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)-B 186 gene transfer, which induces myocardium-specific angiogenesis and arteriogenesis in pigs and rabbits. After acute infarction, AdVEGF-B 186 increased blood vessel area, perfusion, ejection fraction, and collateral artery formation and induced changes toward an ischemia-resistant myocardial phenotype. Soluble VEGF receptor-1 and soluble neuropilin receptor-1 reduced the effects of AdVEGF-B 186 , whereas neither soluble VEGF receptor-2 nor inhibition of nitric oxide production had this result. Key Words: angiogenesis Ⅲ gene therapy Ⅲ metabolism Ⅲ myocardial infarction S evere coronary heart disease is still a leading cause of death in developed countries in spite of improved management of risk factors and more effective treatments. It is estimated that approximately 5 million people in the United States and the European Union have ischemic heart disease; however, a steadily increasing number of patients fall into a category in which currently available revascularization techniques cannot be applied. This is especially true of elderly patients who have had multiple bypass and stenting operations. 1 It is estimated that these patients represent up to 3% to 5% of all patients in specialty cardiology clinics. Thus, there is a clear need to develop efficient, minimally invasive procedures for the treatment of these no-option patients. Clinical Perspective p 856Therapeutic vascular growth (ie, angiogenesis and arteriogenesis) with genes or proteins has been suggested as an alternative approach for the treatment of these patients. 2 Vascular endothelial growth factors (VEGFs) are potent inducers of vascular growth via binding to 3 tyrosine kinase receptors (VEGFRs). VEGFR-2 is the main regulator of angiogenesis, exerting its function via nitric oxide production, whereas the role of VEGFR-1 is far less defined. 3 VEGF-B 4 and placental growth factor (PlGF) 3 share structural and functional characteristics and bind to VEGFR-1, whereas VEGF-A 5 binds to both VEGFR-1 and VEGFR-2. 846 Circulation

Background— Lymphedema after surgery, infection, or radiation therapy is a common and often incurable problem. Application of lymphangiogenic growth factors has been shown to induce lymphangiogenesis and to reduce tissue edema. The therapeutic effect of autologous lymph node transfer combined with adenoviral growth factor expression was evaluated in a newly established porcine model of limb lymphedema. Methods and Results— The lymphatic vasculature was destroyed within a 3-cm radius around an inguinal lymph node. Lymph node grafts and adenovirally (Ad) delivered vascular endothelial growth factor (VEGF)-C (n=5) or VEGF-D (n=9) were used to reconstruct the lymphatic network in the inguinal area; AdLacZ (β-galactosidase; n=5) served as a control. Both growth factors induced robust growth of new lymphatic vessels in the defect area, and postoperative lymphatic drainage was significantly improved in the VEGF-C/D–treated pigs compared with controls. The structure of the transferred lymph nodes was best preserved in the VEGF-C–treated pigs. Interestingly, VEGF-D transiently increased accumulation of seroma fluid in the operated inguinal region postoperatively, whereas VEGF-C did not have this side effect. Conclusions— These results show that growth factor gene therapy coupled with lymph node transfer can be used to repair damaged lymphatic networks in a large animal model and provide a basis for future clinical trials of the treatment of lymphedema.

Lithium was the most effective mood stabilizer, and long-acting injections the most effective antipsychotics, in preventing hospitalization due to mental or physical illness.

Our results suggest that silencing of either SR-A or CD36 alone reduces atherogenesis in mice. However, due to reciprocal upregulation, silencing of both SR-A and CD36 is not effective.

Lymphangiogenic growth factors improve lymphatic vessel regeneration and lymph node function after lymph node transfer. The perinodal route of delivery provides a basis for future clinical trials in lymphedema patients.

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It has remained unclear why schizophrenia typically manifests after adolescence and which neurobiological mechanisms are underlying the cascade leading to the actual onset of the illness. Here we show that the use of induced pluripotent stem cell-derived neurons of monozygotic twins from pairs discordant for schizophrenia enhances disease-specific signal by minimizing genetic heterogeneity. In proteomic and pathway analyses, clinical illness is associated especially with altered glycosaminoglycan, GABAergic synapse, sialylation, and purine metabolism pathways. Although only 12% of all 19,462 genes are expressed differentially between healthy males and females, up to 61% of the illness-related genes are sex specific. These results on sex-specific genes are replicated in another dataset. This implies that the pathophysiology differs between males and females, and may explain why symptoms appear after adolescence when the expression of many sex-specific genes change, and suggests the need for sex-specific treatments.

Introduction: Core psychopathy is characterized by grandiosity, callousness, manipulativeness, and lack of remorse, empathy, and guilt. It is often comorbid with conduct disorder and antisocial personality disorder (ASPD). Psychopathy is present in forensic as well as prison and general populations. In recent years, an increasing amount of neuroimaging studies has been conducted in order to elucidate the obscure neurobiological etiology of psychopathy. The studies have yielded heterogenous results, and no consensus has been reached.Aims: This study systematically reviewed and qualitatively summarized functional and structural neuroimaging studies conducted on individuals with psychopathic traits. Furthermore, this study aimed to evaluate whether the findings from different MRI modalities could be reconciled from a neuroanatomical perspective.Materials and Methods: After the search and auditing processes, 118 neuroimaging studies were included in this systematic literature review. The studies consisted of structural, functional, and diffusion tensor MRI studies.Results: Psychopathy was associated with numerous neuroanatomical abnormalities. Structurally, gray matter anomalies were seen in frontotemporal, cerebellar, limbic, and paralimbic regions. Associated gray matter volume (GMV) reductions were most pronounced particularly in most of the prefrontal cortex, and temporal gyri including the fusiform gyrus. Also decreased GMV of the amygdalae and hippocampi as well the cingulate and insular cortices were associated with psychopathy, as well as abnormal morphology of the hippocampi, amygdala, and nucleus accumbens. Functionally, psychopathy was associated with dysfunction of the default mode network, which was also linked to poor moral judgment as well as deficient metacognitive and introspective abilities. Second, reduced white matter integrity in the uncinate fasciculus and dorsal cingulum were associated with core psychopathy. Third, emotional detachment was associated with dysfunction of the posterior cerebellum, the human mirror neuron system and the Theory of Mind denoting lack of empathy and persistent failure in integrating affective information into cognition.Conclusions: Structural and functional aberrancies involving the limbic and paralimbic systems including reduced integrity of the uncinate fasciculus appear to be associated with core psychopathic features. Furthermore, this review points towards the idea that ASPD and psychopathy might stem from divergent biological processes.