Gene therapy using adeno-associated viral (AAV) vectors is a promising approach for the treatment of monogenic disorders. Long-term multi-year transgene expression has been demonstrated in animal models and clinical studies. Nevertheless, uncertainties remain concerning the nature of AAV vector persistence and whether there is a potential for genotoxicity. Here, we describe the mechanisms of AAV vector persistence in the liver of a severe hemophilia A dog model (male = 4, hemizygous, and female = 4, homozygous), more than a decade after portal vein delivery. The predominant vector form was non-integrated episomal structures with levels correlating with long-term transgene expression. Random integration was seen in all samples (median frequency= 9.3e-4 sites/cell), with small numbers of non-random common integration sites associated with open chromatin. No full-length integrated vectors were found, supporting predominant episomal vector-mediated long-term transgene expression. Despite integration, this was not associated with oncogene upregulation or histopathological evidence of tumorigenesis. These findings support the long-term safety of this therapeutic modality.
Pheniramine is an over-the-counter antihistamine drug. Its accessibility and low cost made it more popular among drug abusers in Pakistan. In this study, pheniramine was quantified in both conventional and alternative specimens of twenty chronic drug abusers, aged 16-50 years, who were positive for pheniramine in comprehensive toxicological screening for drugs by gas chromatography with mass spectral detection in positive electron impact mode. Pheniramine was extracted from biological specimens using solid phase extraction and liquid chromatography tandem mass spectrometry was employed for quantification. Chromatographic separation was carried out on a Poroshell120EC-18 (2.1 mm × 50 mm × 2.7 µm) column using water-acetonitrile in formic acid (0.1%) mobile phase in gradient elution mode with 500 µL/min flow rate. Positive electrospray ionization mode and multi-reaction monitoring with ion transitions m/z 241.3 â 195.8 and 167.1 for pheniramine and m/z m/z 247.6 â 173.1 for pheniramine-d6 were employed. The quantification method showed good linear ranges of 2-1000 ng/mL in blood, urine, and oral fluid; 2-1000 ng/mg in hair and 5-1000 ng/mg in nail with ≥ 0.985% coefficient of linearity. The retention time of pheniramine was 3.0 ± 0.1 min. The detection and lower quantification limits were 1 ng/mL and 2 ng/mL for blood, urine, oral fluid and hair whereas 2.5 ng/mg and 5 ng/mg for nail, respectively. Mean extraction recovery and ionization suppression ranged 86.3-95.1% and -4.6 to -14.4% in the studied matrices. Intra-day and inter-day precision were 4.1-9.3% and 2.8-11.2%, respectively. Pheniramine levels in specimens of drug abusers were 23-480 ng/mL in blood, 72-735 ng/mL in urine, 25-379 ng/mL in oral fluid, 10-170 ng/mg in hair and 8-86 ng/mg in nail specimens. Alternative specimens are of utmost significance in clinical and medico-legal cases. In this study, authors compared matrix-matched calibration curves to blood calibration curve and obtained results within ± 10%; thereby justifying the use of blood calibration curve for urine, oral fluid, hair, and nail specimens.
AKR1B1 and AKR1B10 are important members of aldo-keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule's reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of - 30.84 and - 29.36 kJ/mol respectively. To validate the stability of the protein-ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings.
BACKGROUND: Influenza and tuberculosis both cause significant morbidity and mortality worldwide. Therefore, this study aimed to estimate the burden of influenza A (H1N1)pdm09 virus infection among human tuberculosis patients and the general population. METHODS: A prospective cohort study was conducted among a cohort group (TB positive patients) as exposed and a comparison group (general population) as non-exposed. A total of 304 participants were recruited in both groups and followed for a period of 12 weeks. Of the 304 concurrently enrolled individuals, 152 were TB-positive patients (cohort group) and 152 were from the general population (comparison group).To calculate the sample size, the power of study was kept at 80% for detecting a difference at 5% alpha level assuming the 25% prevalence of respiratory viruses in cohort group compared to 12.5% in general population. An oropharyngeal swab was taken from a participant with symptoms of influenza-like illness (ILI). Samples were tested by conventional reverse transcription polymerase chain reaction (RT-PCR) for the detection of influenza A (H1N1)pdm09. All statistical analyses were conducted using R software. RESULTS: A total of 95 participants developed influenza-like illness (ILI) symptoms. Among these, 64 tested positive for influenza A(H1N1)pdm09, of which 39 were from the exposed group and 25 were from the non-exposed group. During the 12-week period of follow-up, the influenza A (H1N1)pdm09 incidence rate was 20 per 1000 people. The risk of testing positive for influenza A (H1N1)pdm09 was 1.66 times higher in the exposed group compared to the non-exposed group. The cumulative incidence indicated that 25% of the TB cohort and 16% of the comparison group were at risk of getting influenza A (H1N1)pdm09 during the 12 weeks of follow-up. CONCLUSION: Participants from the TB cohort had a higher incidence of influenza A (H1N1)pdm09 than the general population suggesting that they should be prioritized for influenza vaccination.
