Time course, distribution and cell types of induction of transforming growth factor betas following middle cerebral artery occlusion in the rat brain

Transforming growth factor-βs (TGF-β1-3) are cytokines that regulate the proliferation, differentiation, and survival of various cell types. The present study describes the induction of TGF-β1-3 in the rat after focal ischemia at 3 h, 24 h, 72 h and 1 month after transient (1 h) or permanent (24 h) middle cerebral artery occlusion (MCAO) using in situ hybridization histochemistry and quantitative analysis. Double labeling with different markers was used to identify the localization of TGF-β mRNA relative to the penumbra and glial scar, and the types of cells expressing TGF-βs. TGF-β1 expression increased 3 h after MCAO in the penumbra and was further elevated 24 h after MCAO. TGF-β1 was present mostly in microglial cells but also in some astrocytes. By 72 h and 1 month after the occlusion, TGF-β1 mRNA-expressing cells also appeared in microglia within the ischemic core and in the glial scar. In contrast, TGF-β2 mRNA level was increased in neurons but not in astrocytes or microglial cells in layers II, III, and V of the ipsilateral cerebral cortex 24 h after MCAO. TGF-β3 was not induced in cells around the penumbra. Its expression increased in only a few cells in layer II of the cerebral cortex 24 h after MCAO. The levels of TGF-β2 and -β3 decreased at subsequent time points. Permanent MCAO further elevated the levels of all 3 subtypes of TGF-βs suggesting that reperfusion is not a major factor in their induction. TGF-β1 did not co-localize with either Fos or ATF-3, while the co-localization of TGF-β2 with Fos but not with ATF-3 suggests that cortical spreading depolarization, but not damage to neural processes, might be the mechanism of induction for TGF-β2. The results imply that endogenous TGF-βs are induced by different mechanisms following an ischemic attack in the brain suggesting that they are involved in distinct spatially and temporally regulated inflammatory and neuroprotective processes

Cerebral Microcirculatory Responses of Insulin-Resistant Rats are Preserved to Physiological and Pharmacological Stimuli

AbstractWe study a programming language with a built-in ground type for real numbers. In order for the language to be sufficiently expressive but still sequential, we consider a construction proposed by Boehm and Cartwright. The non-deterministic nature of the construction suggests the use of powerdomains in order to obtain a denotational semantics for the language. We show that the construction cannot be modelled by the Plotkin or Smyth powerdomains, but that the Hoare powerdomain gives a computationally adequate semantics. As is well known, Hoare semantics can be used in order to establish partial correctness only. Since computations on the reals are infinite, one cannot decompose total correctness into the conjunction of partial correctness and termination as is traditionally done. We instead introduce a suitable operational notion of strong convergence and show that total correctness can be proved by establishing partial correctness (using denotational methods) and strong convergence (using operational methods). We illustrate the technique with a representative example

Diffuse Adrenal Gland and Pancreas Necrosis in a Patient with Disseminated Cryptococcosis—Case Report

(1) Background: Cryptococcus neoformans is mostly known for causing meningitis, with or without disseminated disease. (2) Case presentation: An immunocompromised 75-year-old gentleman presented post renal transplant with generalized weakness, altered mental status, hypoxemia, and hyponatremia, and was found to have disseminated cryptococcal infection. After an initial improvement, the patient became suddenly hypotensive, and passed away soon after. The autopsy revealed widespread cryptococcal involvement, with the most severely affected organs being the brain, lungs, pancreas, adrenal glands, and spleen. The pancreas and one of the adrenal glands revealed diffuse granulomatous cryptococcal infection, with large areas of necrosis. The spleen also showed a large area of cryptococcal necrosis. In addition, the patient had chylous ascites, without histologically identifiable organisms. (3) Conclusions: This is a rare case of disseminated cryptococcal infection with severe necrotizing adrenalitis and pancreatitis, in addition to significant spleen, lung, and central nervous system involvement. The early recognition and treatment of the adrenal gland and pancreas cryptococcosis with surgical interventions may lead to better outcomes in affected patients. Furthermore, steroid treatment and diabetes mellitus may be risk factors for adrenal gland involvement. Additionally, clinicians should keep cryptococcal infection in their differential diagnosis for isolated adrenal gland and pancreas lesions

Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures.

