Leveraging metabolic modeling to identify functional metabolic alterations associated with COVID-19 disease severity.

OBJECTIVE: Since the COVID-19 pandemic began in early 2020, SARS-CoV2 has claimed more than six million lives world-wide, with over 510 million cases to date. To reduce healthcare burden, we must investigate how to prevent non-acute disease from progressing to severe infection requiring hospitalization. METHODS: To achieve this goal, we investigated metabolic signatures of both non-acute (out-patient) and severe (requiring hospitalization) COVID-19 samples by profiling the associated plasma metabolomes of 84 COVID-19 positive University of Virginia hospital patients. We utilized supervised and unsupervised machine learning and metabolic modeling approaches to identify key metabolic drivers that are predictive of COVID-19 disease severity. Using metabolic pathway enrichment analysis, we explored potential metabolic mechanisms that link these markers to disease progression. RESULTS: Enriched metabolites associated with tryptophan in non-acute COVID-19 samples suggest mitigated innate immune system inflammatory response and immunopathology related lung damage prevention. Increased prevalence of histidine- and ketone-related metabolism in severe COVID-19 samples offers potential mechanistic insight to musculoskeletal degeneration-induced muscular weakness and host metabolism that has been hijacked by SARS-CoV2 infection to increase viral replication and invasion. CONCLUSIONS: Our findings highlight the metabolic transition from an innate immune response coupled with inflammatory pathway inhibition in non-acute infection to rampant inflammation and associated metabolic systemic dysfunction in severe COVID-19.

Emerging work environments in the pandemic era: a gendered approach to work-life balance programs.

As the coronavirus pandemic affects virtually every sector of the economy, this ongoing review examines the effects of remote working on women's job performance-including hypotheses about serious activities and how they may balance work and family. In recent years, psychometric testing has become increasingly popular with organizations worldwide, and they are looking at this method to better understand how women achieve balance in their lives. The aim of this work is to investigate how different aspects of psychometrics and factors relating to work-life balance influence women's satisfaction levels. An exploratory factor assessment (EFA) and a confirmatory factor assessment (CFA) using a seven-point Likert scale were performed on data collected from 385 selected female IT workers whose satisfaction levels toward psychometric assessments in their organization were examined. The current study uses EFAs and CFAs to develop and identify the key factors in women's work-life balance. The results also showed that three significant variables accounted for 74% of the variance: 26% from work and family, 24% from personal factors, and 24% from loving their job.

Corrigendum: Emerging work environments in the pandemic era: a gendered approach to work-life balance programs.

[This corrects the article DOI: 10.3389/fsoc.2023.1120288.].

Capsaicin inhibits benzo(a)pyrene-induced lung carcinogenesis in an in vivo mouse model.

OBJECTIVE: Lung cancer is a serious health problem in most developed countries and its incidence rate is profusely increasing. Capsaicin, a component of red chilli and red pepper has been studied widely for its chemopreventive properties. The aim of the present study is to explore the anti-tumor activity of capsaicin against benzo(a)pyrene-induced lung tumorigenesis in Swiss albino mice. MATERIALS AND METHODS: Benzo(a)pyrene was administered orally (50 mg/kg body weight) to induce lung cancer in Swiss albino mice. Hematological study (hemoglobin content, RBC, WBC count and differential count), histochemical analysis of mast cells and Western blot analysis of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2) and nuclear factor-kappa B (NF-κB) were carried out. RESULTS: Hematological parameters and the histochemical analysis of mast cells showed abnormal changes, and the immunoblotting analysis revealed increased protein expression of TNF-α, IL-6, COX-2 and NF-κB in lung cancer-challenged mice administered with benzo(a)pyrene. Capsaicin (10 mg/kg body weight) supplementation to lung cancer bearing mice considerably prevented all the above abnormalities. CONCLUSION: The results of the present study indicate the protective effect of capsaicin against benzo(a)pyrene-induced lung carcinogenesis in mice.

Genetic analysis of OCT1 gene polymorphisms in an Indian population.

