy is a common cause of heart failure developing on a basis of cardiac inflammation. Cardiac inflammation - or myocarditis - is usually triggered by infections or cardiac damage of any cause. Experimental autoimmune myocarditis refers to a CD4(+) T cell-mediated mouse model of inflammatory cardiomyopathy.

PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns.

Platelet-derived growth factor (PDGF)-BB is a well-known smooth muscle (SM) cell (SMC) phenotypic modulator that signals by binding to PDGF alphaalpha-, alphabeta-, and betabeta-membrane receptors. PDGF-DD is a recently identified PDGF family member, and its role in SMC phenotypic modulation is unknown. Here we demonstrate that PDGF-DD inhibited expression of multiple SMC genes, including SM alpha-actin and SM myosin heavy chain, and upregulated expression of the potent SMC differentiation repressor gene Kruppel-like factor-4 at the mRNA and protein levels.

Macular thickness decreases with age in normal eyes: a study on the macular thickness map protocol in the Stratus OCT.

Background/aim: Retinal and retinal nerve fibre layer (RNFL) thinning with age have been described in histological studies. In vivo techniques like optical coherence tomography (OCT) have shown thinning of optic nerve RNFL and the retina in specific areas. One would expect thinning of the total macula, but so far, no correlation with the quantitative OCT macular map tool and age has been found.

The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth.

Members of the platelet-derived growth factor (PDGF) family are mitogens for cells of mesenchymal origin and have important functions during embryonic development, blood vessel maturation, fibrotic diseases and cancer. In contrast to the two classical PDGFs, the novel and less well-characterized members, PDGF-CC and PDGF-DD, are latent factors that need to be processed extracellularly by activating proteases, before they can mediate PDGF receptor activation. Here, we elucidate the structural requirements for urokinase plasminogen activator (uPA)-mediated activation of PDGF-DD, as well as the intricate interplay with uPA receptor (uPAR) signalling.

Repeatability in and interchangeability between the macular and the fast macular thickness map protocols: a study on normal eyes with Stratus optical coherence tomography.

Purpose: To collect a normal material and to compare the macular and the fast macular thickness map protocols regarding normal values and repeatability.

Methods:  Sixty-seven individuals underwent three repeated scans with the macular thickness protocol; 45 of them also had three scans with the fast thickness protocol in Stratus optical coherence tomography (OCT). The maps were divided into nine ETDRS fields, where thickness values were presented.

Novel role for vascular endothelial growth factor (VEGF) receptor-1 and its ligand VEGF-B in motor neuron degeneration.

Although vascular endothelial growth factor-B (VEGF-B) is a homolog of the angiogenic factor VEGF, it has only minimal angiogenic activity, raising the question of whether this factor has other (more relevant) biological properties. Intrigued by the possibility that VEGF family members affect neuronal cells, we explored whether VEGF-B might have a role in the nervous system. Here, we document that the 60 kDa VEGF-B isoform, VEGF-B(186), is a neuroprotective factor.

Vascular endothelial growth factor-A and platelet-derived growth factor-B combination gene therapy prolongs angiogenic effects via recruitment of interstitial mononuclear cells and paracrine effects rather than improved pericyte coverage of angiogenic vessels.

Vessel stabilization and the inhibition of side effects such as tissue edema are essential in angiogenic gene therapy. Thus, combination gene transfers stimulating both endothelial cell and pericyte proliferation have become of interest. However, there is currently little data to support combination gene transfer in large animal models.

A population-based study of macular thickness in full-term children assessed with Stratus OCT: normative data and repeatability.

Purpose:  We aimed to determine normal macular thickness values, assessed with optical coherence tomography (OCT), in a population of full-term children of normal birthweight.

Methods:  A total of 56 children, aged 5-16 years, randomly chosen from the population register, were examined with Stratus OCT. Only children with visual acuity < 0.

Decreased cardiac glutathione peroxidase levels and enhanced mandibular apoptosis in malformed embryos of diabetic rats.

Objective: To characterize normal and malformed embryos within the same litters from control and diabetic rats for expression of genes related to metabolism of reactive oxygen species (ROS) or glucose as well as developmental genes.

Research Design And Methods: Embryos from nondiabetic and streptozotocin-induced diabetic rats were collected on gestational day 11 and evaluated for gene expression (PCR) and distribution of activated caspase-3 and glutathione peroxidase (Gpx)-1 by immunohistochemistry.

Results: Maternal diabetes (MD group) caused growth retardation and an increased malformation rate in the embryos of MD group rats compared with those of controls (N group).

Prominin-1+/CD133+ bone marrow-derived heart-resident cells suppress experimental autoimmune myocarditis.

Aims: Experimental autoimmune myocarditis (EAM) is a CD4(+) T cell-mediated mouse model of inflammatory heart disease. Tissue-resident bone marrow-derived cells adopt different cellular phenotypes depending on the local milieu. We expanded a specific population of bone marrow-derived prominin-1-expressing progenitor cells (PPC) from healthy heart tissue, analysed their plasticity, and evaluated their capacity to protect mice from EAM and heart failure.

Sudden death after open gastric bypass surgery.

Purpose: Gastric bypass surgery has become a relatively low-risk bariatric surgical intervention in a high-risk patient population (Nguyen et al., Arch Surg, 141:445-449, 2006; Buchwald et al. JAMA, 13:1724-1737, 2004).