Slow Metabolism Research Articles

Can Treatment Support Mitigate Nicotine Metabolism-Based Disparities in Smoking Abstinence? Secondary Analysis of the Helping HAND 4 Trial.

The nicotine metabolite ratio (NMR), a biomarker of CYP2A6-mediated nicotine metabolism, predicts the efficacy of nicotine replacement therapy (NRT), with fast metabolizers benefiting less than slow metabolizers. Whether treatment support to optimize NRT use (henceforth "treatment support") modifies this pharmacogenetic relationship is unknown. Hospitalized adult daily smokers were assigned to one of two post-discharge smoking cessation interventions offering NRT and counseling: (1) Transitional Tobacco Care Management, which delivered enhanced treatment support via free combination NRT at discharge and automated counseling, and (2) a quitline-based approach representing usual care (UC). The primary outcome was biochemically verified 7-day point prevalence abstinence 6 months after discharge. Secondary outcomes were the use of NRT and counseling during the 3-month intervention period. Logistic regression models tested for interactions between NMR and intervention, controlling for sex, race, alcohol use, and BMI. Participants (N = 321) were classified as slow (n = 80) or fast (n = 241) metabolizers relative to the first quartile of NMR (0.012-0.219 vs. 0.221-3.455, respectively). Under UC, fast (vs. slow) metabolizers had lower odds of abstinence at 6 months (aOR 0.35, 95% CI 0.13-0.95) and similar odds of NRT and counseling use. Compared to UC, enhanced treatment support increased abstinence (aOR 2.13, 95% CI 0.98-4.64) and use of combination NRT (aOR 4.62, 95% CI 2.57-8.31) in fast metabolizers, while reducing abstinence in slow metabolizers (aOR 0.21, 95% CI 0.05-0.87; NMR-by-intervention interaction p = .004). Treatment support increased abstinence and optimal use of NRT among fast nicotine metabolizers, thereby mitigating the gap in abstinence between fast and slow metabolizers. In this secondary analysis of two smoking cessation interventions for recently hospitalized smokers, fast nicotine metabolizers quit at lower rates than slow metabolizers, but providing fast metabolizers with enhanced treatment support doubled the odds of quitting in this group and mitigated the disparity in abstinence between fast and slow metabolizers. If validated, these findings could lead to personalized approaches to smoking cessation treatment that improve outcomes by targeting treatment support to those who need it most.

Pharmacokinetic-pharmacodynamic (PK/PD) modeling to study the hepatoprotective effect of Perilla Folium on the acute hepatic injury rats

Ethnopharmacological relevancePerilla Folium (PF), is a traditional medicinal material with the homology of medicine and food in China and has been widely used due to its rich nutritional content and medicinal value. The hepatoprotective effects of PF extract include their protection against acute hepatic injury, tert-butylhydroperoxide (t-BHP) induced oxidative damage, and Lipopolysaccharide (LPS) and D-galactosamine (D-GalN) induced hepatic injury have been well studied. However, there are few reports on the pharmacokinetics studies of PF extract in acute hepatic injury model rats, and the anti-hepatic injury activity of PF is still unclear. Aim of the studyThe differences in the plasma pharmacokinetic of 21 active compounds between the normal and model groups were compared， and established pharmacokinetics/pharmacodynamics (PK/PD) modeling was to analyze the hepatoprotective effects of PF. Materials and methodsThe acute hepatic injury model was induced with an intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-GalN), and the plasma pharmacokinetics of 21 active compounds of PF were analyzed in the normal and model groups using ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS). The correlation between plasma components and hepatoprotective effects indicators (the alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactic dehydrogenase (LDH)) in the model group was also investigated and established a Pharmacokinetic/pharmacodynamic (PK/PD) correlation analysis of the hepatoprotective effects of PF. ResultsThe results revealed that organic acid compounds possessed the characteristics of faster absorption, shorter peak time and slower metabolism, while the flavonoid compounds had slower absorption and longer peak time, and the pharmacokinetics of various components were significantly affected after modeling. The results of PK/PD modeling analysis demonstrated that the plasma drug concentration of each component existed a good correlation with the three AST, ALT, and LDH, and the lag time of the efficacy of each component is relatively long. ConclusionsThe plasma drug concentration of each component existed a good correlation with the three AST, ALT, and LDH, and the lag time of the efficacy of each component is relatively long in vivo.