Influenza A Virus, H1N1 Subtype , Influenza, Human , Tuberculosis , Virus Diseases , Humans , Influenza, Human/complications , Influenza, Human/epidemiology , Prospective Studies , Tuberculosis/epidemiology
A new compound, C23H20BrN3OS, containing a quinoline-based iminothiazoline with a thiazoline ring, was synthesized and its crystal and molecular structures were analyzed through single crystal X-ray analysis. The compound belongs to the triclinic system P - 1 space group, with dimensions of a = 9.2304 (6) Å, b = 11.1780 (8) Å, c = 11.3006 (6) Å, α = 107.146 (5)°, ß = 93.701 (5)°, γ = 110.435 (6)°, Z = 2 and V = 1025.61 (12) Å3. The crystal structure showed that C-H···N and C-H···O hydrogen bond linkages, forming infinite double chains along the b-axis direction, and enclosing R22(14) and R22(16) ring motifs. The Hirshfeld surface analysis revealed that H H (44.1%) and H C/C H (15.3%) interactions made the most significant contribution. The newly synthesized (Z)-4-bromo-N-(4-butyl-3 (quinolin-3-yl)thiazol-2(3H)-ylidene)benzamide, in comparison to oleanolic acid, exhibited more strong potential against elastase with an inhibition value of 1.21 µM. Additionally, the derivative was evaluated using molecular docking and molecular dynamics simulation studies, which showed that the quinoline based iminothiazoline derivative has the potential to be a novel inhibitor of elastase enzyme. Both theoretical and experimental findings suggested that this compound could have a number of biological activities.
Lithium (Li) is the lightest alkali metal and 27th most abundant element in the earth crust. In traces, the element has medicinal value for various disorders in humans, however, its higher concentrations may lead to treatment-resistant depression and altered thyroid functioning. Quinoa (Chenopodium quinoa) has gained popularity owing to its halophytic nature and its potential use as an alternative to the traditional staple foods. However, quinoa response to Li-salt in terms of growth, Li accumulation potential and health risks associated with consumption of the quinoa seeds grown on Li-contaminated soils has not been explored yet. During this study, quinoa was exposed to various concentrations of Li (0, 2, 4, 8 and 16 mM) at germination as well as seedling stages. The results showed that seed germination was the highest (64% higher than control) at Li concentration of 8 mM. Similarly, at 8 mM doses of Li shoot length, shoot dry weight, root length, root dry weight and grain yield were increased by 130%, 300%, 244%, 858% and 185% than control. It was also revealed that Li increased the accumulation of calcium and sodium in quinoa shoots. Carotenoids contents were increased, but chlorophyll contents remained un-changed under Li application. The activities of antioxidants viz. Peroxide dismutase, catalase and super oxide dismutase were also increased with an increase in the levels of Li in the soil. Estimated daily intake and hazard quotient of Li in quinoa were less than the threshold level. It was concluded that Li concentration of 8 mM is useful for quinoa growth and it can be successfully grown on Li contaminated soils without causing any human health risks.
