PCOM Library / Archive for "Hot Topics in Research"

Category: Hot Topics in Research

Hot Topics: Communication Difficulties in Children with Autism Linked to Suicidal Behavior

katheride Developmental Disorders, Hot Topics in Research, Pediatrics

Autistic Traits and Suicidal Thoughts, Plans, and Self-Harm in Late Adolescence: Population-Based Cohort Study
Culpin I, Mars B, Pearson RM, et al. Autistic traits and suicidal thoughts, plans, and self-harm in late adolescence: Population-based cohort study. Journal of the American Academy of Child & Adolescent Psychiatry. 2018;57(5):320.e6. http://dx.doi.org/10.1016/j.jaac.2018.01.023.
Objective
To examine the hypothesis that autism spectrum disorders (ASD) diagnosis and traits in childhood are associated with suicidal thoughts, plans and self-harm at 16 years, and that any observed associations are explained by depression at 12 years.
Method
We examined associations between ASD diagnosis and 4 dichotomized ASD traits (social communication, pragmatic language, repetitive behavior, and sociability) with suicidal and nonsuicidal self-harm, suicidal thoughts, and suicidal plans at age 16 years in 5,031 members of the United Kingdom−based birth cohort study the Avon Longitudinal Study of Parents and Children. We assessed whether any associations were explained by depressive symptoms in early adolescence measured by the Short Moods and Feelings Questionnaire at 12 years.
Results
Children with impaired social communication had a higher risk of self-harm with suicidal intent (relative risk [RR] = 2.14, 95% CI = 1.28–3.58), suicidal thoughts (RR = 1.42, 95% CI = 1.06–1.91), and suicidal plans (RR = 1.95, 95% CI = 1.09–3.47) by age 16 years as compared to those without. There was no evidence for an association between ASD diagnosis and outcomes, although these analyses were imprecise because of small numbers. There was also no evidence of an association between other autism traits and the outcomes. Approximately 32% of the total estimated association between social communication impairment and self-harm was explained by depressive symptoms at 12 years.
Conclusion
Social communication impairments are an important autistic trait in relation to suicidality. Early identification and management of depression may be a preventative mechanism, and future research identifying other potentially modifiable mechanisms may lead to interventions against suicidal behavior in this high-risk group.

Hot Topics: Gut Bacteria May Change Course of Atherosclerosis

katheride Cardiology, Hot Topics in Research

Metabolic Products of the Intestinal Microbiome and Extremes of Atherosclerosis
Bogiatzi C, Gloor G, Allen-Vercoe E, et al. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis. 2018;273:91-97. doi: https://doi.org/10.1016/j.atherosclerosis.2018.04.015.
Background and aims
There is increasing awareness that the intestinal microbiome plays an important role in human health. We investigated its role in the burden of carotid atherosclerosis, measured by ultrasound as total plaque area.
Methods
Multiple regression with traditional risk factors was used to identify three phenotypes among 316/3056 patients attending vascular prevention clinics. Residual score (RES; i.e. the distance off the regression line, similar to standard deviation) was used to identify the 5% of patients with much less plaque than predicted by their risk factors (Protected, RES <−2), the 90% with about as much plaque as predicted (Explained, RES -2 to 2), and the 5% with much more plaque than predicted (Unexplained RES >2). Metabolic products of the intestinal microbiome that accumulate in renal failure – gut-derived uremic toxins (GDUT) – were assayed in plasma by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.
Results
Plasma levels of trimethylamine n-oxide (TMAO), p-cresyl sulfate, p-cresyl glucuronide, and phenylacetylglutamine were significantly lower among patients with the Protected phenotype, and higher in those with the Unexplained phenotype, despite no significant differences in renal function or in dietary intake of nutrient precursors of GDUT. In linear multiple regression with a broad panel of risk factors, TMAO (p = 0.011) and p-cresyl sulfate (p = 0.011) were significant independent predictors of carotid plaque burden.
Conclusions
The intestinal microbiome appears to play an important role in atherosclerosis. These findings raise the possibility of novel approaches to treatment of atherosclerosis such as fecal transplantation and probiotics.

