Functional activation of pyruvate dehydrogenase in human brain using hyperpolarized [1-13 C]pyruvate.

PURPOSE: Pyruvate, produced from either glucose, glycogen, or lactate, is the dominant precursor of cerebral oxidative metabolism. Pyruvate dehydrogenase (PDH) flux is a direct measure of cerebral mitochondrial function and metabolism. Detection of [13 C]bicarbonate in the brain from hyperpolarized [1-13 C]pyruvate using carbon-13 (13 C) MRI provides a unique opportunity for assessing PDH flux in vivo. This study is to assess changes in cerebral PDH flux in response to visual stimuli using in vivo 13 C MRS with hyperpolarized [1-13 C]pyruvate. METHODS: From seven sedentary adults in good general health, time-resolved [13 C]bicarbonate production was measured in the brain using 90° flip angles with minimal perturbation of its precursors, [1-13 C]pyruvate and [1-13 C]lactate, to test the hypothesis that the appearance of [13 C]bicarbonate signals in the brain reflects the metabolic changes associated with neuronal activation. With a separate group of healthy participants (n = 3), the likelihood of the bolus-injected [1-13 C]pyruvate being converted to [1-13 C]lactate prior to decarboxylation was investigated by measuring [13 C]bicarbonate production with and without [1-13 C]lactate saturation. RESULTS: In the course of visual stimulation, the measured [13 C]bicarbonate signal normalized to the total 13 C signal in the visual cortex increased by 17.1% ± 15.9% (p = 0.017), whereas no significant change was detected in [1-13 C]lactate. Proton BOLD fMRI confirmed the regional activation in the visual cortex with the stimuli. Lactate saturation decreased bicarbonate-to-pyruvate ratio by 44.4% ± 9.3% (p < 0.01). CONCLUSION: We demonstrated the utility of 13 C MRS with hyperpolarized [1-13 C]pyruvate for assessing the activation of cerebral PDH flux via the detection of [13 C]bicarbonate production.

Hyperpolarized [1-13C]Acetyl-l-Carnitine Probes Tricarboxylic Acid Cycle Activity In Vivo.

Mitochondrial oxidative phosphorylation (OXPHOS) is sensitive to a variety of biological factors, and dysregulated OXPHOS is observed during the development of numerous pathological conditions. ATP production via OXPHOS is intrinsically dependent on the availability of acetyl-coenzyme A (CoA), which can enter the tricarboxylic acid (TCA) cycle to drive the oxidative pathway. Acetyl-l-carnitine (ALCAR) is an interchangeable endogenous source of acetyl-CoA, and therefore, ALCAR-derived probes are uniquely positioned for the assessment of OXPHOS. In this report, we develop hyperpolarized (HP) [1-13C]ALCAR as a noninvasive probe to investigate cardiac TCA cycle activity in vivo. We initially synthesized the isotopically labeled substrate and demonstrated that the 13C nucleus maintained a suitable T1 value (50.1 ± 0.8 s at 3 T) and polarization levels (21.3 ± 5.3%) to execute in vivo metabolic measurements. HP [1-13C]ALCAR was employed for cardiac analyses of OXPHOS in rats under fed and fasted conditions. [5-13C]Glutamate was successfully detected, and the metabolite was used to analyze the TCA cycle activity in both nutritional states. These assessments were compared to analogous experiments with the HP [1-13C]pyruvate. Our report represents the first study to demonstrate that HP methods using [1-13C]ALCAR enable direct analyses of mitochondrial function and TCA cycle activity, which are fundamental to cardiac cell homeostasis.

The Influence of Family Intervention on the Treatment of Adolescent Patients With Borderline Personality Disorder: A Literature Review.

Borderline personality disorder (BPD) is a widespread mental disorder linked to functional impairment and a high suicide rate. Adolescent BPD is now recognized as a reliable and valid diagnosis in psychiatric classification systems and national treatment guidelines. Family issues, such as parental underinvolvement or neglect, may affect the mentalization process and attachment styles. Thus, the family is crucial to understanding the etiology of BPD in adolescents. Family intervention was primarily used as a component of the psychotherapy strategy in the current treatment of BPD, including pharmacological and psychotherapy measures. The primary objective of this study is to review previous research on the effectiveness of family intervention in treating adolescents with BPD. Although there is currently little data, studies in this paper show that family intervention is a realistic treatment option for adolescents with BPD.