Chenopodium quinoa , Humans , Chenopodium quinoa/metabolism , Lithium , Bioaccumulation , Antioxidants/metabolism , Soil
Stunting in children under five years of age is a significant health problem in many middle and low-income countries worldwide. The study aimed to analyse the prevalence and predictors of stunting in children under five years of age. Preferred reporting items for Systematic Reviews and Meta-Analyses (PRISMA Checklist 2020) were used for data reporting and analysis. Medline, PubMed, Google Scholar, PakMedinet, and direct websites of local journals were searched for relevant publications from 1996 to March 2022. A random-effect model was employed to generate a pooled prevalence and was presented as a percent and 95% confidence interval (CI). A total of thirty-three studies were selected for systematic review. Out of these, nine studies were selected from the last five years to estimate pooled prevalence in children under five years of age. The overall pooled prevalence was 39.11% (95% CI: 33.017 to 45.394). A significant heterogeneity with I2 = 99.39%, p <0.0001, was found among the studies. The remaining twenty-four studies with the prevalence of stunting under five years of age were also divided into two groups based on the age range, either <2 years or 2-5 years of age. The pooled prevalence was 39.11%. Mother's education was the most frequent predictor (85%), followed by socioeconomic status (64 %), breastfeeding (55%), and the weight of the child at birth (40%). Key Words: Prevalence, Predictors, Stunting, Children under five years, Systematic review.
Breast Feeding , Growth Disorders , Female , Infant, Newborn , Pregnancy , Child , Humans , Child, Preschool , Prevalence , Growth Disorders/epidemiology , Parturition
We assessed the efficacy and safety of PB compared with benzodiazepine (BZD)-based protocols in treating AWS in MICU. DESIGN: Single-center, pre-post protocol implementation study. SETTING: The setting is a forty-bed MICU in a tertiary-level academic medical center. PATIENTS: We included all patients admitted to the MICU with a primary diagnosis of AWS. INTERVENTIONS: Intravenous PB 260 mg followed by 130-mg doses every 15-30 minutes as needed up to 15 mg/kg of ideal body weight versus escalating doses of BZD, to achieve a Clinical Institute Withdrawal Assessment Alcohol Scale-Revised score less than 10. MEASUREMENTS AND MAIN RESULTS: ICU and hospital length of stay (LOS), in addition to safety measures were the main outcomes of the study. A total of 102 patients were included, 51 in the PB arm and 51 in the BZD arm. There were no differences in baseline clinical characteristics. Half the patients in each group were admitted with delirium tremens. The use of PB-based protocol was associated with 35% reduction in median ICU LOS (1.5 d [interquartile range, 1.2-2.4 d] vs 2.3 d [1.4-4.8 d]; p = 0.009) and 50% reduction in hospital LOS (3 d [2.7-4 d] vs 6 d [4-10 d]; p < 0.001). After adjustment for comorbidities and clinical factors, PB protocol decreased ICU LOS days by 40% (95% CI; 25.8-53.5%). PB group required fewer adjunctive medications to control symptoms (0.7 [0.5-1] vs 2.5 [2-3]; p < 0.001), less need for intubation (1/51 [2%] vs 10/10 [19.6%]; p = 0.023) and less need for physical restraint (19/51 [37.3%] vs 29/51 [56.9%]; p = 0.047), compared with the BZD group. CONCLUSIONS: A protocol utilizing rapidly escalating doses of PB over a short period is an effective and safe alternative to BZD in treating AWS in MICU.
Psychiatric morbidity commonly coexists with substance abuse and HIV/AIDS around the globe. This review study aimed to determine the available literature on the prevalence of common substance abuse/use and common mental health illnesses among HIV/AIDS patients worldwide to help policymakers design appropriate strategies to limit extensive substance use and prevent common mental and health illnesses. For the comprehensive literature review, Google Scholar, PubMed Central, Medline, and PakMediNet biomedical databases were searched for original and reviewed studies published in English, from January 2000 to September 2021. Selections of studies and extraction of data from the studies were performed based on quality and inclusion criteria. MedCalc Meta-analysis Software Package version 20.009 was used for data analysis. Out of 103,024 HIV/AIDS patients inspected in 30 studies, 6430 HIV/AIDS patients had pooled prevalence of depression 30.31% (95%CI: 26.028 to 34.786), and 6927 study participants reported the overall current pooled prevalence of any substance use was 25.13% (95%CI: 11.526 to 41.897), respectively. Current alcohol consumption and tobacco smoking are the most common substance abuse, and depression and anxiety are the most common mental health disorders among HIV/AIDS patients. There was no significant publication bias, but substantial heterogeneity was observed in the presented studies. The current systematic review and meta-analysis showed a greater prevalence of substance abuse and mental health illnesses among HIV/AIDS patients than the general population at the global level. Key Words: Substances, Substance use, Substance abuse, Alcohol abuse, Tobacco smoking, HIV/AIDS, Depression, Anxiety, Mental health, HIV/AIDS, Worldwide.