Csx28 is a membrane pore that enhances CRISPR-Cas13b-dependent antiphage defense.

Type VI CRISPR-Cas systems use RNA-guided ribonuclease (RNase) Cas13 to defend bacteria against viruses, and some of these systems encode putative membrane proteins that have unclear roles in Cas13-mediated defense. We show that Csx28, of type VI-B2 systems, is a transmembrane protein that assists to slow cellular metabolism upon viral infection, increasing antiviral defense. High-resolution cryo-electron microscopy reveals that Csx28 forms an octameric pore-like structure. These Csx28 pores localize to the inner membrane in vivo. Csx28's antiviral activity in vivo requires sequence-specific cleavage of viral messenger RNAs by Cas13b, which subsequently results in membrane depolarization, slowed metabolism, and inhibition of sustained viral infection. Our work suggests a mechanism by which Csx28 acts as a downstream, Cas13b-dependent effector protein that uses membrane perturbation as an antiviral defense strategy.

Mediation analysis unveils a carcinogenic effect of ADH1B rs1229984 through mechanisms other than change in drinking intensity: oesophageal cancer case-control study.

Ingested alcohol is predominantly oxidized to acetaldehyde by alcohol dehydrogenase 1B (ADH1B), and acetaldehyde is further oxidized to acetate mainly by aldehyde dehydrogenase 2 (ALDH2). Although alcohol consumption is a convincing risk factor for oesophageal cancer, the role of ADH1B rs1229984 (His48Arg), the single-nucleotide polymorphism associated with slow alcohol metabolism, in oesophageal cancer development is unclear. Because this single-nucleotide polymorphism is associated with both increased risk of oesophageal cancer and drinking intensity, its association with oesophageal cancer might operate either through a direct pathway independently of drinking intensity, via an indirect pathway mediated by drinking intensity, or both. To disentangle these different pathways, we applied a mediation analysis to an oesophageal cancer case-control study (600 cases and 865 controls) by defining the ADH1B Arg allele and alcohol consumption as exposure and mediator, respectively, and decomposed the total-effect odds ratio of the ADH1B Arg allele into direct- and indirect-effect odds ratio. The ADH1B Arg allele was associated with oesophageal cancer risk through pathways other than change in drinking intensity (direct-effect odds ratio, 2.03; 95% confidence interval, 1.41-2.92), in addition to the indirect pathway mediated by drinking intensity (indirect-effect odds ratio, 1.27; 95% confidence interval, 1.05-1.53). Further analyses by stratifying genotypes of ALDH2 rs671 (Glu504Lys), the functional single-nucleotide polymorphism that strongly attenuates the enzymatic activity, showed significant direct-effect odds ratio within each stratum. These results indicate that ADH1B Arg allele contributes to oesophageal cancer risk by slowing alcohol breakdown, in addition to its effect on the amount of alcohol consumed.

Research progress on the mitochondrial mechanism of age-related non-alcoholic fatty liver.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. Reduced activity and slower metabolism in the elderly affect the balance of lipid metabolism in the liver leading to the accumulation of lipids. This affects the mitochondrial respiratory chain and the efficiency of β-oxidation and induces the overproduction of reactive oxygen species. In addition, the dynamic balance of the mitochondria is disrupted during the ageing process, which inhibits its phagocytic function and further aggravates liver injury, leading to a higher incidence of NAFLD in the elderly population. The present study reviewed the manifestations, role and mechanism of mitochondrial dysfunction in the progression of NAFLD in the elderly. Based on the understanding of mitochondrial dysfunction and abnormal lipid metabolism, this study discusses the treatment strategies and the potential therapeutic targets for NAFLD, including lipid accumulation, antioxidation, mitophagy and liver-protecting drugs. The purpose is to provide new ideas for the development of innovative drugs for the prevention and treatment of NAFLD.

