Effects of beta-adrenergic antagonism in autism spectrum disorder

Effective treatments for individuals with autism spectrum disorder are lacking, especially when it comes to pharmacological intervention, which can be an important addition to behavioral therapy. Currently available agents target co-occurring symptoms, such as aggression and irritability, and many cause considerable off-target effects. Few agents have been shown to reliably and effectively reduce the impact of other aspects of this disorder, particularly core symptomatology. In the present studies, the noradrenergic system was explored as a target for autism pharmacotherapy, given evidence suggesting elevated anxiety and autonomic dysregulation in individuals with autism. The effects of the beta-adrenergic antagonist propranolol on facial scanning, verbal problem solving, and a measure of social functioning were examined in adults and adolescents with autism via single-dose psychopharmacological challenges. Improvements associated with propranolol administration were observed for each of these domains, and some evidence supports a role of anxiety and autonomic activity in predicting response to treatment. Additionally, the assessment of an ongoing pilot trial investigating the combined effects of propranolol and early intensive behavioral intervention in young children with autism suggests that serial-dose studies with this agent are feasible. This line of work proposes beta-adrenergic antagonism as a potential therapeutic option for individuals with autism that merits further investigation in the form of large, randomized controlled clinical trials

Acute Beet Juice Supplementation Does Not Improve 30- or 60-second Maximal Intensity Performance in Anaerobically Trained Athletes

International Journal of Exercise Science 14(2): 60-75, 2021. Research suggests that beet juice is beneficial during aerobic exercise. However, the impact of beet juice during primarily anaerobic exercise is equivocal. The purpose of this study was to determine the effects of acute beet juice supplementation on maximal intensity performance during 30-s and 60-s maximal-intensity cycling sprints. Using a double-blind, crossover-study design, 14 anaerobically trained male hockey players completed six Wingate cycling tests: familiarization trials of a 30-s and 60-s Wingate test, followed by 30-s Wingate placebo/beet juice trials, and 60-s Wingate placebo/beet juice trials. Repeated measures ANOVAs were used to compare the change in power between conditions over the duration of each trial. Paired t-tests were run to compare performance between conditions of various work and power variables. One-way ANOVAs were utilized to compare the change between conditions of the 30-s test to the change between conditions of the 60-s test. Beet juice supplementation yielded no statistical differences from placebo in any of the measured variables during the 30-s or 60-s tests (p \u3e 0.05). The percent change for fatigue index was significantly different between the 30-s and 60-s tests (p = 0.032) suggesting less fatigue with beet juice supplementation. Overall, beet juice did not improve maximal intensity performance during 30-s or 60-s cycling sprint tests. Performance during the 60-s bout was not impacted to a greater extent than the 30-s bout after beet juice supplementation. These results suggest that beet juice supplementation does not improve short-duration exercise performance in anaerobically trained athletes

Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice

Saposin B derives from the multi-functional precursor, prosaposin, and functions as an activity enhancer for several glycosphingolipid (GSL) hydrolases. Mutations in saposin B present in humans with phenotypes resembling metachromatic leukodystrophy. To gain insight into saposin B's physiological functions, a specific deficiency was created in mice by a knock-in mutation of an essential cysteine in exon 7 of the prosaposin locus. No saposin B protein was detected in the homozygotes (B−/−) mice, whereas prosaposin, and saposins A, C and D were at normal levels. B−/− mice exhibited slowly progressive neuromotor deterioration and minor head tremor by 15 months. Excess hydroxy and non-hydroxy fatty acid sulfatide levels were present in brain and kidney. Alcian blue positive (sulfatide) storage cells were found in the brain, spinal cord and kidney. Ultrastructural analyses showed lamellar inclusion material in the kidney, sciatic nerve, brain and spinal cord tissues. Lactosylceramide (LacCer) and globotriaosylceramide (TriCer) were increased in various tissues of B−/− mice supporting the in vivo role of saposin B in the degradation of these lipids. CD68 positive microglial cells and activated GFAP positive astrocytes showed a proinflammatory response in the brains of B−/− mice. These findings delineate the roles of saposin B for the in vivo degradation of several GSLs and its primary function in maintenance of CNS function. B−/− provide a useful model for understanding the contributions of this saposin to GSL metabolism and homeostasis

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

FAS promoter polymorphism: outcome of childhood acute myeloid leukemia. A children's oncology group report.

