Cerebral palsy in children: A clinical practice review.

Cerebral palsy is a disorder characterized by abnormal tone, posture, and movement. In clinical practice, it is often useful to approach cerebral palsy based on the predominant motor system findings - spastic hemiplegia, spastic diplegia, spastic quadriplegia, extrapyramidal or dyskinetic, and ataxic. The prevalence of cerebral palsy is between 1.5 and 3 per 1,000 live births with higher percentage of cases in low to middle income countries and geographic regions. Pre-term birth and low birthweight are recognized as the most frequent risk factors for cerebral palsy; other risk factors include hypoxic-ischemic encephalopathy, maternal infections, and multiple gestation. In most cases of cerebral palsy, the initial injury to the brain occurs during early fetal brain development. Intracerebral hemorrhage and periventricular leukomalacia are the main pathologic findings found in preterm infants who develop spastic cerebral palsy. The diagnosis of cerebral palsy is primarily based on clinical findings. Early recognition of infants at risk for cerebral palsy as well as those with cerebral palsy is possible based on a combination of clinical history, use of standardized neuromotor assessment and findings on magnetic resonance imaging; however, in clinical practice, cerebral palsy is more reliably diagnosed by 2 years of age. Magnetic resonance imaging scan is indicated to delineate the extent of brain lesions and to identify congenital brain malformations. Genetic testing and tests for inborn errors of metabolism are indicated to identify specific disorders, especially treatable disorders. Because cerebral palsy is associated with multiple associated and secondary medical conditions, its management requires a sustained and consistent collaboration among multiple disciplines and specialties. With appropriate support, most children with cerebral palsy grow up to be adults with good functional abilities.

18F-FDG-PET/MR imaging to monitor disease activity in large vessel vasculitis.

Disease-monitoring in large vessel vasculitis (LVV) is challenging. Simultaneous 18F-fluorodeoxyglucose positron emission tomography with magnetic resonance imaging (PET/MRI) provides functional assessment of vascular inflammation alongside high-definition structural imaging with a relatively low burden of radiation exposure. Here, we investigate the ability of PET/MRI to monitor LVV disease activity longitudinally in a prospective cohort of patients with active LVV. We demonstrate that both the PET and MRI components of the scan can distinguish active from inactive disease using established quantification methods. Using logistic-regression modelling of PET/MRI metrics, we devise a novel PET/MRI-specific Vasculitis Activity using MR PET (VAMP) score which is able to distinguish active from inactive disease with more accuracy than established methods and detects changes in disease activity longitudinally. These findings are evaluated in an independent validation cohort. Finally, PET/MRI improves clinicians' assessment of LVV disease activity and confidence in disease management, as assessed via clinician survey. In summary, PET/MRI may be useful in tracking disease activity and assessing treatment-response in LVV. Based on our findings, larger, prospective studies assessing PET/MRI in LVV are now warranted.

UCP1 expression in human brown adipose tissue is inversely associated with cardiometabolic risk factors.

OBJECTIVE: Brown adipose tissue (BAT) is a therapeutic target for obesity. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is commonly used to quantify human BAT mass and activity. Detectable 18F-FDG uptake by BAT is associated with reduced prevalence of cardiometabolic disease. However, 18F-FDG uptake may not always be a reliable marker of BAT thermogenesis, for example, insulin resistance may reduce glucose uptake. Uncoupling protein 1 (UCP1) is the key thermogenic protein in BAT. Therefore, we hypothesised that UCP1 expression may be altered in individuals with cardiometabolic risk factors. METHODS: We quantified UCP1 expression as an alternative marker of thermogenic capacity in BAT and white adipose tissue (WAT) samples (n = 53) and in differentiated brown and white pre-adipocytes (n = 85). RESULTS: UCP1 expression in BAT, but not in WAT or brown/white differentiated pre-adipocytes, was reduced with increasing age, obesity, and adverse cardiometabolic risk factors such as fasting glucose, insulin, and blood pressure. However, UCP1 expression in BAT was preserved in obese subjects of <40 years of age. To determine if BAT activity was also preserved in vivo, we undertook a case-control study, performing 18F-FDG scanning during mild cold exposure in young (mean age ∼22 years) normal weight and obese volunteers. 18F-FDG uptake by BAT and BAT volume were similar between groups, despite increased insulin resistance. CONCLUSION: 18F-FDG uptake by BAT and UCP1 expression are preserved in young obese adults. Older subjects retain precursor cells with the capacity to form new thermogenic adipocytes. These data highlight the therapeutic potential of BAT mass expansion and activation in obesity.

Epigenetic Impact of Curcumin and Thymoquinone on Cancer Therapeutics.