Sacubitril/Valsartan in Heart Failure Hospitalization: Two Pills a Day to Keep Hospitalizations Away?

Heart failure (HF) is a clinical syndrome with signs and symptoms that result from any structural or functional deterioration of ventricular filling or ejection of blood. It is the final stage of various cardiovascular diseases (e.g., coronary artery disease, hypertension, previous myocardial infarction) and remains one of the leading causes of hospitalization. It poses severe health and economic burden worldwide. Patients usually present with shortness of breath due to impaired cardiac ventricular filling and decreased cardiac output. Cardiac remodeling due to the renin-angiotensin-aldosterone system overactivation is the final pathological mechanism leading to these changes. The natriuretic peptide system is also activated to stop the remodeling. Sacubitril/valsartan, an angiotensin-receptor neprilysin inhibitor, has prompted a substantial conceptual change in HF treatment. Its primary mechanism is the inhibition of cardiac remodeling and the prevention of natriuretic peptide degradation by inhibiting the enzyme neprilysin. It is an efficacious, safe, and cost-effective therapy that improves the quality of life and survival rate in patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction. It has been demonstrated to significantly reduce hospitalization rates and rehospitalization for HF when compared to enalapril. In this review, we have discussed the benefits of sacubitril/valsartan in treating patients with HFrEF, particularly in reducing hospitalizations and readmissions. We have also compiled studies to examine the drug's effect on adverse cardiac events. Finally, the cost benefits of the drug and optimal dosing strategies are also reviewed. Our review article, combined with the recommendations of the 2022 American Heart Association guidelines for heart failure, strongly suggests that sacubitril/valsartan is a cost-effective strategy that reduces hospitalizations for HFrEF patients when started early with optimal doses. There is still much uncertainty regarding the optimal usage of this drug, its use in HFrEF, and the cost benefits when used alone compared with enalapril.

Sleep Disorders in Mild Cognitive Impairment.

We have an increasingly aging population and, therefore, cognitive impairment and dementia are becoming more common. Similarly, sleep disorders are also more common among the older population. There is a bidirectional relationship between mild cognitive impairment and sleep disorders. Additionally, both of these issues are underdiagnosed. By identifying and treating sleep disturbances early, we may delay the onset of dementia. Sleep helps in clearing metabolites like amyloid-beta (A-beta) lipoprotein. Clearance leads to decreased fatigue and proper functioning of the brain. A-beta lipoprotein and tau aggregates lead to neurodegeneration. Slow-wave sleep that decreases with aging is important for memory consolidation. In the initial stages of Alzheimer's disease, A-beta lipoprotein and tau deposits were linked to lower slow-wave activity in non-rapid eye movement sleep. Improvement in sleep decreases oxidative stress which in turn leads to decreased A-beta lipoprotein accumulation.

A Systematic Review of Yoga and Meditation for Attention-Deficit/Hyperactivity Disorder in Children.

With attention-deficit/hyperactivity disorder (ADHD) being a prevalent disorder in childhood, it is essential to acknowledge the different adverse effects the disorder can have on the quality of life in children. Therefore, this systematic review focuses mainly on children. Medical therapy, especially stimulants, can have many side effects. Our systematic review aims to evaluate the potential of other non-medical treatment options for ADHD, such as yoga or meditation. We used PubMed and Google Scholar as databases for this systematic review. Using different combinations of medical subheadings (MeSH) and key terms, followed by the application of several inclusion/exclusion criteria and filters to narrow down our search. From an initial 51,675 articles, we selected 10 papers that passed our screening process and quality check to analyze in depth. Yoga and meditation positively affect various symptoms in children with ADHD, including attention, hyperactivity, and impulsive behavior. If done in family group sessions, it also benefited the parents and family dynamics, suggesting a potential option for family therapy. Furthermore, other psychological symptoms, such as anxiety or low self-esteem, appeared to be positively impacted by these interventions. Although yoga and meditation positively influenced children with ADHD, a more in-depth research is necessary with a more significant number of participants and over a more extended period of time. The results of the included studies suggest a substantial benefit. Nonetheless, as the number of studies is limited, at present yoga and meditation could be beneficial as supplemental therapy rather than being used alone as a therapy for ADHD.