Acquired Immunodeficiency Syndrome , HIV Infections , Mental Disorders , Substance-Related Disorders , Humans , Acquired Immunodeficiency Syndrome/epidemiology , HIV Infections/epidemiology , HIV Infections/psychology , Mental Health , Mental Disorders/epidemiology , Substance-Related Disorders/epidemiology , Anxiety/epidemiology , Prevalence
Soil salinity, drought, and increasing temperatures are serious environmental issues that drastically reduce crop productivity worldwide. Quinoa (Chenopodium quinoa Willd) is an important crop for food security under the changing climate. This study examined the physio-biochemical responses, plant growth, and grain yield of four quinoa genotypes (A7, Titicaca, Vikinga, and Puno) grown in pots containing normal (non-saline) or salt-affected soil exposed to drought and elevated-temperature treatments. Combinations of drought, salinity, and high-temperature stress decreased plant growth and yield more than the individual stresses. The combined drought, salinity, and heat stress treatment decreased the shoot biomass of A7, Puno, Titicaca, and Vikinga by 27, 36, 41, and 50%, respectively, compared to that of control plants. Similar trends were observed for grain yield, chlorophyll contents, and stomatal conductance. The combined application of these three stresses increased Na concentrations but decreased K concentrations in roots and shoots relative to control. Moreover, in the combined salinity, drought, and high-temperature treatment, A7, Puno, Titicaca, and Vikinga had 7.3-, 6.9-, 8-, and 12.6-fold higher hydrogen peroxide contents than control plants. All four quinoa genotypes increased antioxidant enzyme activities (CAT, SOD, and POD) to overcome oxidative stress. Despite A7 producing the highest biomass under stress, it did not translate into increased grain production. We conclude that Puno and Titicaca are more tolerant than Vikinga for cultivation in salt-affected soils prone to drought and heat stress.
Health Care Professionals (HCPs), including doctors, nurses, pharmacists, and paramedics, are a high-risk group for influenza infection due to their continuous exposure to patients having a known or unknown history of influenza-like illnesses. Influenza vaccination is the most effective method of primary prevention. This study was conducted to assess knowledge, attitude, practice, and barriers associated with influenza vaccination among HCPs at tertiary care hospitals in Lahore, Pakistan. A multicenter analytical cross-sectional study was conducted among HCPs. Data were collected using a structured questionnaire. All statistical analyses were conducted in R software. A total of 400 HCPs were enrolled, and among these, 67% had a high level of knowledge and 65.5% had a positive attitude towards influenza vaccination. About 51% of HCPs adopted good practices leading to influenza vaccination. Results identified major barriers for influenza vaccinations, including unfamiliarity with vaccine availability (RII = 0.760), insufficient staff for administering the vaccine (RII = 0.649), lack of proper storage (RII = 0.625), safety concerns (RII = 0.613), and cost of vaccine (RII = 0.602). More than half of the HCPs showed a high level of knowledge, a positive attitude, and good practice against influenza vaccination. Despite the positive Knowledge, Attitude, and Practice (KAP) scores and published guidelines, a very low percentage of HCPs were vaccinated against influenza. Many hindering factors were associated with influenza vaccination.
