Magnitude Of Adverse Effects Research Articles

Halofuginone micelle nanoparticles eradicate Nrf2-activated lung adenocarcinoma without systemic toxicity

The Keap1-Nrf2 system is the master regulator of the cellular response against oxidative and xenobiotic stresses. Constitutive activation of Nrf2 is frequently observed in various types of cancers. Nrf2 hyperactivation induces metabolic reprogramming in cancer cells, which supports the increased energy demand required for rapid proliferation and confers high-level resistance against anticancer radio/chemotherapy. Hence, Nrf2 inhibition has emerged as an attractive therapeutic strategy to counter such acquired resistance in Nrf2-activated tumors. We previously identified Halofuginone (HF) as a promising Nrf2 inhibitor. In this study, we pursued preclinical characterization of HF and found that while HF markedly reduced the viability of cancer cells, it also caused severe hematopoietic and immune cell suppression in a dose-dependent manner. Hence, to overcome this toxicity, we decided to employ a nanomedicine approach to HF. We found that encapsulation of HF into a polymeric micelle (HF micelle; HFm) largely relieved the systemic toxicity exhibited by free HF while maintaining the tumor-suppressive properties of HF. LC-MS/MS analysis revealed that the reduction in the magnitude of adverse effects was the result of the ability to release HF from the HFm core in a slow and sustained manner. These results thus support the contention that HFm will potentially counteract Nrf2-activated cancers in the clinical settings.

PANDEMIC (COVID-19) EFFECT ON FINANCIAL STATEMENTS: THE ROLE OF GOVERNMENT AND ORGANIZATIONS FOR FUTURE PREVENTION

COVID-19 pandemic period impedes business operations and world economic growth. This type of pandemic may happen again in the future. Hence, the objectives of the study are to find out the pandemic effect on items in financial statements; to predict the future effect on items in the financial statements, and to find out the role of government and organizations for future prevention of the adverse effects on financial statements due to the pandemic. The analysis is based on a large number of publicly available sources, including research papers, governmental documents, and reports. The study has taken 8 ratios compared with 80 listed companies around the globe. During the pandemic period the magnitude of adverse effect on business operations depends upon the decision and actions of external bodies (WHO, governments) and internal ones (organizations) parties. The findings revealed that the role of government and organizations for future prevention of ‘Pandemic Effect on Financial Statements’ is vital to defend against future pandemic situations. This study has added a new discussion to the body of knowledge, i.e. examining pandemic (COVID-19) effect on business operational activities and its financial statements; hence, an approach that is not widely discussed in the previous studies.

USING LIVE IMAGING AND FUCCI ESC TO PROVIDE DIRENESS AND STIMULATION INDICES THAT REPORT THAT PFOA HAS GREATER ADVERSE EFFECTS THAN THE PHTHALATE DEP

Di ethyl phthalate (DEP) and perfluorooctanoic acid (PFOA) were tested for speed and magnitude of adverse effects using Fluorescence Ubiquitinated Cell-Cycle Indicator (FUCCI) mouse embryonic stem cells (ESC) during culture in a live imager.

Study of the principles in the first phase of experimental pharmacology: the basic step with assumption hypothesis

BackgroundExperimental pharmacology deals with effects of various test substances studied on different animal species which is aimed at finding out safe therapeutic agent suitable for public health as well as mechanism and site of action of a test substance. It is the basic step in the discovery of new drugs or studying the pharmacological actions of already developed one using both preclinical and clinical study designs in a stepwise phase of investigations. However, the investigations in the first phase of experimental pharmacology are usually concluded with assumption hypothesis without any adequate validation of the scientific evidence. Single dose acute toxicology had been conducted on Balb c mice with three different level of doses prepared from each of three different test chemicals (Dichlorvos, Chlorpyrifos and Cypermethrin) with known median lethal dose (LD50) to define the fundamental principles, cause of toxicity and investigation timeframe in the first phase of experimental pharmacology.MethodsThe methods used for data collection were: procurement of test chemicals, investigation of single dose acute toxicity on Balb c mice and quantitative immunoglobulins test. Data was thematically compiled for validation of the findings from each of the sources.ResultsThe result showed that the dose had never limited the toxic property of tested chemicals but the magnitude of adverse effect and length of time at which adverse effect was manifested on treated Balb c mice. The toxicity of tested chemicals was however limited by the toxic reaction rate of a dose in the biological process of exposed Balb c mice. The toxic effect of tested chemicals became magnified within a short period of time when large amount administered orally. It also remained after a long period of time when small amount administered in the same route.ConclusionAdequate investigation time for acute toxicity study was therefore essential for comprehensive analysis of pharmacological property of tested chemicals at different level of doses.