The Significance of Sleep Disorders in Post-myocardial Infarction Depression.

Sleep disorders are highly prevalent and often missed comorbidities in patients with cardiovascular disease (CVD), especially important in patients with depression associated with post-myocardial infarction (MI). Proactive screening and targeted treatment for sleep disorders are essential to reduce the morbidity and mortality associated with CVDs and MI in particular. We have reviewed all relevant information up to July 2022 regarding sleep disorders in CVD with a focus on post-MI depression and gathered around 350 articles in our research and narrowed it down to 31 articles. The database used was PubMed, and the keywords used were obstructive sleep apnea, sleep disorders, sleep-disordered breathing, major depression, and post-myocardial infarction. We have concluded from the available literature that there is a significant overlap between the etiologies and pathological mechanisms between conditions such as diabetes, obesity, and other comorbidities associated with both sleep disorders and CVD. Treatment such as psychotherapy and pharmacotherapy should be tailored according to the specific needs of the patients. Targeted treatment for sleep disorders has been shown to improve multiple factors and comorbidities associated with prognosis post-MI, including improvement in quality of life and significantly reduced short-term and long-term mortality. The incidence and prevalence of depression post-MI can be significantly reduced by focusing on the treatment of any underlying sleep disorders. We encourage larger-scale observational and interventional studies regarding the quality of sleep post-MI.

A Systematic Review Exploring the Cardiovascular and Renal Effects of Empagliflozin in Patients With Heart Failure With Reduced Ejection Fraction.

The major cause of death in the United States is heart disease. The global burden of illness and mortality from heart failure is substantial. Despite recent innovations in the treatment of heart failure, the prognosis is still poor. To identify, evaluate, and summarize the findings of all relevant studies of a drug that is equally efficacious but rather cost-effective, empagliflozin compared to the other sodium-glucose cotransporter-2 (SGLT2) inhibitors was studied. It is licensed by the Food and Drug Administration (FDA), acts by preventing the reabsorption of glucose from the kidney, and exhibits promising advantages in heart failure. We systematically explored PubMed, PubMed Central (PMC), and Medical Literature Analysis and Retrieval System Online (MEDLINE) for randomized controlled trials (RCTs) and observational studies related to cardiovascular and renal outcomes of empagliflozin in patients with heart failure with reduced ejection fraction (HFrEF). After performing scoping search and search strategy, studies were screened for quality assessment using the Cochrane risk of bias assessment tool. We screened 60 articles by titles, abstract, and exclusion and inclusion criteria, after which eight final randomized controlled trials (RCTs) with 18,659 participants treated with empagliflozin and placebo were used for the systematic review. This systematic review's objective is to investigate and explore the full range of empagliflozin's effects and advantages on cardiac structure, function, and hemodynamics and renal function in patients with heart failure with reduced ejection fraction (EF) in order to better understand the drug's effects and related mechanisms.

Long-Term Symptoms of COVID-19: One-Year Follow-Up Study.

INTRODUCTION:  Persistent and prolonged symptoms, termed as long COVID (coronavirus disease), have been reported in several patients who recovered from the acute phase at different intervals. However, there has been largely unclear data regarding the full range of long-term sequelae of coronavirus disease 2019 (COVID-19) patients. This study aims to evaluate the prevalence of long COVID syndrome. METHODS: A long-term research was conducted in the COVID-19 unit of a tertiary care hospital in Pakistan from July 2020 to December 2021 in which 2,000 patients who had recovered from COVID-19 and had been discharged were included in the study. Symptoms were noted at the time of discharge and at follow-up after 12 months. Data were analyzed using Statistical Package for the Social Sciences (SPSS) v. 22.0 (IBM Corporation, Armonk, New York, United States). RESULTS: The mean age of the participants was 43 ± 10 years, 801 (53.8%) males and 688 (46.2%) females. At the time of discharge, the most common symptom was fatigue (26.93%), followed by dyspnea (20.34%) and muscle pain (8.86%). The most common symptom on follow-up was fatigue (6.78%). CONCLUSION: We strongly emphasize discussing and exploring further knowledge on the post-infection syndrome, with an aim to bring healthcare professionals' attention to the importance of handling COVID patients, their counseling, warning for alarming signs, and a long-term follow-up with necessary investigations and treatment.