BACKGROUND: Genetic variants of the organic cation transporter (OCT1) gene could influence interindividual variation in clinical response to metformin therapy. The genetic basis for the single-nucleotide polymorphism (SNP) of OCT1 gene has been established in other populations, but it remains to be elucidated in the Indian population. This study is focused on OCT1 gene variants rs2282143 (P341L, 1022C>T), rs628031 (M408V, 1222A>G) and rs622342 (1386C>A) frequency distributions in the South Indian Tamilian population. MATERIALS AND METHODS: A total of 112 unrelated healthy subjects of South Indian Tamilian origin, aged 18-60 years, of either sex were recruited for the study. Genotyping was determined using the quantitative real time-polymerase chain reaction and polymerase chain reaction followed by restriction fragment length polymorphism methods. RESULTS: Allele frequencies of rs2282143, rs628031and rs622342 polymorphisms were 8.9%, 80.3% and 24.5%, respectively. Interethnic differences in the genotype and allele frequencies of OCT1 gene polymorphism were observed when compared with other major populations. The SNPs rs2282143, T allele and rs628031, G allele were more common in Asians (5.5-16.8% and 76.2-81%) and African Americans (8.2% and 73.5%) than in Caucasians (0-2% and 57.4-60%). CONCLUSION: This is the first time the frequency of OCT1 gene polymorphism was determined in the Indian population, and is similar to the frequencies observed in African-Americans and other Asian populations but different from those in Caucasians. The data observed in this study would justify further pharmacogenetic studies to potentially evaluate the role of OCT1 gene polymorphism in the therapeutic efficacy of metformin.

Fecal Microbiota Transplantation Increases Colonic IL-25 and Dampens Tissue Inflammation in Patients with Recurrent Clostridioides difficile.

Clostridioides difficile infection (CDI) is the most common hospital-acquired infection in the United States. Antibiotic-induced dysbiosis is the primary cause of susceptibility, and fecal microbiota transplantation (FMT) has emerged as an effective therapy for recurrence. We previously demonstrated in the mouse model of CDI that antibiotic-induced dysbiosis reduced colonic expression of interleukin 25 (IL-25) and that FMT protected in part by restoring IL-25 signaling. Here, we conducted a prospective study in humans to test if FMT induced IL-25 expression in the colons of patients with recurrent CDI (rCDI). Colonic biopsy specimens and blood were collected at the time of FMT and 60 days later. Colon biopsy specimens were analyzed for IL-25 protein levels, total tissue transcriptome, and epithelium-associated microbiota before and after FMT, and peripheral immune cells were immunophenotyped. FMT increased alpha diversity of the colonic microbiota and levels of IL-25 in colonic tissue. In addition, FMT increased expression of homeostatic genes and repressed inflammatory genes. Finally, circulating Th17 cells were decreased post-FMT. The increase in levels of the cytokine IL-25 accompanied by decreased inflammation is consistent with FMT acting in part to protect from recurrent CDI via restoration of commensal activation of type 2 immunity. IMPORTANCE Fecal microbiota transplantation (FMT) is an effective treatment for C. difficile infection for most patients; however, introducing a complex mixture of microbes also has had unintended consequences for some patients. Attempts to create a standardized probiotic therapeutic that recapitulates the efficacy of FMT have been unsuccessful to date. We sought to understand what immune markers are changed in patients undergoing FMT to treat recurrent C. difficile infection and identified an immune signaling molecule, IL-25, that was restored by FMT. This finding indicates that adjunctive therapy with IL-25 could be useful in treating C. difficile infection.

Capsaicin alleviates the imbalance in xenobiotic metabolizing enzymes and tumor markers during experimental lung tumorigenesis.