Viewing evidence of harm accompanying uses of glyphosate-based herbicides under US legal requirements

Some epidemiological experts feel there is sufficient proof that glyphosate use adversely affects human health, and glyphosate has been labeled as probably carcinogenic by the International Agency for Research on Cancer. Federal law in the United States provides two major options under which health concerns about glyphosate use might be addressed. First, registrations of glyphosate-based herbicides (GBHs) need to be cancelled if the costs are greater than its benefits. Since the cancellation of GBH registrations in the United States would lead to higher maize and soybean prices that would adversely affect food security, further analyses are needed. Second, US law requires consideration of the human dietary risk from pesticide residues, and tolerances of allowable amounts of glyphosate residues allowed to remain in or on food items have been established. Social cost curves depicting three options for regulating GBHs show preferred strategies dependent upon the magnitude of adverse effects on human health and food insecurity. Measures to reduce harm to humans can be identified to ameliorate health damages to allow some uses of GBHs to continue, but only if the evidence supports the conclusion that “no harm will result from aggregate exposure to the pesticide chemical residue.”

Efficacy of Complementary Therapies in the Quality of Life of Breast Cancer Survivors.

Breast cancer (BC) is the most common cancer diagnosed in women and the second most common cancer overall, ranking as the fifth cause of death from cancer. The chronicity of the disease produces long-term physiological and psychological manifestations, which adversely affect the quality of life of the individual. The primary treatment while managing cancer presents with various debilitating side effects. With the recent advances in treatment techniques that have improved the survival rate, patients suffer from continuing posttreatment complications. Patients seem to cope well with the stress of treatment of BC and sustain a normal life; however, the deterioration in physical well-being makes the patient functionally inefficient. Exercise has been proven to be an effective, safe, and feasible tool in combating the adverse effects of treatment, prevents complications and decreases the risk of BC-specific mortality. This review briefly presents an overview of the burden of the disease and its management strategies. Owing to the heterogeneity of the population and the multitude of therapies they receive, the response of each patient to treatment is different and so is the magnitude of adverse effects. The review discusses the late sequelae following treatment and evidence supporting the role of physical activity in their management. In conclusion, there is a need for personalized physical activity plans to be developed to suit the individual and their circumstances.

Longterm study of transformation of potentially toxic element pollution in soil/water/sediment system by means of fractionation with sequential extraction procedures

