Integrative Pharmacology in the Treatment of Substance Use Disorders.

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

Management of arsenic-contaminated excavated soils: A review.

Ongoing global sustainable development and underground space utilization projects have inadvertently exposed many excavated soils naturally contaminated with geogenic arsenic (As). Recent investigations have revealed that As in certain excavated soils, especially those originating from deep construction projects, has exceeded regulatory limits, threatening the environment and human health. While numerous remediation techniques exist for treating As-contaminated soil, the unique characteristics of geogenic As contamination in excavated soil require specific measures when leachable As content surpasses established regulatory limits. Consequently, several standard leaching tests have been developed globally to assess As leaching from contaminated soil. However, a comprehensive comparative analysis of these methods and their implementation in contaminated excavated soils remains lacking. Furthermore, the suitability and efficacy of most conventional and advanced techniques for remediating As-contaminated excavated soils remained unexplored. Therefore, this study critically reviews relevant literature and summarize recent research findings concerning the management and mitigation of geogenic As in naturally contaminated excavated soil. The objective of this study was to outline present status of excavated soil globally, the extent and mode of As enrichment, management and mitigation approaches for As-contaminated soil, global excavated soil recycling strategies, and relevant soil contamination countermeasure laws. Additionally, the study provides a concise overview and comparison of standard As leaching tests developed across different countries. Furthermore, this review assessed the suitability of prominent and widely accepted As remediation techniques based on their applicability, acceptability, cost-effectiveness, duration, and overall treatment efficiency. This comprehensive review contributes to a more profound comprehension of the challenges linked to geogenic As contamination in excavated soils.

Understanding gaseous reduction in swine manure resulting from nanoparticle treatments under anaerobic storage conditions.

Manure is an impending source of carbon (C), sulfur (S) and water (H2O). Consequently, microbial populations utilize these constituents to produce methane (CH4), carbon dioxide (CO2), greenhouse gases (GHGs), and hydrogen sulfide (H2S). Application of nanoparticles (NPs) to stored manure is an emerging GHG mitigation technique. In this study, two NPs: nano zinc oxide (nZnO) and nano silver (nAg) were tested in swine manure stored under anaerobic conditions to determine their effectiveness in mitigating gaseous emissions and total gas production. The biological sources of gas production, i.e., microbial populations were characterized via Quantitative Polymerase Chain Reaction (qPCR) analysis. Additionally, pH, redox, and VFAs were determined using standard methods. Each treatment of the experiment was replicated three times and NPs were applied at a dose of 3 g/L of manure. Also, headspace gas from all treatment replicates were analyzed for CH4 and CO2 gas concentrations using an SRI-8610 Gas Chromatograph and H2S concentrations were measured using a Jerome 631X meter. Nanoparticles tested in this study reduced the cumulative gas volume by 16%-79% compared to the control. Among the NPs tested, only nZnO consistently reduced GHG concentrations by 37%-97%. Reductions in H2S concentrations ranged from 87% to 97%. Gaseous reductions were likely due to decreases in the activity and numbers of specific gas producing methanogenic archaea and sulfate reducing bacterial (SRB) species.

Nanoparticles in mitigating gaseous emissions from liquid dairy manure stored under anaerobic condition.

A number of mitigation techniques exist to reduce the emissions of pollutant gases and greenhouse gases (GHGs) from anaerobic storage of livestock manure. Nanoparticle (NP) application is a promising mitigating treatment option for pollutant gases, but limited research is available on the mode of NP application and their effectiveness in gaseous emission reduction. In this study, zinc silica nanogel (ZnSNL), copper silica nanogel (CuSNL), and N-acetyl cysteine (NACL) coated zinc oxide quantum dot (Qdot) NPs were compared to a control lacking NPs. All three NPs tested significantly reduced gas production and concentrations compared to non-treated manure. Overall, cumulative gas volumes were reduced by 92.73%-95.83%, and concentrations reduced by 48.98%-99.75% for H2S, and 20.24%-99.82% for GHGs. Thus, application of NPs is a potential treatment option for mitigating pollutant and GHG emissions from anaerobically stored manure.