Lung cancer is currently a leading cause of death all over the world. Environmental risk factors, particularly genotoxic chemicals such as polycyclic aromatic hydrocarbons (PAH), are likely to account for a much higher mortality. Xenobiotic metabolizing enzymes are potentially chief determinants in both the susceptibility to the mutagenic effects of chemical carcinogens and in the response of tumors to chemotherapy. The well-known carcinogen benzo(a)pyrene (B(a)P) of PAH family was given orally (50 mg/kg body weight) to induce lung cancer in Swiss albino mice. B(a)P induction altered the levels of cytochromes (P450, b5), activities of phase I biotransformation enzymes (NADPH-cytochrome P450 reductase, NADH-cytochrome b5 reductase and epoxide hydrolase), phase II enzymes (glutathione-S-transferase, UDP-glucuronyl transferase and DT-diaphorase), and the levels of serum tumor markers. Treatment with capsaicin (CAP) (10 mg/kg body weight) to the lung carcinoma mice restored back the activities of phase I and II biotransformation enzymes and the levels of tumor markers to near normalcy. The above findings were substantiated by immunoblotting and immunohistochemical analysis of cytochrome P450 1A1 (CYP1A1) in the lung tissues. Our present study unravels that CAP can effectively detoxify the carcinogens which discloses its anti-carcinogenic effect during experimental lung cancer.

Ameliorating effect of capsaicin on alterations in lipid metabolism during mice lung carcinoma.

Spices and vegetables possess antioxidant activity that can be applied for preservation of lipids and lower lipid peroxidation in biological systems. In the present study, we have investigated the effect of capsaicin on lipid metabolism during benzo(a)pyrene induced lung cancer in Swiss albino mice. Benzo(a)pyrene (50 mg/kg wt) induced lung cancer animals showed abnormal changes in the tissue and serum lipids, lipoproteins and lipid metabolizing enzymes. Treatment with capsaicin (10 mg/kg body wt) remarkably attenuated all the above alterations and restored normalcy. These findings reveal the chemomodulatory potential of capsaicin in attenuating the alterations in lipid metabolism during experimental lung carcinogenesis.

Stabilization of pulmonary mitochondrial enzyme system by capsaicin during benzo(a)pyrene induced experimental lung cancer.

The modulatory efficacy of capsaicin on lung mitochondrial enzyme system with reference to mitochondrial lipid peroxidation (LPO), antioxidants, key citric acid cycle enzymes and respiratory chain enzymes during benzo(a)pyrene (B(a)P) induced lung cancer in Swiss albino mice was studied. Elevations in mitochondrial LPO along with decrements in enzymic antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST)), non-enzymic antioxidants (reduced glutathione (GSH), vitamin C, vitamin E and vitamin A), citric acid cycle enzymes (isocitrate dehydrogenase (ICDH), alpha-ketoglutarate dehydrogenase (alpha-KDH), succinate dehydrogenase (SDH) and malate dehydrogenase (MDH)), and respiratory chain enzymes (NADH dehydrogenase and Cytochrome c oxidase) were observed in B(a)P (50mg/kg body weight) administered animals. CAP (10mg/kg body weight) pretreatment decreased lung mitochondrial LPO and augmented the activities of enzymic, non-enzymic antioxidants, citric acid cycle enzymes and respiratory chain enzymes to near normalcy revealing its chemoprotective function during B(a)P induced lung cancer.

Beneficial influence of capsaicin on lipid peroxidation, membrane-bound enzymes and glycoprotein profile during experimental lung carcinogenesis.

This study was designed to examine the impact of a principal component of hot red peppers and chilli peppers, capsaicin, on alterations in lipid peroxidation, membrane-bound enzyme profiles and glycoprotein levels during benzo(a)pyrene (BP)-induced lung cancer in Swiss albino mice. BP (50 mgkg(-1)) induced deleterious changes that were that revealed by alterations in lipid peroxidation, membrane-bound enzyme (Na+/K+ ATPase, Ca2+ ATPase and Mg2+ ATPase) activity, levels of total protein and protein-bound carbohydrate components (sialic acid, hexose, hexosamine, hexuronic acid and fucose). Pre-co-treatment with capsaicin (10 mg kg(-1)) restored the detrimental effects induced by BP, indicating its protective role in BP-induced lung cancer.

Capsaicin modulates pulmonary antioxidant defense system during benzo(a)pyrene-induced lung cancer in Swiss albino mice.

The effect of a pungent ingredient of red pepper, capsaicin, on oxidative stress induced changes in the antioxidant defense system by benzo(a)pyrene in the lungs of mice was studied. Oral gavage administration of benzo(a)pyrene (50 mg/kg body weight) to mice led to a marked increase in oxidative stress indicated by alterations in pulmonary lipid peroxidation, enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase) and non-enzymic antioxidants (reduced glutathione, vitamin C, vitamin E and vitamin A). Pre-co-treatment with capsaicin (10 mg/kg body weight i.p.) restored cellular normalcy, highlighting the antioxidant potential of capsaicin in mitigating the oxidative stress mediated damage produced during benzo(a)pyrene-induced lung cancer.

