Effect of propranolol on facial processing in autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social interaction deficits, communication impairments, and restricted, repetitive behaviors. ASD, with estimates of incidence as high as 1 in 88 individuals, has a largely unknown etiology. Pharmacological intervention is currently being explored to improve symptoms of ASD, including those in the social domain. Social interaction deficits in this population may include facial processing abnormalities, such as reduced eye contact, and increased fixation on less socially-salient facial regions, such as the mouth. However, there is variability in the degree of these deficits in the current literature. Additionally, it has been previously hypothesized that stress mediates poor facial processing in individuals with ASD. This pilot study examines the effect of propranolol, a nonselective beta-adrenergic antagonist anxiolytic, on facial processing in individuals with ASD and typically developing controls

Isofagomine In Vivo Effects in a Neuronopathic Gaucher Disease Mouse

The pharmacological chaperone, isofagomine (IFG), enhances acid β-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFα levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates

Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse

Saposins A, B, C and D are derived from a common precursor, prosaposin (psap). The few patients with saposin C deficiency develop a Gaucher disease-like central nervous system (CNS) phenotype attributed to diminished glucosylceramide (GC) cleavage activity by acid β-glucosidase (GCase). The in vivo effects of saposin C were examined by creating mice with selective absence of saposin C (C−/−) using a knock-in point mutation (cysteine-to-proline) in exon 11 of the psap gene. In C−/− mice, prosaposin and saposins A, B and D proteins were present at near wild-type levels, but the saposin C protein was absent. By 1 year, the C−/− mice exhibited weakness of the hind limbs and progressive ataxia. Decreased neuromotor activity and impaired hippocampal long-term potentiation were evident. Foamy storage cells were observed in dorsal root ganglion and there was progressive loss of cerebellar Purkinje cells and atrophy of cerebellar granule cells. Ultrastructural analyses revealed inclusions in axonal processes in the spinal cord, sciatic nerve and brain, but no excess of multivesicular bodies. Activated microglial cells and astrocytes were present in thalamus, brain stem, cerebellum and spinal cord, indicating regional pro-inflammatory responses. No storage cells were found in visceral organs of these mice. The absence of saposin C led to moderate increases in GC and lactosylceramide (LacCer) and their deacylated analogues. These results support the view that saposin C has multiple roles in glycosphingolipid (GSL) catabolism as well as a prominent function in CNS and axonal integrity independent of its role as an optimizer/stabilizer of GCase

Levels of Polychlorinated Biphenyls (PCBs) and Three Organochlorine Pesticides in Fish from the Aleutian Islands of Alaska

Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and chlorinated pesticides, have been shown to have many adverse human health effects. These contaminants therefore may pose a risk to Alaska Natives that follow a traditional diet high in marine mammals and fish, in which POPs bioaccumulate.This study examined the levels of PCBs and three pesticides [p, p'-DDE, mirex, and hexachlorobenzene (HCB)] in muscle tissue from nine fish species from several locations around the Aleutian Islands of Alaska. The highest median PCB level was found in rock sole (Lepidopsetta bilineata, 285 ppb, wet weight), while the lowest level was found in rock greenling (Hexagrammos lagocephalus, 104 ppb, wet weight). Lipid adjusted PCB values were also calculated and significant interspecies differences were found. Again, rock sole had the highest level (68,536 ppb, lipid weight). Concerning the PCB congener patterns, the more highly chlorinated congeners were most common as would be expected due to their greater persistence. Among the pesticides, p, p'-DDE generally dominated, and the highest level was found in sockeye salmon (Oncorhynchus nerka, 6.9 ppb, wet weight). The methodology developed by U.S. Environmental Protection Agency (USEPA) was used to calculate risk-based consumption limits for the analyzed fish species. For cancer health endpoints for PCBs, all species would trigger strict advisories of between two and six meals per year, depending upon species. For noncancer effects by PCBs, advisories of between seven and twenty-two meals per year were triggered. None of the pesticides triggered consumption limits.The fish analyzed, mainly from Adak, contain significant concentrations of POPs, in particular PCBs, which raises the question whether these fish are safe to eat, particularly for sensitive populations. However when assessing any risk of the traditional diet, one must also consider the many health and cultural benefits from eating fish

