Pectic Galactan Polysaccharide-Based Gene Delivery System for Targeting Neuroinflammation

Treating neuroinflammation-related injuries and disorders through manipulation of neuroinflammation functions is being heralded as a new therapeutic strategy. In this study, a novel pectic galactan (PG) polysaccharide based gene therapy approach is developed for targeting reactive gliosis in neuroinflammation. Galectin-3 (Gal-3) is a cell protein with a high affinity to β-galactoside sugars and is highly expressed in reactive gliosis. Since PG carries galactans, it can target reactive gliosis via specific carbohydrate interaction between galactan and Gal-3 on the cell membrane, and therefore can be utilized as a carrier for delivering genes to these cells. The carrier is synthesized by modifying quaternary ammonium groups on the PG. The resulting quaternized PG (QPG) is found to form complexes with plasmid DNA with a mean diameter of 100 nm and have the characteristics required for targeted gene therapy. The complexes efficiently condense large amounts of plasmid per particle and successfully bind to Gal-3. The in vivo study shows that the complexes are biocompatible and safe for administration and can selectively transfect reactive glial cells of an induced cortical lesion. The results confirm that this PG-based delivery system is a promising platform for targeting Gal-3 overexpressing neuroinflammation cells for treating neuroinflammation-related injuries and neurodegenerative diseases.     

Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.     

Sex and Depot Differences in Palmitoleic Acid Content of Human Blood and Fat

Palmitoleic acid has been classified as an insulin-sensitizing lipokine, but evidence for this from human studies has been inconsistent. We hypothesized that this is related to either the types of samples or conditions under which samples are collected. We measured plasma palmitoleic acid and total free fatty acids (FFA) using ultra-performance liquid chromatography in blood samples collected from 34 adults under a variety of conditions. We collected duplicate samples of adipose (n = 10), FFA (n = 9), and very low density lipoprotein triacylglycerol (VLDL-TAG) (n = 7) to measure the palmitoleic acid as a percentage of total fatty acids. We tested whether the percentage of palmitoleic acid was correlated with insulin resistance, as measured by homeostatic model of insulin resistance (HOMA-IR). Adipose stearoyl-coenzyme A desaturase 1 (SCD-1) protein was measured by capillary Western blotting. FFA-palmitoleic acid percentage increased as a function of total FFA and was greater (p < 0.005) in females than males. Adipose palmitoleic acid percentage was greater in females than males (p < 0.001), as was adipose SCD-1. Palmitoleic acid was greater in femoral fat than in abdominal fat in both females and males (p < 0.001), and correlated positively with HOMA-IR only in females. The test–retest reliability values for percentage palmitoleic acid were 7 ± 10% for adipose, 24 ± 26% for VLDL, and 53 ± 31% for FFA. Because FFA-palmitoleic acid percentage varies as a function of total FFA, investigators should re-evaluate how palmitoleic acid data is presented. The positive relationship between adipose palmitoleic acid and HOMA-IR in females suggests that it is not a potent insulin-sensitizing lipokine in humans.     

Biofeedback improves functional outcome after sphincteroplasty

Pax genes are expressed in specific patterns in the nervous system during development and in the adult. Recent findings suggest a link between the expression of Pax-2 and axonal guidance. Mice with a targeted deletion of Pax-2 are an excellent tool for studying axonal pathfinding at the molecular level, especially with respect to the optic chiasm. The date reviewed here suggest that Pax-2 regulates the expression of surface molecules involved in contact attraction and that the mutual regulation of the expression of Pax-2 and the Sonic hedgehog gene is of importance in the formation of the chiasm region.     

Biological evaluation of two anomeric glucose analogues iodinated in position 6

Two anomeric analogues of glucose labelled with 123 iodine in position 6, proposed as tracers of glucose transport in vivo, have been synthesized: alpha- and beta-methyl-6-deoxy-6-iodo-D-glucopyranoside (alpha MDIG and beta MDIG). The aim of this study was to determine whether these molecules interact with the glucose transporter and whether they could be used as tracers of glucose transport in vivo. The biodistribution of alpha MDIG and beta MDIG was studied in the mouse in vivo. To determine if these two anomers enter the cell via the glucose transporter, their uptake was measured in isolated perfused rat hearts, in human erythrocytes in suspension, and in cardiomyocytes of neonatal rat in culture. Both alpha MDIG and beta MDIG had similar repartitions in the mouse: myocardial uptake averaged 7% of the injected dose/g of organ at 2 min postinjection and alpha MDIG competed with D-glucose to enter the cells. Insulin produced a 123% increase of its uptake in isolated perfused rat hearts and a 100% increase in cardiomyocytes of neonatal rat in culture. alpha MDIG uptake was lowered in the presence of glucose transport inhibitors in each experimental model. An interaction between beta MDIG and glucose transporters was observed only in human erythrocytes in suspension. Only alpha MDIG interacts with the glucose transporter, and thus could be used to estimate glucose transport in vivo.     

Temporal specialization and generalization

A standard relation has two dimensions: attributes and tuples. A temporal relation contains two additional orthogonal time dimensions: valid time records when facts are true in the modeled reality, and transaction time records when facts are stored in the temporal relation. Although there are no restrictions between the valid time and transaction time associated with each fact, in many practical applications the valid and transaction times exhibit restricted interrelationships that define several types of specialized temporal relations. This paper examines areas where different specialized temporal relations are present. In application systems with multiple, interconnected temporal relations, multiple time dimensions may be associated with facts as they flow from one temporal relation to another. The paper investigates several aspects of the resulting generalized temporal relations, including the ability to query a predecessor relation from a successor relation. The presented framework for generalization and specialization allows one to precisely characterize and compare temporal relations and the application systems in which they are embedded. The framework's comprehensiveness and its use in understanding temporal relations are demonstrated by placing previously proposed temporal data models within the framework. The practical relevance of the defined specializations and generalizations is illustrated by sample realistic applications in which they occur. The additional semantics of specialized relations are especially useful for improving the performance of query processing     

Polymorphonuclear neutrophil granulocyte chemotactic hyperresponsiveness in a case of canine acromegaly

Growth hormone (GH) has recently been shown to affect polymorphonuclear neutrophil granulocyte (PMN) function and to be secreted by mononuclear cells, indicating that the hormone may be active in an immunophysiologic network, acting as an endo- or paracrine priming agent. The purpose of the present study was to evaluate the chemotactic responsiveness of canine peripheral PMN in a dog with acromegaly, caused by spontaneous, progesterone-induced hypersecretion of GH and, secondary to this, a seven-fold increase in insulin-like growth factor I (IGF-I). The chemotactic responsiveness towards zymosan-activated serum (ZAS) and leukotriene B4 (LTB4) was evaluated at a time when the dog suffered from acromegaly and again 57 days after corrective surgery (ovariohysterectomy). The experiments showed that PMN from the patient exhibited enhanced chemotactic migration that appeared to be associated with the hypersomatotropic condition as judged from the reversibility of the phenomenon. The glucose intolerance and elevated serum alkaline phosphatase that were observed in the acromegalic dog were also shown to be reversible following surgery.