In first part of the paper a review is given on fractionation methodologies by sequential extraction methodologies applied for risk assessment of environmental pollution by potentially toxic elements (PTE). Main sources of PTE release are the mining-, industrial-, agri-food production-, traffic- and communal-waste. In this latter the medical and health care sources may emerge due to therapeutic and diagnostic applications (Ag, As, Au, Ba, Bi, Cd, Ga, Gd, 131I, Ir, Li, Mn, Fe, Os, Pd, Pt, Rh, Ru, Sb, Sn, Ti, V), to nanomedicines, to ayurvedic herbal medicines with possible contaminant PTEs and non-controlled dietary supplements. The magnitude of adverse effects caused by PTEs in the soil-water-sediment system depends on the various chemical species that can arise. Long-term biological impacts are strongly influenced by mobilization-immobilization processes in the aquatic environment. These can be studied through sequential extraction procedures modelling their pathways. In Europe the simplified extraction scheme proposed by BCR in 1993 and modified in 2001 is mostly used for this purpose. By this approach samples are gradually decomposed and four different fractions of PTEs can be identified, i.e.: i) water-soluble and carbonate-bound fraction; ii) fraction associated with reducible Fe- and Mn-oxides; iii) organic complexed fraction and sulphides; iv) fraction soluble in oxidative acids. The sediment-based Certified Reference Material (CRM) BCR 701 was produced to check the accuracy of the fractionation procedure. The standardization process was hindered by methodological problems, i.e.: i) the solvents used in the BCR system do not mirror completely the natural mobilization processes and partly modify the original chemical species; ii) the time demand of the batch leaching extraction steps is exceedingly long (4–5days); iii) the above CRM, certified for the fractionation of Cu, Cd, Cr, Ni, Pb and Zn, is available only for sediment and cannot be applied to other environmental matrices and other PTEs. The studies aimed at improving the BCR methodology are summarized, in particular to: i) develop continuous flow systems; ii) accelerate the BCR leaching steps by sonication; iii) extend the BCR procedure to other environmental matrices (soils, red mud, composts, biofilms) and further PTEs by multielemental (ICP-OES) detection.In second part of the paper a case study is presented for evaluation of long-term changes of the environmental mobility of PTE contaminations in the fish pond system of Gödöllő town. For vertical and horizontal mapping of PTE content of accumulated sediment layers core samples were taken in 1994, 1995 and 2013. In the sediment layers total soluble PTE content was related to the BCR fractionation. The Chernobyl origine radionuclides were detected by γ-spectroscopy. The BCR sequential extraction procedure for tracking the long-term fate of PTE contamination of different origine in surface water/sediment/systems showed a much potential. By repetition of fractionation of PTEs after 20years clearly reflects the change of PTE concentrations in different fractions. The decrease of PTE concentrations can be explained by leaching the most mobile fractions by water exchange over the sediment and/or by remediation activity.

Cisplatin, Methotrexate and Bleomycin for Advanced Recurrent or Metastatic Penile Squamous Cell Carcinoma

Objective: This study aimed to evaluate the efficacy and toxicity of cisplatin, methotrexate, and bleomycin (CMB) chemotherapy in patients with advanced, recurrent, or metastatic penile squamous cell carcinoma (PSCC). Methods: The CMB regimen was administered to 12 patients with advanced (n=7), recurrent (n=4), or metastatic (n=1) PSCC. Patients received a total of 21 cycles of CMB between 2002 and 2009, and were retrospectively reviewed for treatment efficacy and toxicity of the drugs. The mean patient age was 61 (61.0 ± 8.7) years. Patients received 20.0 mg/m2 of cisplatin intravenously on days 2-6; 200.0 mg/m2 of methotrexate intravenously on days 1, 15 and 22; and 10.0 mg/m2 of bleomycin as a bolus on days 2-6. The CMB regimen consisted of 21-28 days of treatment per cycle. Survival after CMB therapy and frequency and magnitude of adverse effects were assessed. Results: Of the 7 patients with advanced disease who received the CMB regimen as neoadjuvant and/or adjuvant treatment, 5 survived, 1 died of local recurrence and lung metastasis, and 1 died of interstitial pneumonia. Three of the 5 patients with recurrent or metastatic disease died of PSCC. One patient died of interstitial pneumonia due to CMB. Only 1 patient with inguinal lymph node metastasis after penectomy who underwent adjuvant CMB regimen had survived. Eight patients who were disease free survived longer than those who still had the disease. No adverse hematological effects of Grade 3 or higher were observed. Conclusion: The CMB regimen might be effective for advanced PSCC, but not for recurrent or metastatic PSCC. Two patients died of interstitial pneumonitis due to chemotherapy. Hence, we believe that the CMB regimen should not be used as a first-line treatment option in patients with advanced-stage or metastatic PSCC.

Effects of self-administered methamphetamine on discrimination learning and reversal in nonhuman primates.

