Rational Development of a Small-Molecule Activator of CK1γ2 That Decreases C99 and Beta-Amyloid Levels.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of ß-amyloid (Aß), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aß levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD. Our laboratory has discovered that CK1γ2 phosphorylates Presenilin 1 at the γ-secretase complex, leading to decreased C99 and Aß levels. Thus, CK1γ2 activation appears as a promising therapeutic target to lower both C99 and Aß levels. In this study, we demonstrate that CK1γ2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1γ2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1γ2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and Aß levels. Using cultured cells, we investigated the impact of these compounds on C99 and Aß concentrations and confirmed that CK1γ2 activation effectively reduced their levels. Our results provide proof of concept that CK1γ2 is an attractive therapeutic target for AD. Future studies should focus on the identification of specific compounds that can inhibit CK1γ2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment of AD.

Paediatric cardiologist adherence to American Heart Association neurodevelopmental recommendations for CHD patients.

A 2012 American Heart Association statement concluded that children with CHD are at an increased risk for neurodevelopmental delays. Routine surveillance and evaluation throughout childhood are recommended. To assess paediatric cardiologist compliance with American Heart Association guidelines and developmental referral practices, a survey was distributed to paediatric cardiologists nationwide (n = 129). The majority of participants (69%) stated they were somewhat familiar or not familiar with the American Heart Association statement and were concerned about patients not being properly referred to specialists for developmental evaluation. Forty paediatric cardiologists (31%) indicated that their institution did not have a neurodevelopmental cardiology programme. Of these, 25% indicated they generally did not refer CHD patients for neurodevelopmental evaluation, 45% performed surveillance and referred if warranted, and 30% generally referred all patients for surveillance. Lastly, 43% of paediatric cardiologists did not feel responsible for developmental surveillance, and 11% did not feel responsible for referrals. To ensure all children with CHD are appropriately screened and referred, paediatricians and cardiologists must work together to address differing impressions of accountability for surveillance and screening of children with CHD.

Puff bars: a dangerous trend in adolescent disposable e-cigarette use.

PURPOSE OF REVIEW: Puff Bars, a brand of disposable e-cigarettes, have skyrocketed in popularity recently, presenting significant health and safety risks to adolescents. Puff Bars and other disposable e-cigarette products are attractive to children and teenagers because of their vibrant colors and flavors, low cost, and ease of access. This review examines the rise in Puff Bar popularity, describes notable health and safety concerns, and provides advice for parents and pediatricians in identifying and preventing adolescent Puff Bar use. RECENT FINDINGS: Puff Bars have increased in popularity as their product design evaded strict regulations imposed on alternate e-cigarette products, such as Juul. In addition, Puff Bars' sweet and fruit flavors and marketing on social media have made their use pervasive among youth. Puff Bar use can lead to increased risk of e-cigarette product use-associated lung injury (EVALI) and potential exposure to carcinogens. Furthermore, the developmental risks of nicotine use during adolescence include negative effects on cognitive function and detriments to short-term memory. SUMMARY: Puff Bars present a significant danger to adolescents, and it is imperative that parents and pediatricians are aware of the health risks involved with vaping. Pediatricians should explore e-cigarette use during patient visits, and parents must communicate these dangers to their children and be able to identify these products to regulate their use.

The Effects of Host Availability and Fitness on Aedes albopictus Blood Feeding Patterns in New York.

Aedes albopictus is a competent vector of numerous pathogens, representing a range of transmission cycles involving unique hosts. Despite the important status of this vector, variation in its feeding patterns is poorly understood. We examined the feeding patterns of Ae. albopictus utilizing resting collections in Long Island, NY, and contextualized blood meal sources with host availability measured by household interviews and camera traps. We identified 90 blood meals, including 29 humans, 22 cats, 16 horses, 12 opossums, 5 dogs, 2 goats, and 1 each of rabbit, rat, squirrel, and raccoon. This is only the third study of Ae. albopictus blood feeding biology that quantitatively assessed domestic host availability and is the first to do so with wild animals. Host feeding indices showed that cats and dogs were fed upon disproportionately often compared with humans. Forage ratios suggested a tendency to feed on cats and opossums and to avoid raccoons, squirrels, and birds. This feeding pattern was different from another published study from Baltimore, where Ae. albopictus fed more often on rats than humans. To understand whether these differences were because of host availability or mosquito population variation, we compared the fitness of New York and Baltimore Ae. albopictus after feeding on rat and human blood. In addition, we examined fitness within the New York population after feeding on human, rat, cat, horse, and opossum blood. Together, our results do not indicate major mosquito fitness differences by blood hosts, suggesting that fitness benefits do not drive Northeastern Ae. albopictus feeding patterns.