Hypothyroidism treated with homoeopathic medicine natrium muriaticum: A Case report

Reduced production of thyroid hormone is the central feature of the clinical state termed hypothyroidism (also called as underactive thyroid, low thyroid or hypothyreosis). Primary hypothyroidism which is due to disease of thyroid itself, accounts for approximately 99% of cases while < 1% is due to TSH deficiency known as central or secondary hypothyroidism. Since the main purpose of thyroid hormone is to run our body’s metabolism, it is not surprising that people with hypothyroidism often have symptoms associated with a slow metabolism. Worldwide, too little iodine in the diet is the most common cause of hypothyroidism. Hypothyroidism affects approximately 11% of the population of India. This article deals with a case of hypothyroidism homoeopathically managed with a constitutional remedy Natrium Muriaticum. Kent’s method of evaluation of symptoms was adopted in this case as the patient showed mostly mental and physical general symptoms.

377 Randomized Placebo-controlled Trial to Test the Efficacy of genetically informed biomarker Nicotine Metabolite Ratio (NMR), and transdermal nicotine replacement therapy (NRT) versus varenicline

OBJECTIVES/GOALS: The overall aim of the proposed study is to evaluate the effectiveness and clinical utility of the NMR as a biomarker of response to placebo, transdermal nicotine, and varenicline to be utilized within the clinical practice as a point-of-care predictor to tailor an individual’s smoking cessation treatment. METHODS/STUDY POPULATION: A 12-week phase II, stratified multicenter, randomized, placebo-controlled trial of 3 treatment groups to measure treatment-seeking smokers (n-900:150 slow metabolizers; 150 normal metabolizers), randomized to 12-weeks of nicotine patch (active patch + placebo pill), varenicline (active pill + placebo patch), or placebo (placebo pill + patch). At the end of treatment, patients will be followed for 12 months. Study Population: Adult smokers 18–65 years old reported smoking≥10 cigarettes/day for≥6 months (verified by carbon monoxide (CO) &gt;10 ppm). Drug and route of administration: RESULTS/ANTICIPATED RESULTS: The study would conclude the effectiveness of the interventions well defined. DISCUSSION/SIGNIFICANCE: The report will provide robust evidence to support the effectiveness of NRT intervention on smoking cessation.

Low dissolved oxygen supply functions as a global regulator of the growth and metabolism of Aurantiochytrium sp. PKU#Mn16 in the early stages of docosahexaenoic acid fermentation

BackgroundThraustochytrids accumulate lipids with a high content of docosahexaenoic acid (DHA). Although their growth and DHA content are significantly affected by the dissolved oxygen (DO) supply, the role of DO on the transcriptional regulation of metabolism and accumulation of intracellular metabolites remains poorly understood. Here we investigate the effects of three different DO supply conditions (10%, 30%, and 50%) on the fed-batch culture of the Aurantiochytrium PKU#Mn16 strain to mainly reveal the differential gene expressions and metabolite profiles.ResultsWhile the supply of 10% DO significantly reduced the rates of biomass and DHA production in the early stages of fermentation, it achieved the highest amounts of biomass (56.7 g/L) and DHA (6.0 g/L) on prolonged fermentation. The transcriptome analyses of the early stage (24 h) of fermentation revealed several genes involved in the central carbon, amino acid, and fatty acid metabolism, which were significantly downregulated at a 10% DO level. The comparative metabolomics results revealed the accumulation of several long-chain fatty acids, amino acids, and other metabolites, supporting the transcriptional regulation under the influence of a low oxygen supply condition. In addition, certain genes involved in antioxidative systems were downregulated under 10% DO level, suggesting a lesser generation of reactive oxygen species that lead to oxidative damage and fatty acid oxidation.ConclusionsThe findings of this study suggest that despite the slow growth and metabolism in the early stage of fermentation of Aurantiochytrium sp. PKU#Mn16, a constant supply of low dissolved oxygen can yield biomass and DHA content better than that with high oxygen supply conditions. The critical information gained in this study will help to further improve DHA production through bioprocess engineering strategies.