Review: Therapeutic potential of carbonic anhydrase inhibitors.

Enzymes are biological catalyst involve in different biochemical reactions. But over activation of these biomolecules can cause disease thus different inhibitors and knockout therapies are use in current clinical practice. Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and virulence of various pathogens. In addition to the established role of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently emerged that CAIs could have potential as novel anti-obesity, anticancer and anti-infective drugs. Furthermore, recent studies suggest that CA activation may provide a novel therapy for Alzheimer's disease. This article discusses the biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases, and highlights progress in the development of specific modulators of the relevant CA isoforms, some of which are now being evaluated in clinical trials.

Evaluation of microbial fuel cell (MFC) for bioelectricity generation and pollutants removal from sugar beet processing wastewater (SBPW).

Bioelectricity generation from biodegradable compounds using microbial fuel cells (MFCs) offers an opportunity for simultaneous wastewater treatment. This study evaluated the synergy of electricity generation by the MFC while reducing pollutants from sugar beet processing wastewater (SBPW). A simple dual-chamber MFC was constructed with inexpensive materials without using catalysts. Raw SBPW was diluted to several concentrations (chemical oxygen demand (COD) of 505 to 5,750 mg L-1) and fed as batch-mode into the MFC without further modification. A power density of 14.9 mW m-2 as power output was observed at a COD concentration of 2,565 mg L-1. Coulombic efficiency varied from 6.21% to 0.73%, indicating diffusion of oxygen through the cation exchange membrane and other methanogenesis and fermentation processes occurring in the anode chamber. In this study, >97% of the COD and up to 100% of the total suspended solids removals were observed from MFC-treated SBPW. Scanning electron microscopy of anode indicated that a diverse community of microbial consortia was active for electricity generation and wastewater treatment. This study demonstrated that SBPW can be used as a substrate in the MFC to generate electricity as well as to treat for pollutant removal.

Effect of feeding graded doses of citrinin on apoptosis and oxidative stress in male Wistar rats through the F1 generation.

The objective of the present study was to study the effect of graded doses of citrinin (CIT) on apoptosis and oxidative stress in male Wistar rats till F1 generation. The animals were divided into four groups comprising 25 males and 25 females each, that is, group I: 1 ppm CIT; group II: 3 ppm CIT; group III: 5 ppm CIT; and group IV was kept as a control. The male and female animals of all the groups were kept separately and were fed basal rations containing the above-mentioned concentrations of CIT for 10 weeks. After 10 weeks, male and female animals of respective groups were kept for mating (one male/two females). After getting 10 pregnant females, the males were killed. These 10 pregnant females were allowed to give birth to young ones (F1 generation) naturally which were fed CIT in the above-mentioned doses till the age of 6 weeks and then were killed. Apoptosis was analysed in kidneys, liver and testes by DNA ladder pattern, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labelling assay and Bcl-2/Bax ratio. Besides, tissue oxidative stress was also analysed. It was concluded in the present study that CIT induces its toxic effects till F1 generation, and apoptosis and oxidative stress both play a very important role in toxicity. The effect of CIT was observed in a dose-dependent manner. However, in kidneys, both the mechanisms (apoptosis and oxidative stress) play their role in inflicting renal damage, while in liver only reactive oxygen species play a major role. Finally, the CIT toxicity did not lead to apoptosis and oxidative stress in male gonads till F1 generation.

The α-7 Nicotinic Receptor Positive Allosteric Modulator Alleviates Lipopolysaccharide Induced Depressive-like Behavior by Regulating Microglial Function, Trophic Factor, and Chloride Transporters in Mice.