Frequent exposure to methamphetamine has been reported to adversely influence cognitive behavior and, in particular, inhibitory control processes. The present studies were conducted in squirrel monkeys to assess the effects of daily intravenous methamphetamine self-administration on touch screen-based repeated acquisition and discrimination reversal tasks thought to reflect behavioral dimensions of, respectively, learning and response inhibition. First, stable methamphetamine-maintained behavior was established in each subject (0.35-1.6 mg/kg/session), and subsequently, a second daily session of discrimination learning was conducted (20 h later). Subjects first learned to discriminate between two simultaneously presented stimuli (acquisition) and, subsequently, to re-learn the discrimination with the contingencies switched (reversal). The role of the interval between self-administration and touch screen sessions was evaluated, as well as the effects of abrupt methamphetamine discontinuation. Results indicate that daily methamphetamine self-administration markedly disrupted the development of discrimination learning, initially requiring nearly twice the number of trials to master discriminations. The magnitude of adverse effects in individual subjects correlated to the level of daily methamphetamine intake. Importantly, however, behavioral disruption of discrimination learning was surmounted following remedial training. Once criterion levels of discrimination performance were achieved, subsequent development of reversal performance was largely unaffected except when the interval between self-administration and touch screen session was short and, thus, likely a result of methamphetamine’s direct effects. Discontinuation of methamphetamine produced no disruption in acquisition or reversal. These results indicate that self-administered methamphetamine can markedly disrupt learning processes and highlight key differences in its effects on different aspects of discrimination learning.

Effects of self‐administered methamphetamine on learning‐to‐learn in the squirrel monkey (661.1)

Long‐term chronic exposure to methamphetamine (MA) has been related to profound neural impact including, but not limited to, damage to monoamine nerve terminals. In turn, neural changes following repeated MA administration may be related to adverse effects on learning and other cognitive performance. However, the characterization of such neurobehavioral deficits remains incomplete. The present study assessed the effects of ongoing MA self‐administration on touchscreen‐based discrimination learning in nonhuman primates. Prior to daily sessions of MA self‐administration (i.e., 20‐hr after the previous day’s session), monkeys engaged in a repeated acquisition task in which changes in the rate of discrimination learning for a stimulus pair were assessed over the successive presentation of novel stimulus pairs. Results thus far indicate that ongoing MA self‐administration produces markedly deleterious effects on the development of learning sets in discrimination learning. Importantly, the magnitude of adverse effects on learning appears to be correlated with the level of daily MA intake among individual subjects.Grant Funding Source: Supported by grant K01‐DA035974 from NIDA

Assessing ecological risks of offshore wind power on Kattegat cod

Offshore wind power is expanding with particular development plans in the Baltic and the North Sea. To reassure an environmentally acceptable development, regulatory authorities need to make informed decisions even when evidence and experience are scarce. In this study Ecological Risk Assessment (ERA) has been applied on a wind farm project in Kattegat, proposed within a spawning ground for the Kattegat cod, a threatened population of Atlantic cod (Gadus morhua L.). Six stressors with potential impacts on cod and related to wind farms were investigated. Three of them – extreme noise from pile driving, noise from vessels, and disturbances due to cable-trenching – are related to the construction phase, while lubricant spills and noise from turbines together with electric fields from cables are related to the operation phase. The ecological risk was derived from the combined likelihood and magnitude of potential adverse effects from stressors to the cod population using a weight-of-evidence (WOE) ranking procedure. Available evidence was evaluated based on its reliability, and contradictory arguments were balanced against each other using evidence maps. The option of performing hazardous construction events (e.g. pile-driving) outside biologically sensitive periods was incorporated in the assessment. It was shown that the construction of the wind farm poses a high risk to cod, as defined by the ranked and combined likelihoods and magnitudes of adverse effects. However by avoiding particular construction events during the cod recruitment period ecological risks can be significantly reduced. Specifically for this case, ecological risks are reduced from high to low by avoiding pile-driving from December through June, which confirms previous indications that pile-driving is the most ecologically hazardous activity of offshore wind power development. Additional risk reduction is achieved by avoiding cable trenching from January through May. The study thus illustrates the effectiveness of time-planning for risk reduction. Importantly, the study illustrates how combined ERA and WOE methods can be valuable for handling uncertainties of environmental impacts within offshore industrial development.