Pharmacoeconomic analysis of personalized antiplatelet therapy in patients with acute coronary syndromer

Relevance. The problem of antiplatelet therapy resistance is not fully solved, whereas its manifestations in the form of stent thrombosis cause a negative contribution in treatment and can lead to significant economic damage to the healthcare system. Pharmacogenetic testing as a personalization tool can potentially reduce the cost of treatment, which requires pharmacoeconomic research of pharmacogenetic methods. The aim of this study was a pharmacoeconomic evaluation of the pharmacogenetic testing implementation before the antiplatelet therapy in patients with acute coronary syndrome after percutaneous coronary intervention. Methods. In our study, a decision tree model was built with a time horizon of 1 year and a cost-effectiveness analysis was performed for six compared treatment strategies in patients with acute coronary syndrome after stent implantation with and without genotyping for the drugs clopidogrel, ticagrelor and prasugrel. Results. A treatment strategy with pharmacogenetic testing and the choosing of prasugrel for slow and intermediate metabolizers was the most preferred with CER 35 577.40 rubles per 1 unit of effectiveness. The most expensive strategy was the “blind” use of ticagrelor for all patients. Conclusion. Based on the modeling results, it can be concluded that the implementation of pharmacogenetic testing before prescribing antiplatelet drugs in patients with acute coronary syndrome undergoing stenting can potentially reduce the incidence of adverse events such as stent thrombosis and reduce the overall cost of treatment.

Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: a longitudinal analysis and genome-wide association study using UK clinical monitoring data

The antipsychotic, clozapine, is the only licensed drug against the treatment-resistant symptoms that affect 20-30% of people with schizophrenia. Clozapine is markedly underprescribed, partly because of concerns about its narrow therapeutic range and adverse drug reaction profile. Both concerns are linked to drug metabolism, which varies across populations globally and is partly genetically determined. Our study aimed to use a cross-ancestry genome-wide association study (GWAS) design to investigate variations in clozapine metabolism within and between genetically inferred ancestral backgrounds, to discover genomic associations to clozapine plasma concentrations, and to assess the effects of pharmacogenomic predictors across different ancestries. In this GWAS, we analysed data from the UK Zaponex Treatment Access System clozapine monitoring service as part of the CLOZUK study. We included all available individuals with clozapine pharmacokinetic assays requested by their clinicians. We excluded people younger than 18 years, or whose records contained clerical errors, or with blood drawn 6-24 h after dose, a clozapine or norclozapine concentration less than 50 ng/mL, a clozapine concentration of more than 2000 ng/mL, a clozapine-to-norclozapine ratio outside of the 0·5-3·0 interval, or a clozapine dose of more than 900 mg/day. Using genomic information, we identified five biogeographical ancestries: European, sub-Saharan African, north African, southwest Asian, and east Asian. We did pharmacokinetic modelling, a GWAS, and a polygenic risk score association analysis using longitudinal regression analysis with three primary outcome variables: two metabolite plasma concentrations (clozapine and norclozapine) and the clozapine-to-norclozapine ratio. 19 096 pharmacokinetic assays were available for 4760 individuals in the CLOZUK study. After data quality control, 4495 individuals (3268 [72·7%] male and 1227 [27·3%] female; mean age 42·19 years [range 18-85]) linked to 16 068 assays were included in this study. We found a faster average clozapine metabolism in people of sub-Saharan African ancestry than in those of European ancestry. By contrast, individuals with east Asian or southwest Asian ancestry were more likely to be slow clozapine metabolisers than those with European ancestry. Eight pharmacogenomic loci were identified in the GWAS, seven with significant effects in non-European groups. Polygenic scores generated from these loci were associated with clozapine outcome variables in the whole sample and within individual ancestries; the maximum variance explained was 7·26% for the metabolic ratio. Longitudinal cross-ancestry GWAS can discover pharmacogenomic markers of clozapine metabolism that, individually or as polygenic scores, have consistent effects across ancestries. Our findings suggest that ancestral differences in clozapine metabolism could be considered for optimising clozapine prescription protocols for diverse populations. UK Academy of Medical Sciences, UK Medical Research Council, and European Commission.