BACKGROUND: Human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) is still among the leading causes of disease burden and mortality in sub-Saharan Africa (SSA), and the world is not on track to meet targets set for ending the epidemic by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the United Nations Sustainable Development Goals (SDGs). Precise HIV burden information is critical for effective geographic and epidemiological targeting of prevention and treatment interventions. Age- and sex-specific HIV prevalence estimates are widely available at the national level, and region-wide local estimates were recently published for adults overall. We add further dimensionality to previous analyses by estimating HIV prevalence at local scales, stratified into sex-specific 5-year age groups for adults ages 15-59 years across SSA. METHODS: We analyzed data from 91 seroprevalence surveys and sentinel surveillance among antenatal care clinic (ANC) attendees using model-based geostatistical methods to produce estimates of HIV prevalence across 43 countries in SSA, from years 2000 to 2018, at a 5 × 5-km resolution and presented among second administrative level (typically districts or counties) units. RESULTS: We found substantial variation in HIV prevalence across localities, ages, and sexes that have been masked in earlier analyses. Within-country variation in prevalence in 2018 was a median 3.5 times greater across ages and sexes, compared to for all adults combined. We note large within-district prevalence differences between age groups: for men, 50% of districts displayed at least a 14-fold difference between age groups with the highest and lowest prevalence, and at least a 9-fold difference for women. Prevalence trends also varied over time; between 2000 and 2018, 70% of all districts saw a reduction in prevalence greater than five percentage points in at least one sex and age group. Meanwhile, over 30% of all districts saw at least a five percentage point prevalence increase in one or more sex and age group. CONCLUSIONS: As the HIV epidemic persists and evolves in SSA, geographic and demographic shifts in prevention and treatment efforts are necessary. These estimates offer epidemiologically informative detail to better guide more targeted interventions, vital for combating HIV in SSA.
Acquired Immunodeficiency Syndrome , HIV Infections , Male , Female , Adult , Humans , Pregnancy , Adolescent , Young Adult , Middle Aged , HIV , Acquired Immunodeficiency Syndrome/epidemiology , Prevalence , Seroepidemiologic Studies , HIV Infections/prevention & control , Africa South of the Sahara/epidemiology
The enteric system residing notorious Salmonella typhimurium (S. typhi) is an intracellular, food-borne, and zoonotic pathogen causing typhoid fever. Typhoid fever is one of the leading causes of mortality and morbidity in developing and underdeveloped countries. It also increased the prevalence of multidrug resistance globally. Currently, available anti-bacterial modalities are unable to penetrate into the intracellular compartments effectively for eradicating S. typhi infection. Therefore, in this study, we developed nanostructured lipid-based carriers in the form of a self-nanoemulsifying drug delivery system (SNEDDS) for targeted delivery of ciprofloxacin (CIP) into the S. typhi intracellular reservoirs. Capryol 90, Tween 80, and Span 20 were finalized as suitable oil, surfactant, and co-surfactant, respectively, according to the pseudoternary phase diagram emulsifying region. Targeting capability and mucopenetration of the SNEDDS was attributed to the inclusion of amidated pluronic (NH2-F127). Developed NH2-F127 SNEDDS were characterized via physicochemical, in vitro, ex vivo, and in vivo evaluation parameters. The size of the SNEDDS was found to be 250 nm, having positively charged zeta potential. In vitro dissolution of SNEDDS showed 80% sustained release of CIP in 72 h with maximum entrapment efficiency up to 90% as well as good hemocompatibility by showing less than 0.2% hemolysis and 90% biocompatibility. The survival rate of S. typhi in macrophages (RAW 264.7) was minimal, i.e., only 2% in the case of NH2-F127 SNEDDS. Macrophage uptake assay via nanostructures confirmed the maximum cellular uptake as evidenced by the highest fluorescence. Biofilm dispersion assay showed rapid eradication of developed resistant biofilms on the gall bladder. In vivo pharmacokinetics showed improved bioavailability by showing an increased area under the curve (AUC) value. Taken together, NH2-F127-SNEDDS can be utilized as an alternative and efficient delivery system for the sustained release of therapeutic amounts of CIP for the treatment of S. typhi.
Introduction: The process of learning begins in childhood and accurate vision can greatly affects a child's learning capacity. It is documented that visual impairment in children can have a significant impact on their performance at school as well as their social interaction and development. Objective: This research aimed to study the impact of refractive corrections on the academic performance of high school children in Lahore. Methodology: A total of 2,000 students with equal distribution of gender, public, private school, and locality were included in the study. All students were screened for defective vision. The academic performance before and after corrections was recorded on the prescribed proforma. Results: The prevalence of refractive error was high among the public high schools 244 (59.2%) as compared to the private schools 168 (40.8%). The area-based prevalence was higher among the students in urban settings 255 (62%) while in rural it was 157 (38%). It was found that in the public sector, the average score of academic results before the intervention was 56.39 ± 13.24 which was increased to 60.27 ± 14.94 after the intervention while in the private sector, before the intervention, the average score was 63.53 ± 17.50 which was improved to 67.12 ± 18.48. It was found to be statistically significant at p-value < 0.05. Conclusion: A significant impact was observed in the average academic scores of the results after refractive corrections.