Insulin sensitivity and cardiac autonomic function in young male practitioners of yoga.

BACKGROUND: While yoga is thought to reduce the risk of chronic non-communicable diseases such as diabetes, there are no studies on insulin sensitivity in long term practitioners of yoga. We assessed insulin sensitivity and cardiac autonomic function in long term practitioners of yoga. METHODS: Fifteen healthy, young, male practitioners of yoga were compared with 15 young, healthy males who did not practice yoga matched for body-mass index. Fasting insulin sensitivity was measured in the fasting state by the hyperinsulinaemic-euglycaemic clamp. RESULTS: There were no significant differences between the groups in their anthropometry or body composition. However, the fasting plasma insulin was significantly lower in the yoga group. The yoga group was also more insulin sensitive (yoga 7.82 [2.29] v. control 4.86 [11.97] (mg/[kg.min])/(microU/ml), p < 0.001). While the body weight and waist circumference were negatively correlated with glucose disposal rate in the controls, there were no similar correlations in the yoga group. The yoga group had significantly higher low-frequency power and lower normalized high-frequency power. CONCLUSION: Long term yoga practice (for 1 year or more) is associated with increased insulin sensitivity and attenuates the negative relationship between body weight or waist circumference and insulin sensitivity.

Regulation of adherence and virulence by the Entamoeba histolytica lectin cytoplasmic domain, which contains a beta2 integrin motif.

Killing of human cells by the parasite Entamoeba histolytica requires adherence via an amebic cell surface lectin. Lectin activity in the parasite is regulated by inside-out signaling. The lectin cytoplasmic domain has sequence identity with a region of the beta2 integrin cytoplasmic tail implicated in regulation of integrin-mediated adhesion. Intracellular expression of a fusion protein containing the cytoplasmic domain of the lectin has a dominant negative effect on extracellular lectin-mediated cell adherence. Mutation of the integrin-like sequence abrogates the dominant negative effect. Amebae expressing the dominant negative mutant are less virulent in an animal model of amebiasis. These results suggest that inside-out signaling via the lectin cytoplasmic domain may control the extracellular adhesive activity of the amebic lectin and provide in vivo demonstration of the lectin's role in virulence.

Pediatric Hodgkin's disease in India.

Twenty-one percent of all Hodgkin's disease in India was seen in the pediatric age groups at the Tata Memorial Hospital (Bombay, India). From 1975 to 1982, 151 cases of children were reviewed. The youngest presentation was at 3 years in three patients, with a marked male: female ratio of 5.5:1. Twenty-six patients were previously treated before referral while the remaining 125 cases were investigated and treated according to the prevalent protocols in 1975 to 1978 and 1979 to 1982. Clinical staging revealed 54% of patients in stages I and II with symptoms in 20%, and 46% of patients in stages III and IV with symptoms in 67%. Staging laparotomy was performed in 27 patients, with a total changes of staging in 17 children (63%). The mixed cell types (46%) and lymphocytic predominant types (31%) were the most common histologic presentations. Nine percent nodular sclerosis and 9% lymphocytic-depleted varieties were also observed. Five percent of all cases were not classifiable. Minimum adequate treatment was completed in 87 cases. Comparisons were made between the treatments administered to 40 patients during the initial period 1975 to 1978 when individualized treatment was administered, and the later 47 patients during the 1979 to 1982 period, when chemotherapy was the mainstay of treatment with involved field radiation.

Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer.

PURPOSE: To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m(2) of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m(2) of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival. RESULTS: Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P =.0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m(2) for MC versus 480 mg/m(2) for AC (P =.0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months. CONCLUSION: Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.

Total body irradiation in chronic myeloid leukemia.