Diabetes Mellitus with Membranous Nephropathy and H.pylori Infection: A Case Report

Early membranous nephropathy with diabetes mellitus is often easily misdiagnosed as diabetic nephropathy. Tacrolimus is a common drug for the treatment of membranous nephropathy, and CYP3A5 gene plays an important role in its metabolism. The decreased expression activity of CYP3A5 gene leads to the increased blood concentration of tacrolimus and adverse reactions. We report the case of diabetes mellitus with early membranous nephropathy and H.pylori infection in a 55-year-old female. Our patient was diagnosed with membranous nephropathy by renal puncture. Due to the slow metabolism of CYP3A5, tacrolimus was reduced to avoid side effects. After eradication of H.pylori, the patient’s urine protein decreased and the prognosis of membranous nephropathy was good. There was no discomfort during the follow-up period after the patient was discharged.

Evaluation of Caffeine Ingested Timing on Endurance Performance based on CYP1A2 rs762551 Profiling in Healthy Sedentary Young Adults.

Caffeine is generally suggested to increase VO2max in endurance performance. Nevertheless, the response to caffeine ingestion does not seem to be uniform across individuals. Therefore, caffeine ingested timing on endurance performance based on the type of CYP1A2 single nucleotide polymorphism rs762551, that were classified as fast and slow metabolizers, need to be evaluated. Thirty participants participated in this study. DNA was obtained from saliva samples and genotyped using polymerase chain reaction-restriction fragment length polymorphism. Each respondent completed beep tests under three treatments blindly: placebo, 4 mg/kg body mass of caffeine one hour, and two hours before test. Caffeine increased estimated VO2max in fast metabolizers (caffeine=29.39±4.79, placebo=27.33±4.02, p<0.05) and slow metabolizers (caffeine=31.25±6.19, placebo=29.17±5.32, p<0.05) in one hour before test. Caffeine also increased estimated VO2max in fast metabolizers (caffeine=28.91±4.65, placebo=27.33±4.02, p<0.05) and slow metabolizers (caffeine=32.53±6.68, placebo=29.17±5.32, p<0.05) in two hour before test. However, for slow metabolizers, the increasing was greater when caffeine was administered two hours before test (slow=3.37±2.07, fast=1.57±1.62, p<0.05). Genetic variance may affect the optimal caffeine ingestion timing, sedentary individuals who want to enhance their endurance performance may ingest caffeine 1 hour before exercise for fast metabolizers and 2 hours before exercise for slow metabolizers.

CRISPR-Csx28 forms a Cas13b-activated large-pore channel required for robust CRISPR-Cas immunity.

In response to bacterial viruses (bacteriophage) and other environmental stressors, prokaryotes have evolved a myriad of defense strategies including CRISPR-Cas systems. CRISPR-Cas systems have recently been shown to influence biofilm formation and virulence of several pathogenic bacteria that reside in the oral cavity. Of these bacteria, select gram-negative species possess Type VI CRISPR-Cas systems which use the RNA-guided RNase Cas13 to detect and defend against foreign RNA emanating from mobile genetic elements such as plasmids and bacteriophage. Although studied extensively for RNA-based technologies, Type VI CRISPR-Cas systems include underexamined accessory proteins that have unclear roles in Cas13-mediated defense such as Csx28 of Type VI-B2 systems. Therefore, characterization of VI-B2 systems may be useful in future studies by identifying new potential protein targets of pathogenic oral bacteria, which may aid in small molecule drug design and/or phage therapy to treat pathogenic bacterial infections in the oral cavity. Here we show that Csx28 is activated by target-specific cleavage of viral mRNAs by Cas13b. Upon activation, Csx28 results in drastically increased anti-viral defense, membrane depolarization, and slowed metabolism. Our 3.7 Å cryo-EM structure reveals that Csx28 forms an octameric large-pore channel. We find that these Csx28 pore-channels localize to the gram-negative bacterial inner-membrane in vivo. Together, our work reveals an unprecedented mechanism by which Csx28 acts as a downstream, Cas13b-activated, RNA-binding effector protein that uses membrane perturbation as an anti-viral defense strategy.