Hot Topics: Computers Trained to Visually Analyze Living Cells

katheride Biomedical Sciences, Hot Topics in Research

In Silico Labeling: Predicting Fluorescent Labels in Unlabeled Images
Christiansen EM, Yang SJ, Ando DM, et al. In silico labeling: Predicting fluorescent labels in unlabeled images. Cell. 2018;173(3):803.e19. doi: S0092-8674(18)30364-7.
Microscopy is a central method in life sciences. Many popular methods, such as antibody labeling, are used to add physical fluorescent labels to specific cellular constituents. However, these approaches have significant drawbacks, including inconsistency; limitations in the number of simultaneous labels because of spectral overlap; and necessary perturbations of the experiment, such as fixing the cells, to generate the measurement. Here, we show that a computational machine-learning approach, which we call “in silico labeling” (ISL), reliably predicts some fluorescent labels from transmitted-light images of unlabeled fixed or live biological samples. ISL predicts a range of labels, such as those for nuclei, cell type (e.g., neural), and cell state (e.g., cell death). Because prediction happens in silico, the method is consistent, is not limited by spectral overlap, and does not disturb the experiment. ISL generates biological measurements that would otherwise be problematic or impossible to acquire.

Hot Topics: Animal Model May Show How to Reduce Chemotherapy Pain

katheride Hot Topics in Research, Oncology, Pharmaceutical Sciences

Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms
Wahlman C, Doyle TM, Little JW, et al. Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms. Pain. doi: 10.1097/j.pain.0000000000001177
Development of chemotherapy-induced neuropathic pain (CINP) compromises the use of chemotherapy and greatly impacts thousands of lives. Unfortunately, there are no Food and Drug Administration–approved drugs to prevent or treat CINP. Neuropathological changes within CNS, including neuroinflammation and increased neuronal excitability, are driven by alterations in neuro-glia communication; but, the molecular signaling pathways remain largely unexplored. Adenosine is a potent neuroprotective purine nucleoside released to counteract the consequences of these neuropathological changes. Adenosine signaling at its adenosine receptors (ARs) is dictated by adenosine kinase (ADK) in astrocytes, which provides a cellular sink for the removal of extracellular adenosine. We now demonstrate that chemotherapy (oxaliplatin) in rodents caused ADK overexpression in reactive astrocytes and reduced adenosine signaling at the A3AR subtype (A3AR) within the spinal cord. Dysregulation of ADK and A3AR signaling was associated with increased proinflammatory and neuroexcitatory interleukin-1β expression and activation of nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome, but not putative oxaliplatin-associated GSK3β transcriptional regulation. Intrathecal administration of the highly selective A3AR agonist MRS5698 attenuated IL-1β production and increased the expression of potent anti-inflammatory and neuroprotective IL-10. The effects of MRS5698 were blocked by attenuating IL-10 signaling in rats with intrathecal neutralizing IL-10 antibody and in IL-10−/− knockout mice. These findings provide new molecular insights implicating astrocyte-based ADK-adenosine axis and nucleotide-binding oligomerization domain-like receptor protein 3 in the development of CINP and IL-10 in the mechanism of action of A3AR agonists. These findings strengthen the pharmacological rationale for clinical evaluation of A3AR agonists already in advanced clinical trials as anticancer agents as an adjunct to chemotherapy.

Hot Topics: Treating Depression May Counteract Cognitive Impairments

katheride Alzheimer Disease, Geriatrics, Hot Topics in Research, Mood Disorders

Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment
Sugarman MA, Alosco ML, Tripodis Y, Steinberg EG, Stern RA. Neuropsychiatric symptoms and the diagnostic stability of mild cognitive impairment. Journal of Alzheimer’s Disease. 2018:1-15. doi: 10.3233/JAD-170527.
Background:
Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer’s disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses.
Objective:
The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses.
Method:
The sample included 6,763 participants from the National Alzheimer’s Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15).
Results:
1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia.
Discussion:
The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults.
 
 
 

Hot Topics: NIH Releases Big Data for Brain Development Research

katheride Hot Topics in Research, Neurology, Pediatrics, Psychology and Psychiatry

NIH releases first dataset from unprecedented study of adolescent brain development
National Institutes of Health. (2018, February 13). NIH releases first dataset from unprecedented study of adolescent brain development [Press release]. Retrieved from https://www.nih.gov/news-events/news-releases/nih-releases-first-dataset-unprecedented-study-adolescent-brain-development.
The National Institutes of Health Tuesday released to the scientific community an unparalleled dataset from the Adolescent Brain Cognitive Development (ABCD) study. To date, more than 7,500 youth and their families have been recruited for the study, well over half the participant goal.  Approximately 30 terabytes of data (about three times the size of the Library of Congress collection), obtained from the first 4,500 participants, will be available to scientists worldwide to conduct research on the many factors that influence brain, cognitive, social, and emotional development. The ABCD study is the largest long-term study of brain development and child health in the United States.

