Intra-amniotic prostaglandin F2α and urea for abortion

Prostaglandin F_2α (PGF_2α) 20 mg combined with urea 80 g was injected intra-amniotically in 20 patients to induce mid-trimester abortion. Abortion resulted in all subjects within 24 hours in a mean time of 12 hours 38 minutes (range 5 hours 50 minutes to 20 hours 45 minutes).Plasma sex steroids were evaluated before and hourly for 5 hours after the injection. A progressive decline in levels occurred with time. Decreases in plasma progesterone, estrone, estradiol and estriol were significant as soon as one hour after injection.Gastrointestinal side effects occurred with a greater frequency than when a comparable dose of PGF_2α is given alone and 2 patients had small cervical lacerations requiring suture. Further studies are indicated to establish whether a lower dose of PGF_2α will be associated with fewer side effects and be as effective.     

Regulation of Vascular Tone,Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid

Hydrogen sulfide (H₂S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H₂S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H₂S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H₂S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and μmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H₂S levels in rats. 3-MP (10 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3–1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H₂S production depended on enzymatic activity, although at higher concentrations (1–3 mmol/L) there was also evidence for an additional nonenzymatic H₂S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants dl-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H₂S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H₂S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and bioenergetics in hyperglycemia.     

Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions

Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood-brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis.     

Distinguishing epidemic waves from disease spillover in a wildlife population

Serengeti lions frequently experience viral outbreaks. In 1994, one-third of Serengeti lions died from canine distemper virus (CDV). Based on the limited epidemiological data available from this period, it has been unclear whether the 1994 outbreak was propagated by lion-to-lion transmission alone or involved multiple introductions from other sympatric carnivore species. More broadly, we do not know whether contacts between lions allow any pathogen with a relatively short infectious period to percolate through the population (i.e. reach epidemic proportions). We built one of the most realistic contact network models for a wildlife population to date, based on detailed behavioural and movement data from a long-term lion study population. The model allowed us to identify previously unrecognized biases in the sparse data from the 1994 outbreak and develop methods for judiciously inferring disease dynamics from typical wildlife samples. Our analysis of the model in light of the 1994 outbreak data strongly suggest that, although lions are sufficiently well connected to sustain epidemics of CDV-like diseases, the 1994 epidemic was fuelled by multiple spillovers from other carnivore species, such as jackals and hyenas.     

Sand goby (Pomatoschistus minutus) males exposed to an endocrine disrupting chemical fail in nest and mate competition

Endocrine disrupting chemicals (EDCs) are a widely studied group of chemicals that interfere with the endocrinology of organisms. So far, few studies have demonstrated the effect of EDCs on the reproductive behavior of aquatic wildlife. Here we show that sand goby males' (Pomatoschistus minutus) success in mating competition greatly decreases after an exposure for 7 to 24 days to 17α-ethinyl estradiol (EE2, measured concentration 4 ng L^− 1). The sand goby exhibits a polygynous mating system with male parental care, in which males compete for nest sites and females. The aim of this study was to test how EE2 exposure affects the ability of males to compete for breeding resources, i.e. nest sites and mates. First, EE2 exposed males competed over a nest site against a non-exposed, control male of the same size. Secondly, we examined male courtship behavior and female mate preferences for EE2 exposed males and similar-sized non-exposed, control males. In addition to the behavioral experiments we determined the zona radiata protein (Zrp) mRNA gene expression and measured morphometric indicators of sexual maturation. Our study revealed that EE2 treated males were not able to acquire or defend a nest site. Additionally, EE2 treated males spent significantly less time in active courtship and nest leading behavior than control males. As a result, females clearly preferred to mate with control males. However, we found no significant differences in Zrp mRNA expression or the morphometric indicators between treatments. Our study illustrates that exposure to this EDC can greatly reduce the chances of an individual reproducing successfully. Moreover, it demonstrates that severe behavioral effects can be seen before any effects are detectable at the molecular or morphometric level.     