Our objective was to investigate the mitochondrial dynamics following oxygen-glucose deprivation (OGD) in cultured rat cortical neurons. We documented changes in morphology, protein expression, and DNA levels in mitochondria following OGD and examined the roles of mitochondrial fission [dynamin-related protein 1 (Drp1), fission protein-1 (Fis1)] and fusion [mitofusin-1 (Mfn1), mitofusin-2 (Mfn2), and optic atrophy-1 protein (OPA1)] proteins on mitochondrial biogenesis and morphogenesis. We tested the effects of two Drp1 blockers [15-deoxy-Δ12,14-Prostaglandin J2 (PGJ2) and Mitochondrial Division Inhibitor (Mdivi-1)] on mitochondrial dynamics and cell survival. One hour of OGD had minimal effects on neuronal viability but mitochondria appeared condensed. Three hours of OGD caused a 60% decrease in neuronal viability accompanied by a transition from primarily normal/tubular and lesser number of rounded mitochondria during normoxia to either poorly labeled or small and large rounded mitochondria. The percentage of rounded mitochondria remained the same. The mitochondrial voltage-dependent anion channel, Complex V, and mitoDNA levels increased after OGD associated with a dramatic reduction in Drp1 expression, less reduction in Mfn2 expression, an increase in Mfn1 expression, with no changes in either OPA1 or Fis1. Although PGJ2 increased polymerization of Drp1, it did not reduce cell death or alter mitochondrial morphology following OGD and Mdivi-1 did not protect neurons against OGD. In summary, mitochondrial biogenesis and maintained fusion occurred in neurons along with mitochondrial fission following OGD; thus Mfn1 but not Drp1 may be a major regulator of these processes

Bcl-2 or bcl-XL gene therapy increases neural plasticity proteins nestin and c-fos expression in PC12 cells

The anti-apoptotic gene replacements could be an option in preventing hypoxia-induced neuronal loss. In this paper we tested the effect of anti-apoptosis (bcl-2 and bcl-XL) gene transfer on cell plasticity. Nestin, synapsin-1 and c-fos genes and proteins expression were measured in PC12 cells in normal condition, and after hypoxia/re-oxygenation. Gene delivery results a significant increase in both bcl-2 and bcl-XL gene expression. Hypoxia (1h)/re-oxygenation (24h) have a detrimental effect upon cultured cells by increasing the pro-apoptotic, bax gene and protein expression. Bcl-2 or bcl-XL gene delivery resulted in a significant increase in and the cellular levels of the corresponding mRNAs and proteins. Bcl-2 gene augmented the nestin gene and protein expression which has been compromised previously by the hypoxic event. Similarly c-fos mRNA and protein expression decreased significantly after hypoxia, while the anti-apoptotic gene treatment normalized c-fos expression. Synapsin-1 gene or protein expression remained about on the same level under normoxic conditions or following hypoxia after gene treatment. We can conclude that anti-apoptotic gene transfers activate neuronal plasticity proteins nestin and c-fos. This link on anti-apoptotic proteins and cell plasticity is a new finding

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

Hematologic malignancies are known to be associated with numerous cytogenetic and molecular genetic changes. In addition to morphology, immunophenotype, cytochemistry and clinical characteristics, these genetic alterations are typically required to diagnose myeloid, lymphoid, and plasma cell neoplasms. According to the current World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues, numerous genetic changes are highlighted, often defining a distinct subtype of a disease, or providing prognostic information. This review highlights how these molecular changes can alter mitochondrial bioenergetics, cell death pathways, mitochondrial dynamics and potentially be related to mitochondrial genetic changes. A better understanding of these processes emphasizes potential novel therapies