Revision of sediment quality triad indicators in Puget Sound (Washington, USA): I. a Sediment Chemistry Index and targets for mixtures of toxicants

The Washington State Department of Ecology annually conducts sediment quality monitoring in Puget Sound as a component of the Puget Sound Ecosystem Monitoring Program. Sediment samples are analyzed to determine the concentrations of about 170 chemical and physical variables. A Sediment Chemistry Index (SCI) was derived using the State of Washington Sediment Management Standards to account for the presence and concentrations of mixtures of toxicants. Mean Sediment Quality Standard quotients (mSQSq) were calculated as the basis for the SCI and compared to the incidence and degree of toxicity in laboratory tests and to metrics of the diversity and abundance of resident benthic assemblages in a database consisting of as many as 664 samples. These data were evaluated with co-occurrence analyses to identify "cut points" (i.e., thresholds) in the index below which the frequency and magnitude of biological effects were relatively low and above which they occurred with increasing frequency or magnitude. Iterative trials of different sets of cut points established the final cut points in mSQSq of 0.1, 0.3, and 0.5. They defined 4 ranges in chemical exposure: Minimum (<0.1), Low (0.1- < 0.3), Moderate (0.3- < 0.5), and Maximum (≥0.5). Across these 4 exposure ranges both the incidence and magnitude of toxicity in some laboratory tests increased, the abundance of most stress-sensitive benthic taxa decreased, and the abundance of most stress-tolerant taxa increased. The mSQSq cut point of 0.1 appears to be the target value for protection of benthic resources, the value below which the probability and magnitude of adverse effects either in the laboratory or the field are the lowest. The mSQSq values are rescaled from 0 to 100 to form the SCI, used by the Puget Sound Partnership and environmental managers as a Dashboard Indicator, with biologically relevant targets selected to monitor ecosystem recovery.

Adverse Side Effects of 5α‐Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients

5α-reductase inhibitors (5α-RIs), finasteride and dutasteride, have been approved for treatment of lower urinary tract symptoms, due to benign prostatic hyperplasia, with marked clinical efficacy. Finasteride is also approved for treatment of hair loss (androgenetic alopecia). Although the adverse side effects of these agents are thought to be minimal, the magnitude of adverse effects on sexual function, gynecomastia, depression, and quality of life remains ill-defined. The goal of this review is to discuss 5α-RIs therapy, the potential persistent side effects, and the possible mechanisms responsible for these undesirable effects. We examined data reported in various clinical studies from the available literature concerning the side effects of finasteride and dutasteride. Data reported in the literature were reviewed and discussed. Results. Prolonged adverse effects on sexual function such as erectile dysfunction and diminished libido are reported by a subset of men, raising the possibility of a causal relationship. We suggest discussion with patients on the potential sexual side effects of 5α-RIs before commencing therapy. Alternative therapies may be considered in the discussion, especially when treating androgenetic alopecia.

Relevance of Risk Predictions Derived from a Chronic Species Sensitivity Distribution with Cadmium to Aquatic Populations and Ecosystems

Criteria to protect aquatic life are intended to protect diverse ecosystems, but in practice are usually developed from compilations of single-species toxicity tests using standard test organisms that were tested in laboratory environments. Species sensitivity distributions (SSDs) developed from these compilations are extrapolated to set aquatic ecosystem criteria. The protectiveness of the approach was critically reviewed with a chronic SSD for cadmium comprising 27 species within 21 genera. Within the data set, one genus had lower cadmium effects concentrations than the SSD fifth percentile-based criterion, so in theory this genus, the amphipod Hyalella, could be lost or at least allowed some level of harm by this criteria approach. However, population matrix modeling projected only slightly increased extinction risks for a temperate Hyalella population under scenarios similar to the SSD fifth percentile criterion. The criterion value was further compared to cadmium effects concentrations in ecosystem experiments and field studies. Generally, few adverse effects were inferred from ecosystem experiments at concentrations less than the SSD fifth percentile criterion. Exceptions were behavioral impairments in simplified food web studies. No adverse effects were apparent in field studies under conditions that seldom exceeded the criterion. At concentrations greater than the SSD fifth percentile, the magnitudes of adverse effects in the field studies were roughly proportional to the laboratory-based fraction of species with adverse effects in the SSD. Overall, the modeling and field validation comparisons of the chronic criterion values generally supported the relevance and protectiveness of the SSD fifth percentile approach with cadmium.