Today, one of the most prevalent reasons for death among people is carcinoma. Because it is still on the increase throughout the world, there is a critical need for in- -depth research on the pathogenic mechanisms behind the disease as well as for efficient treatment. In the field of epigenetics, gene expression alterations that are inherited but not DNA sequence changes are investigated. Three key epigenetic changes, histone modifications, DNA methylation and non-coding RNA (ncRNA) expression, are principally responsible for the initiation and progression of different tumors. These changes are interconnected and constitute many epigenetic changes. A form of polyphenolic chemical obtained from plants called curcumin has great bioactivity against several diseases, specifically cancer. A naturally occurring substance called thymoquinone is well-known for its anticancer properties. Thymoquinone affects cancer cells through a variety of methods, according to preclinical studies. We retrieved information from popular databases, including PubMed, Google Scholar, and CNKI, to summarize current advancements in the efficiency of curcumin against cancer and its epigenetic regulation in terms of DNA methylation, histone modifications, and miRNA expression. The present investigation offers thorough insights into the molecular processes, based on epigenetic control, that underlie the clinical use of curcumin and thymoquinone in cancerous cells.

Pediatric suicide: Review of a preventable tragedy.

Concepts of suicide are explored in this issue with a focus on suicide in children and adolescents. The epidemiology of pediatric suicide in the United States is reviewed; also, risk and protective factors, as well as prevention strategies, are discussed. Suicide in the pediatric athlete and the potential protective effect of exercise are examined. In addition, this analysis addresses the beneficial role of psychological management as well as current research on pharmacologic treatment and brain stimulation procedures as part of comprehensive pediatric suicide prevention. Though death by suicide in pediatric persons has been and remains a tragic phenomenon, there is much that clinicians, other healthcare professionals, and society itself can accomplish in the prevention of pediatric suicide as well as the management of suicidality in our children and adolescents.

Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.

Despite whole-genome sequencing (WGS), many cases of single-gene disorders remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection. Since early WGS data analytic steps prioritize protein-coding sequences, to simultaneously prioritize variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY, an analytic tool that integrates coordinates for regions with experimental evidence of functionality. Applied to WGS data from solved and unsolved hereditary hemorrhagic telangiectasia (HHT) recruits to the 100,000 Genomes Project, GROFFFY-based filtration reduced the mean number of variants/DNA from 4,867,167 to 21,486, without deleting disease-causal variants. In three unsolved cases (two related), GROFFFY identified ultra-rare deletions within the 3' untranslated region (UTR) of the tumor suppressor SMAD4, where germline loss-of-function alleles cause combined HHT and colonic polyposis (MIM: 175050). Sited >5.4 kb distal to coding DNA, the deletions did not modify or generate microRNA binding sites, but instead disrupted the sequence context of the final cleavage and polyadenylation site necessary for protein production: By iFoldRNA, an AAUAAA-adjacent 16-nucleotide deletion brought the cleavage site into inaccessible neighboring secondary structures, while a 4-nucleotide deletion unfolded the downstream RNA polymerase II roadblock. SMAD4 RNA expression differed to control-derived RNA from resting and cycloheximide-stressed peripheral blood mononuclear cells. Patterns predicted the mutational site for an unrelated HHT/polyposis-affected individual, where a complex insertion was subsequently identified. In conclusion, we describe a functional rare variant type that impacts regulatory systems based on RNA polyadenylation. Extension of coding sequence-focused gene panels is required to capture these variants.

The serotonin transporter sustains human brown adipose tissue thermogenesis.

Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.

Ergogenic Aids and Testing in Pediatric Athletes.

In the quest for winning the game, some athletes take various chemicals (ie, drugs, herbs, or supplements) in attempts to develop greater strength, endurance, or other elements that bring a competitive advantage. There are more than 30,000 chemicals sold throughout the world with unrestrained and unproven claims; however, some athletes consume them with hopes of increasing their athletic abilities, often without knowledge of the potential adverse effects and with limited evidence of efficacy. Complicating this picture is that research on ergogenic chemicals is typically conducted with elite adult male athletes and not with athletes who are in high school. A few of these ergogenic aids include creatine, anabolic androgenic steroids, selective androgen receptor modulators, clenbuterol, androstenedione, dehydroepiandrosterone, human growth hormone, ephedrine, gamma hydroxybutyrate, caffeine, stimulants (amphetamines or methylphenidate), and blood doping. In this article, we describe the purpose of ergogenic aids as well as the potential side effects. [Pediatr Ann. 2023;52(6):e207-e212.].

Scope of Wnt signaling in the precise diagnosis and treatment of breast cancer.

Malignant breast cancers are responsible for a growing number of deaths among women globally. The latest research has demonstrated that Wnt signaling is pivotal in this disease, regulating a safe microenvironment for the growth and proliferation of cancer cells, sustained stemness, resistance to therapy, and aggregate formation. The three highly conserved Wnt signaling pathways, Wnt-planar cell polarity (PCP), Wnt/ß-catenin signaling and Wnt-Ca2+ signaling, assume various roles in the maintenance and amelioration of breast cancer. In this review, we examine ongoing studies on the Wnt signaling pathways and discuss how dysregulation of these pathways promotes breast cancers. We also look at how Wnt dysregulation could be exploited to foster new treatments for malignant breast cancers.