Disruption of sexual selection in sand gobies (Pomatoschistus minutus) by 17α-ethinyl estradiol, an endocrine disruptor

In aquatic environments, endocrine disrupting chemicals (EDCs) that interfere with the reproductive physiology of males form a threat to the reproduction of populations. This is often manifested as decreased sexual performance or sterility among males. We show that exposure to EDCs can directly affect the mating system of a marine fish, the sand goby (Pomatoschistus minutus). We exposed males for 1 to 4 weeks to two different concentrations (5 ng L^− 1 and 24 ng L^− 1) of 17α-ethinyl estradiol (EE2); a synthetic compound mimicking estrogen and a water control. The sand goby exhibits a polygynous mating system, in which male mating success is typically skewed towards the largest males, resulting in strong sexual selection for increased male size. Our experiment shows that when males have been exposed to EE2, male size has a smaller effect on mating success, resulting in weaker sexual selection on male size as compared to the control. There was an interaction between treatment and exposure time on the expression of vitellogenin and zona radiata protein mRNAs. Males exposed to high EE2 reached much higher expression levels than males exposed to low EE2. Of the somatic markers, the hepatosomatic index was lower in males exposed to high EE2 than in the low EE2 and control males. Our results suggest that exposure to EDCs can have effects on the mating system before physiological changes are observable. These effects can be of profound nature as they interfere with sexual selection, and may in the long run lead to the loss of traits maintained through sexual selection.     

Enhanced muscarinic M1 receptor gene expression in the corpus striatum of streptozotocin-induced diabetic rats

Acetylcholine (ACh), the first neurotransmitter to be identified, regulate the activities of central and peripheral functions through interactions with muscarinic receptors. Changes in muscarinic acetylcholine receptor (mAChR) have been implicated in the pathophysiology of many major diseases of the central nervous system (CNS). Previous reports from our laboratory on streptozotocin (STZ) induced diabetic rats showed down regulation of muscarinic M1 receptors in the brainstem, hypothalamus, cerebral cortex and pancreatic islets. In this study, we have investigated the changes of acetylcholine esterase (AChE) enzyme activity, total muscarinic and muscarinic M1 receptor binding and gene expression in the corpus striatum of STZ – diabetic rats and the insulin treated diabetic rats. The striatum, a neuronal nucleus intimately involved in motor behaviour, is one of the brain regions with the highest acetylcholine content. ACh has complex and clinically important actions in the striatum that are mediated predominantly by muscarinic receptors. We observed that insulin treatment brought back the decreased maximal velocity (V_max) of acetylcholine esterase in the corpus striatum during diabetes to near control state. In diabetic rats there was a decrease in maximal number (B_max) and affinity (K_d) of total muscarinic receptors whereas muscarinic M1 receptors were increased with decrease in affinity in diabetic rats. We observed that, in all cases, the binding parameters were reversed to near control by the treatment of diabetic rats with insulin. Real-time PCR experiment confirmed the increase in muscarinic M1 receptor gene expression and a similar reversal with insulin treatment. These results suggest the diabetes-induced changes of the cholinergic activity in the corpus striatum and the regulatory role of insulin on binding parameters and gene expression of total and muscarinic M1 receptors.     

Glutamate (mGluR-5) gene expression in brain regions of streptozotocin induced diabetic rats as a function of age: role in regulation of calcium release from the pancreatic islets in vitro

Metastatic renal cell carcinoma (RCC) is highly resistant to conventional systemic treatments, including chemotherapy, radiotherapy and hormonal therapies. Previous studies have shown over-expression of EGFR is associated with high grade tumors and a worse prognosis. Recent studies suggest anticancer therapies targeting the EGFR pathway have shown promising results in clinical trials of RCC patients. Therefore, characterization of the level and localization of EGFR expression in RCC is important for target-dependent therapy. In this study, we investigated the clinical significance of cellular localization of EGFR in human normal renal cortex and RCC. RCC and adjacent normal kidney tissues of 63 patients were obtained for characterization of EGFR expression. EGFR protein expression was assessed by immunohistochemistry on a scale from 0 to 300 (percentage of positive cells × staining intensity) and Western blotting. EGFR membranous staining was significantly stronger in RCC tumors than in normal tissues (P < 0.001). In contrast, EGFR cytoplasmic staining was significantly higher in normal than in tumor tissues (P < 0.001). The levels of membranous or cytoplasmic EGFR expression in RCC tissues were not correlated with sex, tumor grade, TNM stage or overall survival (P > 0.05). These results showed abundant expression of membranous EGFR in RCC, and abundant expression of cytoplasmic EGFR in normal tissues. EGFR expression in RCC was mostly located in the cell membrane, whereas the EGFR expression in normal renal tissues was chiefly seen in cytoplasm. Our results suggest different locations of EGFR expression may be associated with human renal tumorigenesis.