Violence and Mental Disorders: Data and Public Policy

Violence and Mental Disorders: Data and Public Policy

Violence and Mental Disorders: Data and Public Policy

Violence and Mental Disorders: Data and Public Policy

Pharmacological profile and clinical effects of montelukast sodium (Singulair chewable tablet), an antiasthmatic agent

Montelukast (Singulair) is an antiasthmatic agent that has the chemical structure of a quinoline. Montelukast has a high affinity for the CysLT1 receptor and a potency that is not influenced by human serum protein. Montelukast antagonizes contractions of guinea-pig trachea induced by LTD4 in a competitive manner. Intravenous montelukast inhibited bronchoconstriction induced by LTD4 in guinea pigs. Oral montelukast inhibited increased airway resistance induced by antigen in squirrel monkeys. Montelukast also inhibited both inflammatory and immunologic responses induced by either LTD4 or antigen in guinea pigs and rats. Plasma concentrations of montelukast after oral administration of 10 mg in humans were shown to be over the effective level for at least 24 h. These lines of evidence support the effectiveness of a regimen of 10 mg/day for asthmatic symptoms in humans. In a number of clinical experiments, montelukast not only improved asthmatic symptoms and respiratory indices, but also inhibited airway inflammation and exercise-induced bronchoconstriction. These effects persisted during extended treatment. Montelukast produced an additive effect to basic therapy with an inhaled steroid. There were no differences in the incidence and magnitude of adverse effects between montelukast and placebo groups in clinical experiments. Montelukast is expected to serve as a first line of asthmatic therapy because of its consistent efficacy and good safety profile and it is associated with good compliance in patients because of its simple regimen of one 10 mg tablet/day.

A quantitative risk assessment for fumonisins B1 and B2 in US corn

Quantitative risk analysis permits modifying risk estimates with changes in variables such as exposure. This analysis for exposure to the mycotoxin fumonisin describes the magnitude of adverse effects, variability in the population and uncertainty of models as a range of possible outcomes. The most sensitive adverse response in rats, nephrotoxic lesions, was used for the dose-response analysis. Dietary intake of corn products was estimated from a 3-day consumption survey. Levels of corn in each product were estimated by standard methods. Fumonisin levels in corn products were estimated from Food and Drug Administration (FDA) surveillance data and distributions of fumonisin consumption were modelled for each eater in the survey population. Uncertainty for predictions made from each model and uncertainty resulting from model selection were described. Results of the dose-response and exposure analyses were assimilated in a two-dimensional Monte-Carlo simulation. Distributions representing variability and uncertainty were iteratively selected to form an array of estimates of the risk. On the basis of this analysis, current dietary levels of fumonisin would not result in renal lesions even at upper levels of exposure. To avoid toxicity at much higher doses, limiting corn intake would be more effective than would limiting the level of fumonisin in corn.

Policy on wetland impact mitigation

Important policy issues concerning the mitigation of impacts from construction and development affecting wetlands are under examination by the U.S. Congressional Office of Technology Assessment, the Environment and Public Works Committee of the U.S. Senate, and the National Wetlands Technical Council. The issues divide into two main parts: (1) how the current strategy to simplify federal regulation of wetlands is limiting the success of mitigation; and (2) how to change the present strategy for mitigation under the U.S. Clean Water Act, if at all. Requirements for site-specific analysis of impacts and their mitigation requirements are being replaced by simple, uniform national guidelines on impact mitigation; these guidelines are designed to streamline the regulatory process in which the proposed activities typically generate only minor impacts. This trend ignores how the intrinsic values of the affected wetland modify the actual severity of impact. A change in regulatory strategy may be necessary so that the efforts at impact mitigation are scaled to wetland values as well as the magnitude of adverse effects normally expected with particular activities.