Analysis of temporal changes in HIV-1 CRF01_AE gag genetic variability and CD8 T-cell epitope evolution.

Currently, little is known about the time-dependent evolution of human immunodeficiency virus-1 (HIV-1) circulating recombinant forms (CRF) 01_AE, a dominant recombinant form associated with HIV-1 epidemics worldwide. Since gag is a highly immunodominant HIV-1 protein, we performed a comparative analysis of the CRF01_AE gag protein's time-dependent changes and evolution. A total of 3105 HIV-1 CRF01_AE gag sequences representing 17 countries from the timeline 1990-2017 were obtained. The sequences' phylogenetic relationship and epidemic dynamics were analyzed through a Maximum Likelihood tree and Bayesian Skyline plot, respectively. Genomic variability was measured through Shannon entropy and time-dependent immunoevolution was analyzed using changes in proteasomal degradation pattern, cytotoxic T lymphocytes (CTL) epitopes, and Human leukocyte antigens (HLA) restriction profile. The most recent common ancestor of the HIV CRF01_AE epidemic was estimated to be 1974±1. A period of exponential growth in effective population size began in 1982, fluctuated, and then stabilized in 1999. Genetic variability (entropy) consistently increased, however, epitope variability remained comparable; the highest number of novel CTL epitopes were present in 1995-1999, which were lost over time. The spread of the HIV-1 CRF01_AE epidemic is predominant in countries within Asia. Population immunogenetic pressures in the region may have contributed to the initial changes and following adaptation/stabilization of epitope diversity within gag sequences.

A Systematic Review of Mixed Studies Exploring the Effects of Probiotics on Gut-Microbiome to Modulate Therapy in Children With Autism Spectrum Disorder.

Autism spectrum disorder(ASD) is a complex neurodevelopmental disorder characterized by social deficits, repetitive typical behaviors, insistence on the same routines, and communication impairments. The prevalence of ASD has increased in the past decade. While we are aware that there is no cure for ASD, attempts are being made to reduce its symptoms and improve the learning, overall growth, and well-being of ASD patients. Gastrointestinal (GI) symptoms are frequent occurrences in patients with ASD, but the underlying mechanisms are unknown. Recent studies show that the microbiota-gut-brain axis is the key modulator of neuropsychiatric health. Although fecal transplants have shown positive outcomes in treating dysbiosis and symptoms of autism, lifestyle modifications such as dietary intervention will prevent and treat this disorder without causing major adverse effects. Probiotics enhance the microbiome to provide necessary metabolites, which help in gut permeability, cognitive function, and immunity. In some studies, children with increased GI symptoms have also shown increased behavioral disturbances. In this study, a systematic review of mixed studies is conducted to obtain more robust and conclusive results. We included randomized controlled studies with larger sample sizes and specifications on probiotics.

Amoxycillin and clavulanic acid induced Stevens-Johnson syndrome: A case report.

Stevens-Johnson syndrome (SJS) is an immune mediated hypersensitivity reaction. Significant involvement of oral, nasal, eye, vaginal, urethral, GI and lower respiratory tract mucous membrane may develop. It is usually a reaction due to a medication or due to an infection. In 95 % of case reports, drugs were found to be an important cause for the development of SJS. In this case report, a 32 year old female reported chief complaint of itch skin eruptions all over the body along with erosive lesions on tongue, lips, buccal mucosa and genital mucosa. The reaction occurred after administration of augmentin (containing amoxycillin and clavulanic acid). She was treated with antimicrobials, antiallergics and conservative management. The patient improved and was discharged from the hospital. Causality assessment using Naranjo Adverse Drug Reaction Probability Scale revealed that amoxycillin and clavulanic acid combination was a possible cause for the adverse reaction with a score of 4.