Effect of glutamine supplementation in elderly people with emphasis on sarcopenia, immunity and hypertrophy: a concise systematic review

Currently, the aging of the population is no longer a forgotten subject for health professionals in Brazil. This is due to the decrease in the birth rate in the country and the improvement in quality of life, this first factor was boosted after the ease of access to information on contraceptive methods and their distribution by the health system. As a result, the Nutrition area has been studying more diligently ways to provide elderly people with methods that contribute to a more comfortable, healthy, and long-lasting life. The nutritionist is essential to identify the deficits and disharmonization of the body of the elderly caused naturally over the years in people's lives, such as loss of muscle mass, and lack of nutrients, among others. Given this scenario, this work will be focused on showing that the use of oral Glutamine supplementation contributes to the gain of muscle mass in the elderly since this natural amino acid present mainly in the muscle tissue of the human body is greatly reduced due to loss of mass skin and body weight gain caused by the slow metabolism found in older people. In this way, supplementation along with a well-designed nutritional table and an exercise routine will promote less chance of injury to the elderly due to a lack of nutrients and greater physical resistance. To reinforce and prove this study, we will use the literature review method distributed in topics.

P791 Up to one third of rapid thiopurine-S-methyltransferase metabolizers manifest clinical and/or laboratory azathioprine side effects: A single centre experience

Abstract Background According to ECCO-ESPGHAN consensus guidelines, azathioprine (AZA) can be used for maintenance of remission in paediatric Inflammatory Bowel Disease (IBD). AZA side effects are well documented. Haematological toxicity affects 2-14% of patients and pancreatitis affects up to 7% of them, requiring modification of AZA dosage or its cessation. Thiopurine-S-methyltransferase (TPMT) activity should be tested prior to AZA commencement. Slow metabolizers should not be started on AZA and intermediate ones should get a dose reduction. This study evaluates the incidence of AZA side effects in TPMT rapid metabolizers. Methods Retrospective evaluation of prospectively collected data in children tested for TPMT and who received AZA between 3/13 and 10/22. Focusing on the incidence of both clinical and laboratory side effects in rapid metabolizers. Results Ninety children had TPMT tested. Only 1 intermediate a 1 slow metabolizer were identified. All rapid metabolizers were diagnosed with IBD, 62 (70,5%) with Crohn’s (CD), 16 (18,2%) with Ulcerative Colitis (UC), 7 with Very Early Onset IBD (VEO-IBD) and 1 with IBD undifferentiated. Forty-seven were male (53,4%) and 41 female. The median age at diagnosis was 13.5±3,9 years. Of the 88 rapid metabolizers, 82 (93%) received AZA. The remaining 6 had different treatment strategies. Clinical and/or laboratory side effects were documented in 27 cases (32,9%). Haematological toxicity was most frequent affecting 19 participants (23.1%). In 13 cases (68,4%) leukopenia resolved spontaneously, in 4 cases (21%) dose reduction was required, and in 3 cases (15,8%) AZA had to be stopped. Pancreatitis was identified in 6 patients (7,3%). Half of the cases were discovered by laboratory findings and the remainder had a clinical correlate. In 2 cases, laboratory pancreatitis normalized on follow-up examination, in the remaining ones AZA had to be withdrawn. Clinical intolerance was found twice, once requiring split dosage, and once dose reduction. Haematological toxicity manifested on average within 10,9 months since treatment start (0.5-43 months), pancreatitis within 0,54 months with one case manifesting after 79 months of treatment. In this single case, autoimmune pancreatitis is debated. Clinical intolerance appeared within days from AZA commencement. Boys had AZA side effects slightly more frequently (15/27, 55%). CD patients had AZA side effects the most (16/27, 59%). However, CD was the most common diagnosis in the cohort. Conclusion Being a rapid TPMT metabolizer should reduce the risk of AZA side effects. However, these data demonstrate a 32,9% occurrence of them, emphasising the importance of clinical and laboratory follow-up in patients on AZA.