PURPOSE: FAS is a cell surface receptor involved in apoptotic signal transmission. Deregulation of this pathway results in down-regulation of apoptosis and subsequent persistence of a malignant clone. A single nucleotide polymorphism resulting in guanine-to-adenine transition in the FAS promoter region (position -1377) is thought to reduce stimulatory protein 1 transcription factor binding and decrease FAS expression. Previous work has shown increased risk of developing acute myeloid leukemia (AML) in adult patients with a variant allele at this site. The same authors have shown that the presence of an adenine residue rather than a guanine residue at -1,377 bp significantly attenuates transcription factor stimulatory protein 1 binding and may contribute to a reduction in FAS expression and ultimately to the enrichment of apoptosis-resistant clones in AML. We hypothesized that FAS genotype by altering susceptibility to apoptosis might affect outcome of childhood AML therapy. EXPERIMENTAL DESIGN: Four hundred forty-four children treated for de novo AML on a uniform protocol were genotyped for FAS 1377. RESULTS: There were no significant differences in overall survival, event-free survival, treatment-related mortality, or relapse rate between patients with FAS 1377GG genotype versus 1377GA/1377AA genotypes. CONCLUSIONS: FAS 1377 genotype does not alter outcome of de novo AML in children

Inhibition of Hippocampal Synaptic Activity by ATP, Hypoxia or Oxygen-Glucose Deprivation Does Not Require CD73

Adenosine, through activation of its A1 receptors, has neuroprotective effects during hypoxia and ischemia. Recently, using transgenic mice with neuronal expression of human equilibrative nucleoside transporter 1 (hENT1), we reported that nucleoside transporter-mediated release of adenosine from neurons was not a key mechanism facilitating the actions of adenosine at A1 receptors during hypoxia/ischemia. The present study was performed to test the importance of CD73 (ecto-5′-nucleotidase) for basal and hypoxic/ischemic adenosine production. Hippocampal slice electrophysiology was performed with CD73+/+ and CD73−/− mice. Adenosine and ATP had similar inhibitory effects in both genotypes, with IC50 values of approximately 25 µM. In contrast, ATP was a less potent inhibitor (IC50 = 100 µM) in slices from mice expressing hENT1 in neurons. The inhibitory effects of ATP in CD73+/+ and CD73−/− slices were blocked by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and were enhanced by the nucleoside transport inhibitor S-(4-nitrobenzyl)-6-thioinosine (NBTI), consistent with effects that are mediated by adenosine after metabolism of ATP. AMP showed a similar inhibitory effect to ATP and adenosine, indicating that the response to ATP was not mediated by P2 receptors. In comparing CD73−/− and CD73+/+ slices, hypoxia and oxygen-glucose deprivation produced similar depression of synaptic transmission in both genotypes. An inhibitor of tissue non-specific alkaline phosphatase (TNAP) was found to attenuate the inhibitory effects of AMP and ATP, increase basal synaptic activity and reduce responses to oxygen-glucose deprivation selectively in slices from CD73−/− mice. These results do not support an important role for CD73 in the formation of adenosine in the CA1 area of the hippocampus during basal, hypoxic or ischemic conditions, but instead point to TNAP as a potential source of extracellular adenosine when CD73 is absent

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

Global gene expression profile progression in Gaucher disease mouse models

<p>Abstract</p> <p>Background</p> <p>Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure.</p> <p>Results</p> <p>To elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct <it>Gba1 </it>point-mutated mice (V394L/V394L and D409 V/null). About 0.9 to 3% of genes had altered expression patterns (≥ ± 1.8 fold change), representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk) of INFγ-regulated pro-inflammatory (13) and IL-4-regulated anti-inflammatory (11) cytokine/mediator networks showed tissue differential profiles in the lung and liver of the <it>Gba1 </it>mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the <it>Gba1 </it>mutation.</p> <p>Conclusions</p> <p>Biochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology.</p

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