Neuroinflammation contributes to the pathophysiology of major depressive disorder (MDD) by inducing neuronal excitability via dysregulation of microglial brain-derived neurotrophic factor (BDNF), Na-K-Cl cotransporter-1 (NKCC1), and K-Cl cotransporter-2 (KCC2) due to activation of BDNF-tropomyosin receptor kinase B (TrkB) signaling. Allosteric modulation of α7 nAChRs has not been investigated on BDNF, KCC2, and NKCC1 during LPS-induced depressive-like behavior. Therefore, we examined the effects of PNU120596, an α7 nAChR positive allosteric modulator, on the expression of BDNF, KCC2, and NKCC1 in the hippocampus and prefrontal cortex using Western blot analysis, immunofluorescence assay, and real-time polymerase chain reaction. The effects of ANA12, a TrkB receptor antagonist, on LPS-induced cognitive deficit and depressive-like behaviors were determined using the Y-maze, tail suspension test (TST), and forced swim test (FST). Pharmacological interactions between PNU120596 and ANA12 were also examined. Experiments were conducted in male C57BL/6J mice. LPS administration (1 mg/kg) resulted in increased expression of BDNF and the NKCC1/KCC2 ratio and decreased expression of KCC2 in the hippocampus and prefrontal cortex. PNU120596 pretreatment (4 mg/kg) attenuated the LPS-induced increase in the expression of BDNF and NKCC1/KCC2 ratio and the reduction in KCC2 expression in these brain regions. In addition, ANA12 (0.25 or 0.50 mg/kg) reduced the LPS-induced cognitive deficit and depressive-like behaviors measured by a reduced spontaneous alternation in the Y-maze and increased immobility duration in TST and FST. Coadministration of PNU120596 (1 mg/kg) and ANA12 (0.25 mg/kg) prevented the LPS-induced cognitive deficit and depressive-like behaviors. Overall, PNU120596 prevented the LPS-induced depressive-like behavior by likely decreasing neuronal excitability via targeting microglial α7 nAChR in the hippocampus and prefrontal cortex.

Remediation of cadmium-contaminated soil: GLDA-assisted extraction and sequential FeCl3-CaO-based post-stabilization.

Cadmium (Cd) contamination of farmland soils is a growing concern because of its highly toxic impact on ecosystems and human health. Chelator-assisted washing and chemical immobilization are effective remediation strategies for Cd-contaminated soils. Ethylenediaminetetraacetic acid (EDTA) has traditionally been used for soil washing, but its persistence in the environment and subsequent toxicity have raised significant ecological concerns. Consequently, biodegradable chelators have gained increasing attention as eco-friendly alternatives to the persistent chelator, EDTA. Therefore, this study evaluated the performance and efficacy of three biodegradable chelators: L-glutamate-N,N'-diacetic acid (GLDA), methylglycine-diacetic acid (MGDA), and 3-hydroxy-2,2'-iminodisuccinic acid (HIDS) in comparison to EDTA for remediating a real Cd-contaminated agricultural soil. The influence of treatment parameters, including chelator variants, washing time, chelator concentration, solution pH, and liquid-to-soil ratio (L/S) on Cd extraction was studied and optimized to attain the maximum removal rate. Following chelator-assisted washing, the efficacy of a stabilization preference combining FeCl3 and CaO in reducing the leaching potential of residual Cd in chelator-washed soil residues was also investigated. GLDA demonstrated comparable Cd extraction efficiency to EDTA, and the Cd extraction efficiency was found to be positively correlated with the soil washing parameters. However, under the optimized conditions (chelator concentration: 10 mmol L-1; washing time: 3 h; solution pH: 3; L/S ratio: 10:1), GLDA exhibited a higher Cd extraction rate than EDTA or the other chelators. Furthermore, a post-treatment process incorporating FeCl3 and CaO substantially diminished the water-leachable Cd content in the resultant soil residues. The proposed remediation strategy, which combines chemically assisted washing and stabilization, could be a practical option for extracting bulk Cd from soil and reducing the leaching potential of residual Cd.

Greenhouse gas emissions from beef cattle pen surfaces in North Dakota.