Maternal per- and poly-fluoroalkyl substances exposures associated with higher depressive symptom scores among immigrant women in the Chemicals in Our Bodies cohort in San Francisco

BackgroundExposure to per- and poly-fluoroalkyl substances (PFAS) remains an important public health issue due to widespread detection and persistence in environmental media, slow metabolism in humans, and influences on physiological processes such as neurological signaling. Maternal depression is highly prevalent during pregnancy and postpartum and is potentially sensitive to PFAS. The health risks associated with PFAS may be further amplified in historically marginalized communities, including immigrants. ObjectiveEvaluate maternal concentrations of PFAS in association with depression scores during pregnancy and whether effects differ between US born and immigrant women. MethodsOur study sample included 282 US born and 235 immigrant pregnant women enrolled in the Chemicals in Our Bodies prospective birth cohort based in San Francisco, CA. We measured 12 PFAS in serum samples collected in the second trimester and depressive symptom scores were assessed using the Center for Epidemiologic Studies Depression Scale. Associations were estimated using linear regression, adjusting for maternal age, education, pre-pregnancy body mass index, and parity. Associations with a PFAS mixture were estimated using quantile g-computation. ResultsIn adjusted linear regression models, a twofold increase in two PFAS was associated with higher depression scores in the overall sample, and this association persisted only among immigrant women (β [95 % confidence interval]: perfluorooctane sulfonic acid (2.7 [0.7–4.7]) and methyl-perfluorooctane sulfonamide acetic acid (2.9 [1.2–4.7]). Quantile g-computation indicated that simultaneously increasing all PFAS in the mixture by one quartile was associated with increased depressive symptoms among immigrant women (mean change per quartile increase = 1.12 [0.002, 2.3]), and associations were stronger compared to US born women (mean change per quartile increase = 0.09 [-1.0, 0.8]). ConclusionsFindings provide new evidence that PFAS are associated with higher depression symptoms among immigrant women during pregnancy. Results can inform efforts to address environmental factors that may affect depression among US immigrants.

A Low Tacrolimus Concentration-to-Dose Ratio Increases Calcineurin Inhibitor Nephrotoxicity and Cytomegalovirus Infection Risks in Kidney Transplant Recipients: A Single-Center Study in Japan

Tacrolimus (TAC) has several problems due to its narrow therapeutic window and variations pharmacokinetics and pharmacodynamics. Recently, several studies reported that TAC metabolism, defined by TAC blood trough concentration to dose (C/D) ratio, was associated with TAC toxicity. Reports on once-daily extended-release TAC (TAC-ER) are limited. The present study aimed to investigate the effect of the TAC metabolic rate on TAC-ER and compare TAC area under the curve (AUC) between fast and slow metabolizers. A total of 58 recipients were included in this study. The optimal cut-off value and time of the C/D ratio on TAC-ER for fast and slow metabolizers was determined using receiver operating characteristic curve analysis for biopsy-proven calcineurin inhibitor (CNI) nephrotoxicity. The optimal time to evaluate the C/D ratio was 1 month after kidney transplantation (KT) and the cut-off value was 0.9. The multivariate analysis for CNI nephrotoxicity risk showed that only TAC metabolism was associated with CNI nephrotoxicity (hazard ratio 10.60, P=.005, 95% CI 2.03-55.22). Cytomegalovirus infection occurred more frequently in fast metabolizers when the cut-off value of the C/D ratio was set to 0.9 at 3 months after KT (P=.04). The TAC C4, AUC2-8, was higher in fast metabolizers than in slow metabolizers (P < .01, P=.03, respectively). The study revealed that TAC fast metabolizers on TAC-ER may be classified as a high-risk group for CNI nephrotoxicity and cytomegalovirus infection. The result of TAC AUC supported the hypothesis that fast metabolizers tended to be overexposed to immunosuppressive agents early after oral administration.