Testing of an Echelle Spectrometer as a LIBS Detector at Sandia

Some useful information has been obtained regarding the potential use of the echelle spectrometer system for Laser-Induced Breakdown Spectroscopy (LIBS) monitoring applications, despite the AOTF-computer operational problems during the Sandia site-test. Currently, the use of the echelle spectrometer with the LIBS system is not suitable for trace-level analyte detection. This is due, in part, to the lower light throughput of the echelle spectrometer system compared to the SpectraPro-275. The low duty cycle of the LIBS system, which results from the use of a low-repetition-rate (but low-cost and portable) laser, also limits the detection sensitivity achievable using a high-resolution spectrometer. At high analyte concentrations, the echelle spectrometer is able to resolve spectral interferences including the Cd-As line pair at 228.8-nm and other LIBS emission features not resolved using the SpectraPro-275. A definite positive result obtained is the determination that at the high resolution of the echelle spectrometer, time-gating of the CCD detector is not necessary to discriminate analyte spectral signals from the LIBS background emission. The cost of the gated CCD and associated electronics is a significant portion of the cost of the Sandia LIBS system. Incorporation of a low-cost version of the echelle spectrometer for process monitoring applications not requiring trace-level detection could make LIBS a more viable technique where cost is a limiting factor. We hope to have the opportunity to perform additional collaborative work using the AOTF-echelle spectrometer for on-line LIBS monitoring applications, in order to demonstrate the advantage of rapid line-switching (using the AOTF) and simultaneous detection of multiple emission features across the spectral range of the echelle

Peptide-based approaches to treat asthma, arthritis, other autoimmune diseases and pathologies of the central nervous system

In this review we focus on peptide- and peptidomimetic-based approaches that target autoimmune diseases and some pathologies of the central nervous system. Special attention is given to asthma, allergic rhinitis, osteoarthritis, and Alzheimer's disease, but other related pathologies are also reviewed, although to a lesser degree. Among others, drugs like Diacerhein and its active form Rhein, Pralnacasan, Anakinra (Kineret), Omalizumab, an antibody "BION-1", directed against the common beta-chain of cytokine receptors, are described below as well as attempts to target beta-amyloid peptide aggregation. Parts of the review are also dedicated to targeting of pathologic conditions in the brain and in other tissues with peptides as well as methods to deliver larger molecules through the "blood-brain barrier" by exploring receptor-mediated transport, or elsewhere in the body by using peptides as carriers through cellular membranes. In addition to highlighting current developments in the field, we also propose, for future drug targets, the components of the inflammasome protein complex, which is believed to initiate the activation of caspase-1 dependent signaling events, as well as other pathways that signal inflammation. Thus we discuss the possibility of targeting inflammasome components for negative or positive modulation of an inflammatory response

Cancer-selective therapy of the future : Apoptin and its mechanism of action

Classical chemotherapy that specifically targets rapidly proliferating cells has been in existence for over eighty years and has proven to be fully successful in only a limited number of cancers. Thus, this review focuses on a novel, emerging approach for cancer therapy that uses alternative, and more unique features of cancer cells. This new approach facilitates the selective targeting of cancer, while sparing normal, non-transformed cells. Examples of molecules that kill cancer cells selectively are: apoptin, E4orf4, viral protein R (VpR), and Brevinin-2R. Below we focus on apoptin, a product of the third open reading frame (VP3) of the chicken anemia virus. Besides discussing apoptin's mechanism of action, we also provide concise insight into the biology of a chicken anemia virus infection. Since apoptin's cancer-selective toxicity depends on its nuclear localization, we broadly discuss mechanism(s) involved in its nuclear retention (both nuclear import and export). We also discuss recent findings on apoptin's molecular mechanism of action, with a focus on the role of Nur77 in apoptin's nucleo-cytoplasmic signaling. Finally, we compare the current findings on apoptin to the mechanism of cancer selective toxicity of E4orf4. In the 'summary' section, besides highlighting important issues related to cancer-selective therapy, we also discuss concurrent approaches towards therapy personalization, particularly those related to the in vivo, and real time cancer therapy efficacy monitoring, using "lab-on-the-chip" and other emerging technologies