There is a global interest to quantify and mitigate greenhouse gas (GHG) (e.g. methane-CH4, nitrous oxide-N2O and carbon dioxide-CO2) emissions in animal feeding operations. The goal of this study was to quantify GHG emissions from the feedlot pen surface under North Dakota climatic conditions. In this study gaseous flux from the pen surfaces was generated using a custom-made wind tunnel at different times of the year (summer, fall, winter and spring). Gaseous fluxes (air samples) were drawn in the Tedlar bags using a vacuum chamber and gas concentrations were measured using a gas chromatograph within 24 h of sampling. The CH4 concentrations and flux rates (FRs) or flux among the months were not significantly different. Overall CH4, CO2 and N2O concentrations over a 7-month period were 2.66, 452 and 0.67 ppm, respectively. Estimated overall CH4, CO and N2O FRs were 1.32, 602 and 0.90 g m(-2) d(-1), respectively. Estimated emission rates using the wind tunnel were 38 g hd(-1) d(-1), 17 kg hd(-1) d(-1) and 26 g hd(-1) d(-1) for CH4, CO2 and N2O, respectively. The emission factors for GHG estimated in the research for North Dakota climate were the first of its kind, and these emission estimates can be used as a basis for planning and implementing management practices to minimize GHG emissions.

E-cigarettes may serve as a gateway to conventional cigarettes and other addictive drugs.

Electronic cigarettes (e-cigarettes) are devices that allow the user to inhale nicotine in a vapor, and are primarily marketed as a means of quitting smoking and a less harmful replacement for traditional cigarette smoking. However, further research is needed to determine if vaping nicotine via e-cigarettes can be effective. Conversely, nicotine has been considered a gateway drug to alcohol and other addictive drugs and e-cigarettes containing nicotine may have the same effects. Previous reports have shown that e-cigarette use may open the gate for the use of other drugs including conventional cigarettes, cannabis, opioids, etc. The increasing prevalence of e-cigarettes, particularly among youth and adolescents in the last decade have led to an increase in the dual use of e-cigarettes with alcohol, cannabis, and other illicit drug use like heroin and 3-4-methylenedioxymethamphetamine (MDMA). The advent of e-cigarettes as a device to self-administer addictive agents such as cocaine and synthetic cathinones may bring about additional adverse health effects associated with their concurrent use. This review aims to briefly describe e-cigarettes and their different generations, and their co-use with other addictive drugs as well as the use of the device as a tool to self-administer addictive drugs, such as cocaine, etc.

The Role of Beta-Endorphin in Food Deprivation-Mediated Increases in Food Intake and Binge-Eating.

Food deprivation and binge eating represent significant public health concerns. Previous studies have implicated that hypothalamic opioids are affected following food deprivation. However, the role of each opioid peptide is not fully understood. Therefore, we investigated the role of endogenous beta-endorphin in food deprivation-mediated increases in food intake and binge eating. Male mice lacking beta-endorphin and their respective controls were subjected to 24 h food deprivation and then were randomly assigned to receive a regular diet (RD) or a high-fat diet (HFD). After four to five weeks, animals were re-exposed to an HFD to assess if previous exposure to HFD would enhance binge-eating behavior. We report that food deprivation significantly increases food intake; however, beta-endorphin may not be involved in this process. In addition, our findings suggest that prior exposure to an HFD promotes binge-eating behavior in wildtype mice, and that these effects were modestly decreased in beta-endorphin knockout mice. Overall, our results support that beta-endorphin may play a modest role in mediating palatability-driven feeding, but not hunger-associated feeding. A better understanding of neural mechanisms involved in binge eating and deprivation-induced increases in food intake may inspire new prevention or treatment options to decrease the burden of eating disorders.