DMNP, a Synthetic Analog of Erogorgiaene, Inhibits the ppGpp Synthetase Activity of the Small Alarmone Synthetase RelZ

Suppression of the stringent response is a promising strategy for the treatment of persistent bacterial infections. A novel class of compounds having a mechanism of action based on alarmone synthetase inhibition and suppressing the synthesis of (p)ppGpp alarmones in bacteria may provide a more effective treatment for latent infections and resolve problems associated with bacterial persistence. Conventional antibiotics primarily act on actively growing bacteria, but they are inactive against persister cells with a slowed metabolism. Alarmone synthetase inhibitors have antipersister properties that may enhance conventional antibiotics’ antibacterial action. Two groups of RSH proteins are responsible for the synthesis of alarmones: long RelA/SpoT homologs and small alarmone synthetases. Many species of bacteria possess both types of enzymes. Despite the fact that a number of inhibitors of bifunctional long synthetases/hydrolases have been described to date, their properties with respect to monofunctional small alarmone synthetases have been studied poorly. This study investigated the effect of the alarmone synthetase inhibitor DMNP on the purified RelZ small alarmone synthetase protein from Mycolicibacterium smegmatis.

VARIANTS OF THE FORMATION AND COURSE OF DRUG-RESISTANT EPILEPSY IN CHILDREN WITH GENETIC POLYMORPHISMS OF CYP2C9, CYP2C19, CYP3A4.

The aim: To clarify the frequency with which various variants of the formation and course of drug-resistant epilepsy occur in children with genetic polymor¬phisms of cytochromes CYP2C9, CYP2C19, CYP3A4. Materials and methods: The genotyping of CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP3A4*1B by the allele-specific polymerase chain reaction was performed in 116 children with drug-resistant epilepsy aged from 2 to 17 years. Thirty cases (boys-15; girls-15) with a follow-up period of more than 5 years were analyzed in detail. Results: Of 30 cases analyzed, polymorphisms were not detected in 8 (26.67%) children, and 22 (73.33%) had polymorphisms of the CYP2C9, CYP2C19 and CYP3A4 genes associated with a slow metabolism of AED. In children with polymorphisms of the CYP450 genes, the wave-like course of the disease with the periods of remission and its failures was characteristic, while for children with a presumably normal metabolism there was the initial resistance to the treatment with AED. Conclusions: Individual changes in the AED metabolism affect the course of drug-resistant epilepsies. For patients with a slow metabolism of AED the wave-like course of the disease and the "slipping off" phenomenon were more characteristic.

Investigation and Scaling of Hydrogen Production by Klebsiella sp. ABZ11 for Optimal Yield and the Kinetics of Batch Fermentation Process

The slow metabolism of bacteria at low temperatures affects the catalytic efficiency of enzymes and productivity. This article investigates the use of a psychrotolerant bacteria (Klebsiella sp. ABZ11) for biohydrogen production, yield and scaling at optimal temperature, pH and glucose in a batch fermentation process within a 2-liter bioreactor using Response Surface Methodology (RSM) to report the process performance. The results show 33.5°C, pH 6.75 and 9.15 g glucose as the optimal conditions. Scale-up yielded 137.56 mol/L biohydrogen, 22.13% more than production under optimized conditions. Biomass grew at 0.081/h and doubled in 17 h with 0.71 g cells to reach maximum production. Compared to 0.062/h, 22 h with 0.87 g cells in optimal condition to achieve maximum biohydrogen production. This result shows the potential of biohydrogen production using Antarctic psychrotolerant bacteria at mesophilic temperature.