Hot Topics: Ineffective Arthritis Drug Could Treat Opioid Addiction

katheride Hot Topics in Research, Substance Use Disorders

Slowly Signaling G Protein–Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence
Lin X, Dhopeshwarkar AS, Huibregtse M, Mackie K, Hohmann AG. Slowly Signaling G Protein–Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence. Mol Pharmacol. 2018;93:49-62; doi: 10.1124/mol.117.109355.
The CB2 cannabinoid agonist LY2828360 lacked both toxicity and efficacy in a clinical trial for osteoarthritis. Whether LY2828360 suppresses neuropathic pain has not been reported, and its signaling profile is unknown. In vitro, LY2828360 was a slowly acting but efficacious G protein–biased CB2 agonist, inhibiting cAMP accumulation and activating extracellular signal-regulated kinase 1/2 signaling while failing to recruit arrestin, activate inositol phosphate signaling, or internalize CB2 receptors. In wild-type (WT) mice, LY2828360 (3 mg/kg per day i.p. × 12 days) suppressed chemotherapy-induced neuropathic pain produced by paclitaxel without producing tolerance. Antiallodynic efficacy of LY2828360 was absent in CB2 knockout (KO) mice. Morphine (10 mg/kg per day i.p. × 12 days) tolerance developed in CB2KO mice but not in WT mice with a history of LY2828360 treatment (3 mg/kg per day i.p. × 12 days). LY2828360-induced antiallodynic efficacy was preserved in WT mice previously rendered tolerant to morphine (10 mg/kg per day i.p. × 12 days), but it was absent in morphine-tolerant CB2KO mice. Coadministration of LY2828360 (0.1 mg/kg per day i.p. × 12 days) with morphine (10 mg/kg per day × 12 days) blocked morphine tolerance in WT but not in CB2KO mice. WT mice that received LY2828360 coadministered with morphine exhibited a trend (P = 0.055) toward fewer naloxone-precipitated jumps compared with CB2KO mice. In conclusion, LY2828360 is a slowly signaling, G protein–biased CB2 agonist that attenuates chemotherapy-induced neuropathic pain without producing tolerance and may prolong effective opioid analgesia while reducing opioid dependence. LY2828360 may be useful as a first-line treatment in chemotherapy-induced neuropathic pain and may be highly efficacious in neuropathic pain states that are refractive to opioid analgesics.

Hot Topics: Existing Cupping Therapy Research Inconclusive on Benefits or Drawbacks

katheride Alternative and Complementary Medicine, Hot Topics in Research, Sports Medicine

Effects of Cupping Therapy in Amateur and Professional Athletes: Systematic Review of Randomized Controlled Trials
Bridgett R, Klose P, Duffield R, Mydock S, Lauche R. Effects of cupping therapy in amateur and professional athletes: Systematic review of randomized controlled trials. The Journal of Alternative and Complementary Medicine. 2017. https://doi.org/10.1089/acm.2017.0191.
Objective: Despite the recent re-emergence of the process of cupping by athletes, supporting evidence for its efficacy and safety remains scarce. This systematic review aims to summarize the evidence of clinical trials on cupping for athletes.
Methods: SCOPUS, Cochrane Library, PubMed, AMED, and CNKI databases were searched from their inception to December 10, 2016. Randomized controlled trials on cupping therapy with no restriction regarding the technique, or cointerventions, were included, if they measured the effects of cupping compared with any other intervention on health and performance outcomes in professionals, semi-professionals, and leisure athletes. Data extraction and risk of bias assessment using the Cochrane Risk of Bias Tool were conducted independently by two pairs of reviewers.
Results: Eleven trials with n = 498 participants from China, the United States, Greece, Iran, and the United Arab Emirates were included, reporting effects on different populations, including soccer, football, and handball players, swimmers, gymnasts, and track and field athletes of both amateur and professional nature. Cupping was applied between 1 and 20 times, in daily or weekly intervals, alone or in combination with, for example, acupuncture. Outcomes varied greatly from symptom intensity, recovery measures, functional measures, serum markers, and experimental outcomes. Cupping was reported as beneficial for perceptions of pain and disability, increased range of motion, and reductions in creatine kinase when compared to mostly untreated control groups. The majority of trials had an unclear or high risk of bias. None of the studies reported safety.