Novel Pulmonary Delivery of Drugs for the Management of Atrial Fibrillation.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, affecting approximately 335 million patients worldwide. Comprehensive pharmacological treatment of AF includes medications for rate or rhythm control and anticoagulants to reduce the risk of thromboembolism; yet, these agents have significant limitations. Oral anti-arrhythmic agents have a slow onset of action, and rapid onset formulations require hospitalization for intravenous therapy. Orally administered drugs also require high doses to attain therapeutic levels, and thus dose-related severe adverse effects are often unavoidable. Given the therapeutic benefits of inhaled drug delivery, including rapid onset of action and very low doses to achieve therapeutic efficacy, this review will discuss the benefits of novel pulmonary delivery of drugs for the management of AF.

Glial Glutamate Transporter Modulation Prevents Development of Complete Freund's Adjuvant-Induced Hyperalgesia and Allodynia in Mice.

Glial glutamate transporter (GLT-1) modulation in the hippocampus and anterior cingulate cortex (ACC) is critically involved in nociceptive pain. The objective of the study was to investigate the effects of 3-[[(2-methylphenyl) methyl] thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator, against microglial activation induced by complete Freund's adjuvant (CFA) in a mouse model of inflammatory pain. Furthermore, the effects of LDN-212320 on the protein expression of glial markers, such as ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation molecule 11b (CD11b), mitogen-activated protein kinases (p38), astroglial GLT-1, and connexin 43 (CX43), were measured in the hippocampus and ACC following CFA injection using the Western blot analysis and immunofluorescence assay. The effects of LDN-212320 on the pro-inflammatory cytokine interleukin-1ß (IL-1ß) in the hippocampus and ACC were also assessed using an enzyme-linked immunosorbent assay. Pretreatment with LDN-212320 (20 mg/kg) significantly reduced the CFA-induced tactile allodynia and thermal hyperalgesia. The anti-hyperalgesic and anti-allodynic effects of LDN-212320 were reversed by the GLT-1 antagonist DHK (10 mg/kg). Pretreatment with LDN-212320 significantly reduced CFA-induced microglial Iba1, CD11b, and p38 expression in the hippocampus and ACC. LDN-212320 markedly modulated astroglial GLT-1, CX43, and, IL-1ß expression in the hippocampus and ACC. Overall, these results suggest that LDN-212320 prevents CFA-induced allodynia and hyperalgesia by upregulating astroglial GLT-1 and CX43 expression and decreasing microglial activation in the hippocampus and ACC. Therefore, LDN-212320 could be developed as a novel therapeutic drug candidate for chronic inflammatory pain.

Floating raft culture of Gracilariopsis longissima for optimum biomass yield performance on the coast of Cox's Bazar, Bangladesh.

Seaweed cultivation is an eco-friendly method and attracts growing interest which needs a multi-criteria approach for its sustainability. In our present study, an economically significant red alga, Gracilariopsis longissima was cultured using a floating raft method on the coast of Cox's Bazar, Bangladesh for a period of 90 days from January to March 2022. The effects of different factors such as rope materials, culture type, raft shape, seeding intensity, harvesting phase and water depth on the biomass yield production of G. longissima were evaluated during a 90-day culture period. The biomass yield production and daily growth rate (DGR% day-1) were estimated to evaluate the possibilities of G. longissima cultures in a floating raft culture method. The range of biomass yield production (3.03-13.37 kg/m2) and DGR (3.08-4.72% day-1) is satisfactory in the floating raft culture method. Different water quality variables, the seasonal appearance of epiphytic algae and a cost-benefit analysis of seaweed culture were also performed. A total of eight epiphytic algal species were recorded, which resulted in major challenges for the growth of Gracilariopsis. The per month income for a seaweed farmer was estimated to be US$175.17 for 20 rafts. Our research concluded that farming of G. longissima in the floating raft method could be successfully performed from January to March on the coast of Cox's Bazar.

Quantitative analysis of serum cell-free DNA as a predictive and prognostic marker in breast cancer patients.