Academic Performance , Refractive Errors , Child , Cross-Sectional Studies , Humans , Refractive Errors/epidemiology , Rural Population , Schools
Fungal infections have increased in number since the onset of this lethal pandemic. This study aimed to assess risk factors and case fatality in COVID-19 cases with aspergillosis or mucormycosis. A systematic review was done according to PRISMA guidelines. Databases used were Google scholar, Pakmedinet, PUBMED, and MEDLINE. Twenty-one case reports and case series of mucormycosis in COVID-19 patients were identified and the mean age was 56.3 years (36 men and 12 women). The most common comorbidity was diabetes and the site was rhino orbital mucormycosis. Case fatality of 48 combined cases was calculated to be 52%. Nineteen articles of aspergillosis were included. Diabetes was the most common comorbidity in cases. The number of affected men cases was more than women. The incidence of aspergillosis in critically sick COVID-19 patients was calculated to be 9.3%. Case fatality was calculated to be 51.2%. Screening can be a beneficial tool for decreasing morbidity and mortality. Key Words: COVID-19, Mucormycosis, Aspergillosis.
Aspergillosis , COVID-19 , Diabetes Mellitus , Mucormycosis , Diabetes Mellitus/epidemiology , Female , Humans , Male , Middle Aged , Mucormycosis/diagnosis , Mucormycosis/epidemiology , SARS-CoV-2
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy mainly occurring at an advanced age with no single major genetic driver. Transgenic expression of TCL1 in B cells leads after a long latency to a CLL-like disease in aged Eµ-TCL1 mice suggesting that TCL1 overexpression is not sufficient for full leukemic transformation. In search for secondary genetic events and to elucidate the clonal evolution of CLL, we performed whole exome and B-cell receptor sequencing of longitudinal leukemia samples of Eµ-TCL1 mice. We observed a B-cell receptor stereotypy, as described in patients, confirming that CLL is an antigen-driven disease. Deep sequencing showed that leukemia in Eµ-TCL1 mice is mostly monoclonal. Rare oligoclonality was associated with inability of tumors to develop disease upon adoptive transfer in mice. In addition, we identified clonal changes and a sequential acquisition of mutations with known relevance in CLL, which highlights the genetic similarities and therefore, suitability of the Eµ-TCL1 mouse model for progressive CLL. Among them, a recurrent gain of chromosome 15, where Myc is located, was identified in almost all tumors in Eµ-TCL1 mice. Interestingly, amplification of 8q24, the chromosomal region containing MYC in humans, was associated with worse outcome of patients with CLL.
Clonal Evolution , Gain of Function Mutation , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins/metabolism , Animals , Chromosomes , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Proto-Oncogene Proteins/genetics
Importance of extracellular nucleotides is widely understood. These nucleotides act as ligand for P2X and P2Y receptors and modulate a variety of biological functions. However, their extracellular concentration is maintained by a chain of enzymes termed as ecto-nucleotidases. Amongst them, nucleoside triphosphate diphosphohydrolases (NTPDases) is an important enzyme family responsible for the dephosphorylation of these nucleotides. Overexpression of NTPDases leads to many pathological conditions such as cancer and thrombosis. So far, only a few NTPDase inhibitors have been reported. Considering this scarcity of (NTPDase) inhibitors, a number of thiadiazole amide derivatives were synthesized and screened against human (h)-NTPDases. Several compounds showed promising inhibitory activity; compound 5a (IC50 (µM); 0.05 ± 0.008) and 5g (IC50 (µM); 0.04 ± 0.006) appeared to be the most distinguished molecules corresponding to h-NTPDase1 and -2. However, h-NTPDase3 was the least susceptible isozyme and only three compounds (5d, 5e, 5j) strongly inhibited h-NTPDase3. Interestingly, compound 5e was recognized as the most active compound that showed dual inhibition against h-NTPDase3 as well as against h-NTPDase8. For better comprehension of binding mode of these inhibitors, most potent inhibitors were docked with their respective isozyme.
