Impact of neurocognitive function on academic difficulties in pediatric bipolar disorder: A clinical translation.

BACKGROUND: Previous research has demonstrated that academic and neuropsychological functions are compromised in pediatric bipolar disorder (PBD). Investigation of the degree to which neuropsychological deficits might contribute to those academic problems is needed to aid in the recognition and intervention for school achievement difficulties in PBD. METHODS: A sample of 55 children and adolescents with PBD with and without attention-deficit/hyperactivity disorder (ADHD) (PBD group, n = 28; PBD+ADHD group, n = 27) were tested with a computerized neurocognitive battery and standardized neuropsychological tests. Age range of subjects was 7-17 years, with the mean age of 11.97 (3.18) years. Parents completed a structured questionnaire on school and academic functioning. RESULTS: Logistic regression analyses indicated that executive function, attention, working memory, and verbal memory scores were poorer in those with a history of reading/writing difficulties. A separate logistic regression analysis found that attentional dysfunction predicted math difficulties. These relationships between neuropsychological function and academic difficulties were not different in those with PBD+ADHD than in those with PBD alone. CONCLUSIONS: In PBD neuropsychological deficits in the areas of attention, working memory, and organization/problem solving skills all contribute to academic difficulties. Early identification and intervention for these difficulties might help prevent lower academic achievement in PBD.     

Potentiation of cholinergic activity with pyridino[1,2-a]imidazo[5,4-b]indole: in vitro studies

1. Effects of a novel imidazoindole derivative on cholinergic function were studied in isolated tissue preparations. 2. The compound demonstrated a dose-dependent (10(-11)-10(-9) potentiation (20-60%) of acetylcholine induced tension in guinea pig ileal tissue. 3. Increases in the size of end-plate potentials and nerve evoked muscle twitches were observed in frog nerve-skeletal muscle preparations. 4. Cholinesterase activity was not inhibited. 5. The results suggest that the compound has actions at the post-synaptic muscarinic receptor complex in smooth muscle and causes pre-synaptic increases in ACh release at the neuromuscular junction.     

Affective neural circuitry during facial emotion processing in pediatric bipolar disorder.

BACKGROUND: Facial emotions are central to human interaction. Identifying pathophysiology in affect processing circuitry that supports the ability to assess facial emotions might facilitate understanding of affect regulation in pediatric bipolar disorder. METHODS: Ten euthymic, unmedicated pediatric bipolar patients and 10 healthy control subjects matched for age, gender, race, socioeconomic status, and IQ were scanned with functional magnetic resonance imaging. Angry, happy, and neutral faces were presented in 30-sec blocks, with a 20-sec rest period between blocks. Subjects were asked to press a button when each face appeared, to ensure that attention was maintained on-task. RESULTS: In bipolar patients, in response to both angry and happy faces relative to neutral faces, we observed reduced activation of right rostral ventrolateral prefrontal cortex together with increased activity in right pregenual anterior cingulate, amygdala, and paralimbic cortex. Bipolar patients also showed reduced activation of visual areas in occipital cortex together with greater activation in higher-order visual perceptual areas, including superior temporal sulcus and fusiform gyrus with angry faces and posterior parietal cortex with happy faces. CONCLUSIONS: Findings document a disturbance in affective neurocircuitry in pediatric bipolar disorder. Reduced activation in ventrolateral prefrontal cortex might reflect diminished top-down control that leads to the observed exaggerated activation in amygdala and paralimbic areas. Changes in occipital areas might represent an effort to gate sensory input when affective responses to the faces could not be successfully modulated. Disturbances in affect processing circuitry could contribute to emotional dysregulation and social cognitive difficulties in bipolar youth.     

Sex-Dependent Effects of 7,8-Dihydroxyflavone on Metabolic Health Are Associated with Alterations in the Host Gut Microbiome

7,8-Dihydroxyflavone (DHF) is a naturally occurring flavonoid that has been reported to protect against a variety of pathologies. Chronic administration of DHF prevents high-fat diet (HFD)-induced obesity in female, but not male, mice. However, the mechanisms underlying this sexual dimorphism have not been elucidated. We have discovered that oral DHF supplementation significantly attenuates fat mass, hepatic lipid accumulation, and adipose tissue inflammation in female mice. In contrast, male mice were not protected from adiposity, and had a paradoxical worsening of hepatic lipid accumulation and adipose tissue inflammation upon DHF supplementation. Consistent with these sexually dimorphic effects on body weight and metabolic health, 7,8-DHF induced early and stable remodeling of the female intestinal microbiome. DHF supplementation significantly increased gut microbial diversity, and suppressed potentially detrimental bacteria, particularly Desulfovibrionaceae, which are pro-inflammatory and positively associated with obesity and inflammation. Changes in the female gut microbiome preceded alterations in body weights, and in silico analyses indicated that these early microbial changes were highly predictive of subsequent weight gain in female mice. While some alterations in the intestinal microbiome were also observed in male DHF-supplemented mice, these changes were distinct from those in females and, importantly, were not predictive of subsequent body weight changes in male animals. The temporality of microbial changes preceding alterations in body weight in female mice suggests a role for the gut microbiome in mediating the sexually dimorphic effects of DHF on body weight. Given the significant clinical interest in this flavonoid across a wide range of pathologies, further elucidation of these sexually dimorphic effects will aid the development of effective clinical therapies.     