Introduction: According to the GLOBOCAN (Global Cancer Observatory) 2020 report, 13,028 new cases of breast cancer (19%) were diagnosed in the United States, and 6,783 of them succumbed to the disease, making it the most common cancer among women. The clinical stage at the time of diagnosis is one of the most significant survival predictors in breast cancer. With delayed illness detection comes a lower survival rate. The prognosis of breast cancer may be predicted using circulating cell-free DNA (cfDNA), a non-invasive diagnosis technique. Objective: This study aimed to determine the most sensitive and effective method for detecting changes in cfDNA levels and for using cfDNA as a diagnostic and prognostic marker of breast cancer. Methods: The potential function of serum cfDNA levels as a marker for early breast cancer diagnosis was investigated using UV spectrophotometric, fluorometric, and real-time qPCR assays. Results: This research suggests that the most successful way to measure the amount of cfDNA described decades ago could be used as a "liquid biopsy" to track cancer in real time. The RT-qPCR (ALU115) method produced the most statistically significant results (p=0.000). At the threshold concentration of 395.65 ng/ml of cfDNA, the ROC curve reflects the maximum AUC= 0.7607, with a sensitivity of 0.65 and specificity of 0.80. Conclusion: For a preliminary assessment of total circulating cfDNA, a combination of all of the above techniques will be most efficacious. Based on our results, we conclude that the RT-qPCR technique combined with fluorometric measurement can identify a statistically significant difference in cfDNA levels between cohorts of breast cancer patients and healthy controls.

Evaluation of newly designed flushing techniques for on-site remediation of arsenic-contaminated excavated debris.

Excavated debris (soil and rock) contaminated with geogenic arsenic (As) is an increasing concern for regulatory organizations and construction stakeholders. Chelator-assisted soil flushing is a promising method for practical on-site remediation of As-contaminated soil, offering technical, economic, and environmental benefits. Ethylenediaminetetraacetic acid (EDTA) is the most prevalent chelator used for remediating As-contaminated soil. However, the extensive environmental persistence and potential toxicity of EDTA necessitate the exploration of eco-compliant alternatives. In this study, the feasibility of the conventional flushing method pump-and-treat and two newly designed immersion and sprinkling techniques were evaluated at the laboratory scale (small-scale laboratory experiments) for the on-site treatment of As-contaminated excavated debris. Two biodegradable chelators, L-glutamic acid-N,N'-diacetic acid (GLDA) and 3-hydroxy-2,2'-iminodisuccinic acid (HIDS), were examined as eco-friendly substitutes for EDTA. Additionally, this study highlights a useful post-treatment measure to ensure minimal mobility of residual As in the chelator-treated debris residues. The pump-and-treat method displayed rapid As-remediation (t, 3 h), but it required a substantial volume of washing solution (100 mL g-1). Conversely, the immersion technique demonstrated an excellent As-extraction rate using a relatively smaller washing solution (0.33 mL g-1) and shorter immersion time (t, 3 h). In contrast, the sprinkling technique showed an increased As-extraction rate over an extended period (t, 48 h). Among the chelators employed, the biodegradable chelator HIDS (10 mmol L-1; pH, 3) exhibited the highest As-extraction efficiency. Furthermore, the post-treatment of chelator-treated debris with FeCl3 and CaO successfully reduced the leachable As content below the permissible limit.

The relation of ventricular arrhythmia electrophysiological characteristics to cardiac phenotype and circadian patterns in hypertrophic cardiomyopathy.