Conclusions: No explicit recommendation for or against the use of cupping for athletes can be made. More studies are necessary for conclusive judgment on the efficacy and safety of cupping in athletes.

Hot Topics: Key Molecule Found To Protect Brain From Depression

katheride Hot Topics in Research, Mood Disorders, Psychology and Psychiatry

Loss of eIF4E Phosphorylation Engenders Depression-like Behaviors via Selective mRNA Translation
Amorim IS, Kedia S, Kouloulia S, et al. Loss of eIF4E phosphorylation engenders depression-like behaviors via selective mRNA translation. J Neurosci. 2018;38(8):2118-2133. doi: 10.1523/JNEUROSCI.2673-17.2018.

The MAPK/ERK (mitogen-activated protein kinases/extracellular signal-regulated kinase) pathway is a cardinal regulator of synaptic plasticity, learning, and memory in the hippocampus. One of major endpoints of this signaling cascade is the 5′ mRNA cap binding protein eIF4E (eukaryotic Initiation Factor 4E), which is phosphorylated on Ser 209 by MNK (MAPK-interacting protein kinases) and controls mRNA translation. The precise role of phospho-eIF4E in the brain is yet to be determined. Herein, we demonstrate that ablation of eIF4E phosphorylation in male mice (4Eki mice) does not impair long-term spatial or contextual fear memory, or the late phase of LTP. Using unbiased translational profiling in mouse brain, we show that phospho-eIF4E differentially regulates the translation of a subset of mRNAs linked to inflammation, the extracellular matrix, pituitary hormones, and the serotonin pathway. Consequently, 4Eki male mice display exaggerated inflammatory responses and reduced levels of serotonin, concomitant with depression and anxiety-like behaviors. Remarkably, eIF4E phosphorylation is required for the chronic antidepressant action of the selective serotonin reuptake inhibitor fluoxetine. Finally, we propose a novel phospho-eIF4E-dependent translational control mechanism in the brain, via the GAIT complex (gamma IFN activated inhibitor of translation). In summary, our work proposes a novel translational control mechanism involved in the regulation of inflammation and depression, which could be exploited to design novel therapeutics.

SIGNIFICANCE STATEMENT We demonstrate that downstream of the MAPK (mitogen-activated protein kinase) pathway, eukaryotic Initiation Factor 4E (eIF4E) Ser209 phosphorylation is not required for classical forms of hippocampal LTP and memory. We reveal a novel role for eIF4E phosphorylation in inflammatory responses and depression-like behaviors. eIF4E phosphorylation is required for the chronic action of antidepressants, such as fluoxetine in mice. These phenotypes are accompanied by selective translation of extracellular matrix, pituitary hormones, and serotonin pathway genes, in eIF4E phospho-mutant mice. We also describe a previously unidentified translational control mechanism in the brain, whereby eIF4E phosphorylation is required for inhibiting the translation of gamma IFN activated inhibitor of translation element-containing mRNAs. These findings can be used to design novel therapeutics for depression.

 

Hot Topics: Stress of Healthcare Staff Can Affect Service During Disasters

katheride Emergency Medicine, Hot Topics in Research

Staff Stress: The Sleeping Cell of Healthcare Failure
Achour N, Munokaran S, Barker F, Soetanto R. Staff stress: The sleeping cell of healthcare failure. Procedia Engineering. 2018;212:459-466. doi: 10.1016/j.proeng.2018.01.059.
Much research has been conducted to increase the resilience of healthcare service to major hazards; however, every time a major hazard takes place we discover that this critical service is yet to reach the anticipated resilient state. This paper reports an ongoing research work that looked at: the resilience of the structure of healthcare facilities, equipment stability, lifeline (utility) supplies, the interaction between hospitals and emergency agencies and the support the latter can provide during major emergencies. This paper presents findings on the ability of human resources to deal with the stress associated with major hazards. A mixed research method was adopted, including a systematic literature review followed by a survey to gather evidence about the stress level amongst healthcare staff in hospitals and their motivation. The literature review was conducted to find information about the level of stress healthcare staff experience with during major emergencies. Findings suggest that healthcare staff remain at high risk of stress and thus represent a major weakness of healthcare service resilience. The research concludes with a set of recommendations to address this issue.