Total body irradiation (TBI), given as 10 rad daily for five days a week for a total dose of 150 rad has been used in an attempt to control the chronic phase of chronic myeloid leukemia (CML). Thirteen patients with CML received fractionated TBI leading to rapid and good control of WBC count without any adverse reaction. The chronic phase of CML could also be controlled with TBI, even in three patients who were resistant to busulfan. Following TBI, WBC count remained under control for a period of 32 weeks as compared to 40 weeks following busulfan alone. Repeat TBI was also well tolerated with good response. It appears that TBI is an effective and safe therapy for controlling the chronic phase of CML.

A tetracycline-inducible gene expression system in Entamoeba histolytica.

We have developed an episomal inducible gene expression system in Entamoeba histolytica based on the TetR repressor. The tetR gene was placed under control of 5' and 3' ferredoxin (fdx) regulatory sequences on a plasmid encoding the hygromycin resistance gene directed by 5' and 3' hgl sequences. The reporter luciferase constructs were introduced on a second episome bearing the neomycin resistance gene controlled by 5' and 3' actin sequences. The reporter constructs were driven by the hgl5 promoter in which the tetO sequence was introduced. We found that the optimal tetO location for induction by tetracycline was +4 from the start of transcription. The efficiency of repression and the induction ratio could be improved by increasing hygromycin levels, presumably by increasing tetR plasmid levels. Under these conditions, maximal induction of reporter luciferase could be effected with 5 micrograms/ml tetracycline in 18 h. This system permits regulated expression of the reporter gene over two orders of magnitude and should be useful in the analysis of gene function.

Characterisation of blast cells during blastic phase of chronic myeloid leukaemia by immunophenotyping--experience in 60 patients.

The blast cell population of 60 patients with chronic myeloid leukaemia in blast crisis (CML-BC) were analyzed with a panel of monoclonal antibodies to determine the cell surface antigen phenotypes. In addition, cytochemical stains periodic acid Schiff (PAS), myeloperoxidase (MP), Sudan black B (SBB) and terminal deoxynucleotidyl transferase (TdT) were also utilized for subtyping. Nineteen cases (31.6%) expressed lymphoid phenotypes characteristic of common ALL cells and one case with extramedullary lymph node crisis expressed T-cell surface phenotypes. Thirty cases (50%) expressed solely myelomonocytic surface antigens with significant TdT activity in three. Cytochemical stains contributed to recognize only 57% of these myeloid blasts. Seven cases (11.7%) were with a mixture of heterogenous group of cells expressing phenotypic characteristics for various haemopoietic cells of different lineage--five of them from the cells of non-lymphoid series (myelomono-erythromegakaryocytic series) and the other two with cells from both lymphoid and myeloid series. Additionally, in two cases (3.3%), the precursor cells reacted only with the erythroid monoclonals. Finally, in one case, the blast cells remained unclassified due to nonreactivity with any of the monoclonals used but expressed significant TdT positivity. The response to uniform vincristine and prednisolone (V + P) therapy has shown that lymphoid blast crisis cases were highly responsive in contrast to the cases with non-lymphoid blast crisis (complete remission rate 86 vs 21.4%). The results confirm the evidence of multilineage blast crisis involving either single or mixed haemopoietic differentiation pathway and the utility of having phenotypic characterisation for designing protocols for chemotherapy in the CML patients at the time of blast crisis.

Epidemic iatrogenic Acinetobacter spp. meningitis following administration of intrathecal methotrexate.

We report the first outbreak of Acinetobacter species meningitis in a group of children with acute leukaemia following the administration of intrathecal chemotherapy. Eight of twenty patients receiving methotrexate injections on a single day developed signs and symptoms of meningitis within 18 h of treatment, and cases were clustered by time of administration. A cohort study comparing case and non-case patients did not identify any specific host factor associated with meningitis. Acinetobacter calcoaceticus var anitratus was isolated from the cerebrospinal fluid (CSF) of five patients; three patients died. Our investigation determined that the methotrexate was extrinsically contaminated by reused needles, used for reconstitution and administration, which had been inadequately sterilized. Acinetobacter calcoaceticus var anitratus was isolated from an autoclaved needle and a vial of methotrexate used for chemotherapy; these and the clinical isolates had similar antibiograms. After introduction of single-use disposable needles no subsequent cases occurred.