Sugar feeding patterns of New York Aedes albopictus mosquitoes are affected by saturation deficit, flowers, and host seeking.

BACKGROUND: Sugar feeding is an important behavior which may determine vector potential of female mosquitoes. Sugar meals can reduce blood feeding frequency, enhance survival, and decrease fecundity, as well as provide energetic reserves to fuel energy intensive behaviors such as mating and host seeking. Sugar feeding behavior can be harnessed for vector control (e.g. attractive toxic sugar baits). Few studies have addressed sugar feeding of Aedes albopictus, a vector of arboviruses of public health importance, including dengue and Zika viruses. To address this knowledge gap, we assessed sugar feeding patterns of Ae. albopictus for the first time in its invasive northeastern USA range. METHODOLOGY/PRINCIPAL FINDINGS: Using the cold anthrone fructose assay with robust sample sizes, we demonstrated that a large percentage of both male (49.6%) and female (41.8%) Ae. albopictus fed on plant or homopteran derived sugar sources within 24 hrs prior to capture. Our results suggest that sugar feeding behavior increases when environmental conditions are dry (high saturation deficit) and may vary by behavioral status (host seeking vs. resting). Furthermore, mosquitoes collected on properties with flowers (>3 blooms) had higher fructose concentrations compared to those collected from properties with few to no flowers (0-3). CONCLUSIONS/SIGNIFICANCE: Our results provide the first evidence of Ae. albopictus sugar feeding behavior in the Northeastern US and reveal relatively high rates of sugar feeding. These results suggest the potential success for regional deployment of toxic sugar baits. In addition, we demonstrate the impact of several environmental and mosquito parameters (saturation deficit, presence of flowers, host seeking status, and sex) on sugar feeding. Placing sugar feeding behavior in the context of these environmental and mosquito parameters provides further insight into spatiotemporal dynamics of feeding behavior for Ae. albopictus, and in turn, provides information for evidence-based control decisions.

Rate and Risk Factors Associated with Autism Spectrum Disorder in Congenital Diaphragmatic Hernia.

To determine the rate and predictors of autism spectrum disorder (ASD) in congenital diaphragmatic hernia (CDH). Between 06/2004 and 09/2015 a total of 110 CDH survivors underwent neurodevelopmental (ND) testing and screening for ASD, followed by a full autism diagnostic evaluation if indicated at our institution. We found a 9 time higher rate of ASD in CDH children compared to the general population (P = 0.0002). Multiple patient-related and clinical variables risk factors of ASD were identified by univariate analysis. However, only short-term and long-term neurodevelopmental delays were strongly associated with ASD in CDH by multivariate comparisons. There is a striking prevalence of ASD in CDH survivors and our findings suggest that all CDH children should be regularly screened for ASD.

Short-Term Neurodevelopmental Outcome in Children Born With High-Risk Congenital Lung Lesions.

BACKGROUND: This study sought to evaluate neurodevelopmental outcome in survivors of high-risk congenital lung lesions (CLLs) who underwent prenatal intervention or postnatal surgery within the first month of life. METHODS: Forty-five high-risk CLL survivors underwent assessment using the Bayley Scales of Infant Development, 3rd Edition between July 2004 and December 2016. Scores were grouped as average, at-risk, and delayed based on SD intervals. Correlations between outcome and risk factors were analyzed by Fisher's exact test or two-sided t test as appropriate, with significant p values <0.05. RESULTS: Open prenatal intervention was required in 13 (28.9%) children (fetal surgical resection, n = 4 , ex utero intrapartum treatment, n = 9), whereas 32 (71.1%) children had respiratory distress postnatally and required resection within the first month of life. Mean age at follow-up was 19.3 ± 10.3 months. Mean composite scores were within the expected average range. A total of 62.2% scored within the average range for all domains. At-risk scores were found in 26.7% of children in at least one domain, and 11.1% had delays in at least one domain. Neurodevelopmental outcome was similar between treatment groups. Prolonged ventilator support and neonatal intensive care unit stay, need for supplemental oxygen at day of life 30, gastroesophageal reflux disease, and delayed enteral feeding were associated with neurologic delays (all p < 0.05). CONCLUSIONS: Neurodevelopmental scores for high-risk CLL survivors in infancy and toddlerhood are age appropriate. Neither fetal intervention nor the need for postnatal resection within the first month of life increases the risk of delays. Surrogate markers of a complicated neonatal course are predictive of adverse outcome.

Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination and neurodegeneration throughout the CNS, which lead over time to a condition of irreversible functional decline known as progressive MS. Currently, there are no satisfactory treatments for this condition because the mechanisms that underlie disease progression are not well understood. This is partly due to the lack of a specific animal model that represents progressive MS. We investigated the effects of intracerebroventricular injections of cerebrospinal fluid (CSF) derived from untreated primary progressive (PPMS), secondary progressive (SPMS), and relapsing/remitting (RRMS) MS patients into mice. We found discrete inflammatory demyelinating lesions containing macrophages, B cell and T cell infiltrates in the brains of animals injected with CSF from patients with progressive MS. These lesions were rarely found in animals injected with RRMS-CSF and never in those treated with control-CSF. Animals that developed brain lesions also presented extensive inflammation in their spinal cord. However, discrete spinal cord lesions were rare and only seen in animals injected with PPMS-CSF. Axonal loss and astrogliosis were seen within the lesions following the initial demyelination. In addition, Th17 cell activity was enhanced in the CNS and in lymph nodes of progressive MS-CSF injected animals compared to controls. Furthermore, CSF derived from MS patients who were clinically stable following therapy had greatly diminished capacity to induce CNS lesions in mice. Finally, we provided evidence suggesting that differential expression of pro-inflammatory cytokines present in the progressive MS CSF might be involved in the observed mouse pathology. Our data suggests that the agent(s) responsible for the demyelination and neurodegeneration characteristic of progressive MS is present in patient CSF and is amenable to further characterization in experimental models of the disease.

Mesenchymal stem cells enhance the engraftment and myelinating ability of allogeneic oligodendrocyte progenitors in dysmyelinated mice.

Multiple sclerosis is an autoimmune disease characterized by demyelination and axonal loss throughout the central nervous system. No regenerative treatment exists for patients who fail to respond to conventional immunosuppressive and immunomodulating drugs. In this scenario, stem cell therapy poses as a rational approach for neurological regeneration. Transplantation of embryonic-derived oligodendrocyte progenitor cells (OPCs) has been shown to promote remyelination and ameliorate animal models of neurodegenerative diseases. However, its therapeutic application is limited due to potential transplant rejection. In multiple sclerosis, an added concern is that transplant rejection would be most pronounced at sites of previous lesions, exacerbating a hyperactive immune response which could prevent remyelination and precipitate additional demyelination. Routine systemic immunosuppression may not be sufficient to prevent transplant rejection-associated immune reactions in the cerebral microenvironment. Mesenchymal stem cells (MSCs), due to their homing properties and inherent immunosuppressive nature, are a promising tool for clinical application targeted toward immunosuppression at sites of injury. In this study, we used a co-transplantation strategy to investigate the effect of syngeneic MSCs on the survival and remyelination abilities of allogeneic OPCs in adult nonimmunosuppressed shiverer mice. At all time points examined, cotransplantation with MSCs increased OPC engraftment, migration, and maturation in myelinating oligodendrocytes, which produced widespread myelination in the host corpus callosum. In addition, MSCs reduced microglia activation and astrocytosis in the brain of transplanted animals as well as T-cell proliferation in vitro. These data suggest that combining the immunomodulatory and trophic properties of MSCs with the myelinating ability of OPCs might be a suitable strategy for promoting neurological regeneration in demyelinating diseases.

Duloxetine in the treatment of major depression and other psychiatric disorders.

Duloxetine is a new antidepressant agent approved for use in major depressive disorder, generalized anxiety disorder and diabetic peripheral neuropathic pain. It potently inhibits the reuptake of serotonin and norepinephrine in the synaptic cleft. This dual mechanism of action is thought to provide a favorable pharmacological profile with regards to efficacy, onset of action and analgesic properties. Pilot studies on the efficacy of duloxetine in the treatment of dysthymia and other psychiatric disorders have also shown promising results. Duloxetine appears well tolerated and its safety profile is similar to that of the selective serotonin-reuptake inhibitors.