Adenosine Triphosphatases/antagonists & inhibitors , Amides/pharmacology , Apyrase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Thiadiazoles/pharmacology , Adenosine Triphosphatases/metabolism , Amides/chemical synthesis , Amides/chemistry , Apyrase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry
The COVID-19 pandemic is one of the unprecedented devastating catastrophes with severe public health threat globally. Low and middle income countries (LMICs) are trying hard to cope with the rapidly changing global scenario and trying to mitigate this double crisis of pandemic and economic recession. This pandemic, has led to major changes in global and regional health care delivery proceedings with surge in telemedicine to provide the required services and also giving priority to control the disease spread.
Quinoline derivatives have interesting biological profile. In continuation for the comprehensive evaluations of substituted quinoline derivatives against human nucleoside triphosphate diphosphohydrolases (h-NTPDases) a series of substituted quinoline derivatives (2a-g, 3a-f, 4, 5a-c, 6) was synthesized. The inhibitory activities of the synthesized compounds were evaluated against four isoenzymes of human nucleoside triphosphate diphosphohydrolases (h-NTPDases). These quinoline derivatives had IC50 (µM) values in the range of 0.20-1.75, 0.77-2.20, 0.36-5.50 and 0.90-1.82 for NTPDase1, NTPDase2, NTPDase3 and NTPDase8, respectively. The derivative 3f was the most active compound against NTPDase1 (IC50, 0.20 ± 0.02 µM) that also possessed selectivity towards NTPDase1. Similarly, derivative 3b (IC50, 0.77 ± 0.06), 2h (IC50, 0.36 ± 0.01) and 2c (IC50, 0.90 ± 0.08) displayed excellent activity corresponding to NTPDase2, NTPDase3 and NTPdase8. The compound 5c emerged as a selective inhibitor of NTPDase8. The most active compounds were then investigated to determine their mode of inhibition and finally binding interactions of the active compounds were analyzed through molecular docking studies. The obtained results strongly support the quinoline scaffold's potential as potent and selective NTPDase inhibitor.
Adenosine Triphosphatases/antagonists & inhibitors , Apyrase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Quinolines/pharmacology , Adenosine Triphosphatases/metabolism , Apyrase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity Relationship
IMPORTANCE: In-hospital cardiac arrest survival among coronavirus disease 2019 patients has been reported to range from 0% to 12%. These numbers are significantly lower than reported prepandemic in-hospital cardiac arrest survival rates of approximately 20-25% in the United States for non-coronavirus disease 2019 patients. OBJECTIVE: To assess the incidence of in-hospital cardiac arrest survival of coronavirus disease 2019 patients. DESIGN: A retrospective cohort study of adult patients with coronavirus disease 2019 subsequently found to have in-hospital cardiac arrest and underwent cardiopulmonary resuscitation (cardiopulmonary resuscitation). SETTING: Multiple hospitals of the Cleveland Clinic Health System. PATIENTS: All adult patients (age ≥ 18 yr) admitted to Cleveland Clinic Health System with a diagnosis of coronavirus disease 2019 who experienced in-hospital cardiac arrest requiring cardiopulmonary resuscitation. MEASUREMENTS AND MAIN RESULTS: From March 01, 2020 to October 15, 2020, 3,555 patients with coronavirus disease 2019 were hospitalized; 1,372 were admitted to the ICU; 58 patients had in-hospital cardiac arrest. Median age of this cohort was 66.5 years (interquartile range, 55.0-76.0 yr). Patients were predominantly male (62.5%), White (53.4%), with a median body mass index of 29.7 (interquartile range, 25.8-34.6). Most in-hospital cardiac arrests were in critical care environments (ICU), 51 of 58 (87.9%); seven of 58 (12.1%) were on ward locations. Thirty-four of 58 patients (58.6%) were on mechanical ventilation prior to in-hospital cardiac arrest with a median duration of mechanical ventilation of 9 days (interquartile range, 2-18 d). Twenty-four of 58 patients (44%) were on vasopressors prior to arrest. Initial arrest rhythm was pulseless electrical activity at (63.8%), asystole (29.3%), and pulseless ventricular tachycardia/fibrillation (6.9%). Of the 58 patients, 35 (60.3%) attained return of spontaneous circulation, and 13 of 58 (22.4%) were discharged alive. CONCLUSIONS: We report a 22% survival to discharge after in-hospital cardiac arrest in coronavirus disease 2019 patients, a survival rate similar to before the coronavirus disease 2019 pandemic.
