Cerebrospinal Fluid Aβ42 Levels: When Physiological Become Pathological State

Impaired amyloid beta (Aβ) metabolism is currently considered central to understand the pathophysiology of Alzheimer's disease (AD). Measurements of cerebrospinal fluid Aβ levels remain the most useful marker for diagnostic purposes and to individuate people at risk for AD. Despite recent advances criticized the direct role in neurodegeneration of cortical neurons, Aβ is considered responsible for synaptopathy and impairment of neurotransmission and therefore remains the major trigger of AD and future pharmacological treatment remain Aβ oriented. However, experimental and clinical findings showed that Aβ peptides could have a wider range of action responsible for cell dysfunction and for appearance of clinico‐pathological entities different from AD. Such findings may induce misunderstanding of the real role played by Aβ in AD and therefore strengthen criticism on its centrality and need for CSF measurements. Aim of this review is to discuss the role of CSF Aβ levels in light of experimental, clinical pathologic, and electrophysiological results in AD and other pathological entities to put in a correct frame the value of Aβ changes.     

Dengue Fever among Renal Transplant Recipients: A Series of 10 Cases in a Tropical Country

Few studies have focused on Rift Valley fever virus (RVFV) transmission in less arid, transitional landscapes surrounding known high-risk regions. The objective of this study was to identify evidence of RVFV exposure in Bodhei Village in a forested area at the edge of the RVFV-epidemic Garissa region. In a household cluster-based survey conducted between epidemics in early 2006, 211 participants were enrolled. Overall seroprevalence for anti-RVFV was high (18%) and comparable with rates in the more arid, dense brush regions farther north. Seroprevalence of adults was 28%, whereas that of children was significantly lower (3%; P < 0.001); the youngest positive child was age 3 years. Males were more likely to be seropositive than females (25% versus 11%; P < 0.01), and animal husbandry activities (birthing, sheltering, and butchering) were strongly associated with seropositivity. The results confirm that significant RVFV transmission occurs outside of recognized high-risk areas and independent of known epidemic periods.     

Steroid hyperglycemia: Prevalence,early detection and therapeutic recommendations: A narrative review

Steroids are drugs that have been used extensively in a variety of conditions. Although widely prescribed for their anti-inflammatory and immunosuppressive properties, glucocorticoids have several side effects, being hyperglycemia one of the most common and representative. In the present review, we discuss the main epidemiologic characteristics associated with steroid use, with emphasis on the identification of high risk populations. Additionally we present the pathophysiology of corticosteroid induced hyperglycemia as well as the pharmacokinetics and pharmacodynamics associated with steroid use. We propose a treatment strategy based on previous reports and the understanding of the mechanism of action of both, the different types of glucocorticoids and the treatment options, in both the ambulatory and the hospital setting. Finally, we present some of the recent scientific advances as well as some options for future use of glucocorticoids.     

A 6q14.1‐q15 microdeletion in a male patient with severe autistic disorder,lack of oral language,and dysmorphic features with concomitant presence of a maternally inherited Xp22.31 copy number gain

We report on a male patient with severe autistic disorder, lack of oral language, and dysmorphic features who carries a rare interstitial microdeletion of 4.96 Mb at chromosome 6q14.1‐q15. The patient also harbors a maternally inherited copy number gain of 1.69 Mb at chromosome Xp22.31, whose pathogenicity is under debate.     

PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine

The mucosa of the small intestine is renewed completely every 3–5 d throughout the entire lifetime by small populations of adult stem cells that are believed to reside in the bottom of the crypts and to migrate and differentiate into all the different populations of intestinal cells. When the cells reach the apex of the villi and are fully differentiated, they undergo cell death and are shed into the lumen. Reactive oxygen species (ROS) production is proportional to the electron transfer activity of the mitochondrial respiration chain. ROS homeostasis is maintained to control cell death and is finely tuned by an inducible antioxidant program. Here we show that peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β) is highly expressed in the intestinal epithelium and possesses dual activity, stimulating mitochondrial biogenesis and oxygen consumption while inducing antioxidant enzymes. To study the role of PGC-1β gain and loss of function in the gut, we generated both intestinal-specific PGC-1β transgenic and PGC-1β knockout mice. Mice overexpressing PGC-1β present a peculiar intestinal morphology with very long villi resulting from increased enterocyte lifespan and also demonstrate greater tumor susceptibility, with increased tumor number and size when exposed to carcinogens. PGC-1β knockout mice are protected from carcinogenesis. We show that PGC-1β triggers mitochondrial respiration while protecting enterocytes from ROS-driven macromolecule damage and consequent apoptosis in both normal and dysplastic mucosa. Therefore, PGC-1β in the gut acts as an adaptive self-point regulator, capable of providing a balance between enhanced mitochondrial activity and protection from increased ROS production.The intestine represents the interface between the organism and its luminal environment and is constantly challenged by mechanical stress, diet-derived toxins and oxidants, and endogenously generated reactive oxygen species (ROS), which can induce serious damage to all biological molecules and cell structures (1). To preserve cellular integrity and tissue homeostasis, the intestine possesses self-renewing capacity via the continuous migration of new enterocytes that undergo differentiation from the crypt to the apical compartment of the villus, where they become competent to apoptosis and are shed into the lumen. ROS accumulation within intestinal epithelial cells promotes apoptotic cell death in the differentiated compartment (2). The mitochondrial electron transport chain is a major site of ROS production in the cells. Under physiological conditions, the balance between ROS generation and detoxification is controlled by a set of cellular enzymes including superoxide dismutase and catalase. Important components of the ROS-scavenging pathways are linked to mitochondrial oxidative metabolism via the peroxisome proliferator-activated receptor-γ coactivators 1α and 1β (PGC-1α and PGC-1β), apparently enabling cells to maintain normal redox status in response to changing oxidative capacity (3). PGC-1α and PGC-1β are master regulators of mitochondrial biogenesis and oxidative metabolism as well as antioxidant defense. Both PGC-1α and PGC-1β are preferentially expressed in tissues with high oxidative capacity where they participate, through mitochondrial biogenesis, in the metabolic response to high energy demand (4), such as cold-adapted thermogenesis in brown adipose tissue (5), fiber-type switching in striated muscle (6), and fatty acid β oxidation and gluconeogenesis in liver during a fasting state (7, 8). The increase in mitochondrial biogenesis and activity stimulated by PGC-1 proteins may cause an increase in the production of ROS. However, PGC-1α also has been shown to increase the expression of the major mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2) (3, 9). Therefore, PGC-1α is able to upgrade aerobic energy metabolism while preserving ROS homeostasis, by simultaneously promoting ROS formation and detoxification. Recently, it has been shown in Drosophila that the PGC-1α homolog spargel is able to induce mitochondrial function and oxygen consumption, which is coupled to the induction of scavenger systems and ROS reduction, finally leading to increased longevity (10). On the other hand, in the differentiated intestinal epithelium of mice, PGC-1α induces mitochondrial biogenesis and oxygen consumption, but it is not able to induce the ROS-scavenging apparatus, thus promoting ROS-dependent apoptotic cell death (2).PGC-1β is highly similar to PGC-1α, both in amino acid sequence and ability to regulate several metabolic pathways (8, 11). Therefore, in the present study we focus on the function of PGC-1β in the intestinal epithelium, giving special attention to the effect of this coactivator in enterocyte homeostasis. We first show that PGC-1β is highly expressed in intestinal epithelium with an almost ubiquitous pattern of localization along the entire crypt–villus axis. To study its activation, we generated mice overexpressing PGC-1β selectively in the enterocytes. We show that in these cells PGC-1β enhances mitochondrial biogenesis and respiration and induces a parallel increase in antioxidant enzymes, such as Sod2 and glutathione peroxidase 4 (Gpx4), as well as peroxiredoxins. As a result, the intestinal morphology is severely affected, with significant increases in enterocyte longevity and mucosal villi length. Concomitantly, PGC-1β overexpression leads to a significant increase in tumor number and size in two distinct models of intestinal carcinogenesis. Moreover, to confirm the role of PGC-1β activity in the intestine, we also generated intestinal-specific PGC-1β (iPGC-1β) knockout mice that, in line with the evidence from transgenic mice, show reduced expression of several metabolic pathways and mitochondrial antioxidant systems as well as decreased susceptibility to tumors. Indeed, tumors may use adaptive mechanisms to keep their ROS burden within a range that permits their growth and survival. In such contest, PGC-1β acts as a gatekeeper of redox status, allowing enterocyte survival and, in cancer-promoting conditions, tumor progression.