BACKGROUND: The triggers of ventricular arrhythmias (VAs) leading to sudden cardiac death in hypertrophic cardiomyopathy (HCM) are ill defined. We sought to examine the electrophysiological characteristics of VAs in HCM and study their relation to cardiac phenotype and circadian patterns using stored intracardiac electrocardiograms from implantable cardioverter defibrillators (ICDs). METHODS AND RESULTS: A single centre, observational cohort study of 230 consecutively evaluated ICD recipients with HCM [median age 42 years, 97% primary prevention, 51% with anti-tachycardia pacing (ATP)]. Fifty-six non-clustered VAs (39 initially treated with ATP and 17 with shocks) from 29 patients were analysed. Monomorphic ventricular tachycardia was the culprit arrhythmia in 86% of cases, ventricular fibrillation/flutter in 9%, and polymorphic ventricular tachycardia in 5%. Prior to the onset of VA the rhythm was sinus in 67%, atrial fibrillation/flutter in 19%, and 15% were paced ventricularly; tachycardia (cycle length <600 ms) was present in 25%. Ventricular arrhythmias were triggered by premature ventricular complexes (PVCs) in 72%, which were late-coupled (84%). Short-long-short initiation was seen in 2% and 26% of VAs were sudden-onset without preceding PVCs. Ventricular arrhythmia peaked at midday (with 20% occurring between 2300 and 0700), on Sundays and in May. The cardiac phenotype and time of the day did not predict the mode of initiation. Age at ICD implantation was the only independent predictor of VA cycle length (linear regression coefficient 0.67, 95% CI 0.02-1.32, P= 0.04). Anti-tachycardia pacing terminated 67% of VAs, but patients with ATP therapy had a similar incidence of appropriate shocks (log-rank test P= 0.25) and syncope (log rank P= 0.23) to patients with shock as initial therapy. CONCLUSIONS: Most VAs are monomorphic ventricular tachycardias triggered by late-coupled PVCs. They are frequently terminated by ATP, but ATP does not reduce the frequency of ICD shocks. Younger HCM patients have more rapid VAs, which may explain the peak of sudden cardiac death in early adulthood. The circadian periodicity is different from that observed in ischaemic heart disease, and is likely to relate to the distinct character of the arrhythmogenic substrate in HCM and its modulators.

Novel Pulmonary Delivery of Antiviral Drugs for Treating COVID-19 in Patients with Parkinson's Disease.

The COVID-19 pandemic has caused a significant burden on public health worldwide. Currently, there are limited medications for the treatment of COVID-19 in patients with Parkinson's disorder (PD). Several antiviral drugs and other pharmacotherapies have shown promising results and are used by various delivery methods. Among the antiviral drugs, amantadine alone was reported to provide therapeutic benefit against COVID-19 in patients with PD. Here, we propose novel strategies for pulmonary drug delivery technology of antiviral drug, amantadine. As such pulmonary delivery of this drug or in combination with the additional antiviral drugs could be a more effective strategy for the treatment of COVID-19-related complications in patients with PD. Furthermore, the important benefits and limitations of this novel delivery technology will be discussed.

The Effect of an α-7 Nicotinic Allosteric Modulator PNU120596 and NMDA Receptor Antagonist Memantine on Depressive-like Behavior Induced by LPS in Mice: The Involvement of Brain Microglia.

Nicotinic acetylcholine receptors (nAChRs), particularly the α7 nAChR, play a critical role in neuroinflammation and microglial activation associated with major depressive disorder (MDD). Microglial quinolinic acid (QUIN), which is synthesized by 3-hydroxyanthranilic acid dioxygenase (HAAO), is an N-methyl-D-aspartate (NMDA) receptor agonist and has been implicated in the development of MDD-related symptoms. In the present study, we assessed the effects of PNU120596, an α7 nAChR positive allosteric modulator (PAM), on HAAO expression and QUIN formation in the hippocampus and prefrontal cortex. We also investigated the effects of memantine, an NMDA receptor antagonist, alone and in combination with PNU120596 on cognitive deficit and depressive-like behaviors induced by lipopolysaccharide (LPS) in mice using the Y-maze and forced swim test, respectively. LPS (1 mg/kg, i.p.) elevated HAAO expression and QUIN formation in the hippocampus and prefrontal cortex, which were reduced with pretreatment with PNU120596 (4 mg/kg, i.p.). Furthermore, memantine (1 or 3 mg/kg, i.p.) prevented the cognitive deficit and depressive-like behaviors induced by LPS in mice. Together, these results suggest that the antidepressant-like effects of PNU120596 are mediated by attenuation of LPS-induced QUIN formation. Therefore, α7 nAChR PAM could be a potential therapeutic candidate for MDD associated with neurotoxic glutamatergic transmission.