An overview on in situ micronization technique – An emerging novel concept in advanced drug delivery

The use of drug powders containing micronized drug particles has been increasing in several pharmaceutical dosage forms to overcome the dissolution and bioavailability problems. Most of the newly developed drugs are poorly water soluble which limits dissolution rate and bioavailability. The dissolution rate can be enhanced by micronization of the drug particles. The properties of the micronized drug substance such as particle size, size distribution, shape, surface properties, and agglomeration behaviour and powder flow are affected by the type of micronization technique used. Mechanical communition, spray drying and supercritical fluid (SCF) technology are the most commonly employed techniques for production of micronized drug particles but the characteristics of the resulting drug product cannot be controlled using these techniques. Hence, a newer technique called in situ micronization is developed in order to overcome the limitations associated with the other techniques. This review summarizes the existing knowledge on in situ micronization techniques. The properties of the resulting drug substance obtained by in situ micronization were also compared.     

Effects of meconium aspiration in isolated perfused rat lungs

Our objective was to study meconium-induced lung injury in isolated perfused rat lungs exposed to anoxia. Our working hypothesis was that meconium-induced lung injury is independent of preexisting hypoxia, and that hypoxia will increase severity of lung injury observed after meconium aspiration. We compared five different groups of animals (n = 5) for pulmonary arterial pressure (PAP), weight lung changes, and TNFalpha expression. Group I had lungs instilled with 4 ml of normal saline. Group II had lungs exposed to 5 min of anoxia. Group III had lungs instilled with 4 ml of 30% filtered human meconium. Group IV had lungs exposed to 5 min of anoxia and then instilled with 4 ml of 30% filtered human meconium. Group V had lungs instilled with 4 ml of 30% unfiltered human meconium. Our subjects were adult Sprague-Dawley rats. The isolated rat lung model was prepared according to Levey and Gast (J Appl Physiol 1966;21:313-316). Lungs were ventilated with room air. Anoxia was caused by the use of N(2). The pulmonary artery was cannulated, and pulmonary arterial pressure and lung weight were measured. Lung weight and pulmonary arterial pressure were monitored for 120 min, and TNFalpha levels were measured in effluent at 15, 30, 60, and 120 min. Experiments were done at the Michael Reese Hospital (Chicago, IL). At the end of the experiment, PAP reached its highest values in group V (10.0 +/- 1.7 mmHg). Final PAPs in groups I-IV were: 4.85 +/- 0.3, 4.99 +/- 0.4, 5.93 +/- 0.3, and 7.25 +/- 0.51 mmHg, respectively). Lung wet weight increased significantly only in groups IV and V vs. group I; at 120 min, they were: 0.96 +/- 0.3 g, P < 0.01, and 1.5 g +/- 0.2 g, P < 0.01, respectively. TNFalpha levels did not change significantly over time in group I. TNFalpha is a marker as well as proprietor of pulmonary inflammatory response. TNFalpha reached its highest levels in groups IV and V: 595 and 753 pg/ml at 120 min, respectively. In conclusion, a short episode of anoxia prior to meconium aspiration may increase lung sensitivity to meconium-induced lung injury. This effect may be moderated by the TNFalpha present in the pulmonary circulation.     

Antibody responses to endemic coronaviruses modulate COVID-19 convalescent plasma functionality

SARS-CoV-2 (CoV2) antibody therapies, including COVID-19 convalescent plasma (CCP), monoclonal antibodies, and hyperimmune globulin, are among the leading treatments for individuals with early COVID-19 infection. The functionality of convalescent plasma varies greatly, but the association of antibody epitope specificities with plasma functionality remains uncharacterized. We assessed antibody functionality and reactivities to peptides across the CoV2 and the 4 endemic human coronavirus (HCoV) genomes in 126 CCP donations. We found strong correlation between plasma functionality and polyclonal antibody targeting of CoV2 spike protein peptides. Antibody reactivity to many HCoV spike peptides also displayed strong correlation with plasma functionality, including pan-coronavirus cross-reactive epitopes located in a conserved region of the fusion peptide. After accounting for antibody cross-reactivity, we identified an association between greater alphacoronavirus NL63 antibody responses and development of highly neutralizing antibodies against CoV2. We also found that plasma preferentially reactive to the CoV2 spike receptor binding domain (RBD), versus the betacoronavirus HKU1 RBD, had higher neutralizing titer. Finally, we developed a 2-peptide serosignature that identifies plasma donations with high anti-spike titer, but that suffer from low neutralizing activity. These results suggest that analysis of coronavirus antibody fine specificities may be useful for selecting desired therapeutics and understanding the complex immune responses elicited by CoV2 infection.     

Time course of recovery showing initial prefrontal cortex changes at 16 weeks,extending to subcortical changes by 3 years in pediatric bipolar disorder

Objective

Activation changes at the interface of affective and cognitive systems are examined over a 3 year period in pediatric bipolar disorder (PBD).

Methods

Thirteen participants with PBD and 10 healthy controls (HC) matched on demographics and IQ were scanned at baseline, at 16 weeks, and after 3 years. All patients received pharmacotherapy based on a medication algorithm. A pediatric affective color matching paradigm was used to probe cognitive processing under emotional challenge.

Results

At baseline, in response to emotional vs. neutral words, patients with PBD showed greater activation than HC in the right dorsal lateral prefrontal cortex (DLPFC) and amygdala, ventral lateral prefrontal cortex (VLPFC), bilateral anterior cingulate cortex (ACC), and ventral striatum. Increased activation in DLPFC in the PBD group normalized by 16 weeks. By 3 years, normalization was observed in VLPFC, ACC, amygdala, and striatum.

Limitations

Small sample size renders the present findings preliminary.

Conclusions

Greater activation in fronto-striatal and fronto-limbic circuits were observed in unmedicated patients with PBD. Present findings suggest the possibility that DLPFC is most malleable to pharmacological intervention with systematic pharmacotherapy leading to immediate response, which extended to amygdalostriatal and ventral cortical regions at 3 years. The seminal observation from this study is the prolonged length of recovery time in the normalization of subcortical activity along with their interfacing cortical regions. Findings from this proof of concept study need to be replicated in a larger sample.