Genotoxic and cytotoxic evaluation of venlafaxine in an acute and a subchronic assay in mouse

The present research was made to determine the micronuclei and cytotoxic capacity of the antidepressant venlafaxine in an in vivo acute and subchronic assays in mouse. In the first study, we administered once 5, 50, and 250 mg/kg of the drug, and included a negative and a daunorubicin treated group. Observations were daily made during four days. The subchronic assay lasted 5 weeks with daily administration of venlafaxine (1, 5, and 10 mg/kg) plus a negative and an imipramine administered groups. Observations were made each week. In the first assay results showed no micronucleated polychromatic erythrocytes (MNPE) increase, except with the high dose at 72 h. The strongest cytotoxic effect was found with 250 mg/kg at 72 h (a 51% cytotoxic effect in comparison with the mean control level). In the subchronic assay no MNPE increase was found; however, with the highest dose a significant increase of micronucleated normochromatic erythrocytes was observed in the last three weeks (a mean of 51% respect to the mean control value). A cytotoxic effect with the two high doses in the last two weeks was observed (a polychromatic erythrocyte mean decrease of 52% respect to the mean control value). Results suggest caution with venlafaxine.

First- and Second-generation Health Condition Affected by Radiation

Research relevance: article presents the incidence of children and grandchildren for 2018–2019 of liquidator workers who took part in cleaning up the contaminated area around the Chernobyl nuclear power plant, as well as residents evacuated from the city of Pripyat and other settlements within a radius of 70 km from the station. The consequences of radiation exposure of Chernobyl accident remain a topical issue. Research objectives: in order to study health status of children and grandchildren of liquidators, outpatient cards and reporting forms no. 15-zdrav “On medical care for people affected by radiation and included in the Kyrgyz State Medical and Dosimetric Register” examined. Research materials and methods: diseases of the endocrine and nervous systems, nutritional disorders, metabolic disorders, mental disorders, diseases of the eye and its adnexa, ear diseases of and mastoid process were studied. Circulatory and respiratory system diseases were analyzed. Research results: animal and cell culture studies show that high doses of ionizing radiation can lead to mutations in offspring. However, there have not been sufficiently large-scale studies on humans that would allow assessing the effect of radiation on the health of offspring. The exposure provokes mutations and incurable diseases, but it is still unclear how it might affect the children affected. It is known that exposure to ionizing radiation increases DNA mutagenesis compared to background values. Conclusions: obtained data substantiate the need for further monitoring of their health, organization of differentiated dispensary observation of this contingent and timely implementation of medical, rehabilitation and preventive measures in order to preserve health of “children and grandchildren of Chernobyl” at all subsequent stages of their life.

Electrical Stimulation for Immune Modulation in Cancer Treatments

Immunotherapy is becoming a very common treatment for cancer, using approaches like checkpoint inhibition, T cell transfer therapy, monoclonal antibodies and cancer vaccination. However, these approaches involve high doses of immune therapeutics with problematic side effects. A promising approach to reducing the dose of immunotherapeutic agents given to a cancer patient is to combine it with electrical stimulation, which can act in two ways; it can either modulate the immune system to produce the immune cytokines and agents in the patient’s body or it can increase the cellular uptake of these immune agents via electroporation. Electrical stimulation in form of direct current has been shown to reduce tumor sizes in immune-competent mice while having no effect on tumor sizes in immune-deficient mice. Several studies have used nano-pulsed electrical stimulations to activate the immune system and drive it against tumor cells. This approach has been utilized for different types of cancers, like fibrosarcoma, hepatocellular carcinoma, human papillomavirus etc. Another common approach is to combine electrochemotherapy with immune modulation, either by inducing immunogenic cell death or injecting immunostimulants that increase the effectiveness of the treatments. Several therapies utilize electroporation to deliver immunostimulants (like genes encoded with cytokine producing sequences, cancer specific antigens or fragments of anti-tumor toxins) more effectively. Lastly, electrical stimulation of the vagus nerve can trigger production and activation of anti-tumor immune cells and immune reactions. Hence, the use of electrical stimulation to modulate the immune system in different ways can be a promising approach to treat cancer.

Wood Ash Based Treatment of Anaerobic Digestate: State-of-the-Art and Possibilities

The problem of current agricultural practices is not limited to land management but also to the unsustainable consumption of essential nutrients for plants, such as phosphorus. This article focuses on the valorization of wood ash and anaerobic digestate for the preparation of a slow-release fertilizer. The underlying chemistry of the blend of these two materials is elucidated by analyzing the applications of the mixture. First, the feasibility of employing low doses (≤1 g total solids (TS) ash/g TS digestate) of wood ash is explained as a way to improve the composition of the feedstock of anaerobic digestion and enhance biogas production. Secondly, a detailed description concerning high doses of wood ash and their uses in the downstream processing of the anaerobic digestate to further enhance its stability is offered. Among all the physico-chemical phenomena involved, sorption processes are meticulously depicted, since they are responsible for nutrient recovery, dewatering, and self-hardening in preparing a granular fertilizer. Simple activation procedures (e.g., carbonization, carbonation, calcination, acidification, wash, milling, and sieving) are proposed to promote immobilization of the nutrients. Due to the limited information on the combined processing of wood ash and the anaerobic digestate, transformations of similar residues are additionally considered. Considering all the possible synergies in the anaerobic digestion and the downstream stages, a dose of ash of 5 g TS ash/g TS digestate is proposed for future experiments.

Case Report: High Doses of Intravenous Immunoglobulins as a Successful Treatment for Late Onset Immune Agranulocytosis After Rituximab Plus Bendamustine

Late onset neutropenia (LON) related to rituximab or rituximab plus chemotherapy is defined as an unexplained absolute neutrophil count of ≤1.5 × 109/L starting at least four weeks after the last rituximab administration. LON is infrequent and its pathophysiology remains unknown. There are no guidelines or consensus strategies for the optimal management of patients developing LON. The majority of the patients recover promptly with no specific treatment and only some cases need to be managed with granulocytic colony stimulating factor (G-CSF), usually with a rapid response. Here, we describe a 69-year-old patient with Waldenström’s macroglobulinemia who presented a septic event in the context of severe LON after rituximab plus bendamustine. The diagnosed of agranulocytosis was established by bone marrow examination. Interestingly, anti-neutrophil antibodies bound to the patient’s granulocytes were found suggesting an autoimmune mechanism. The patient did not respond to G-CSF but achieved a rapid response after high doses of intravenous immunoglobulins with full white blood cell recovery.

Ultraviolet-C Irradiation, Heat, and Storage as Potential Methods of Inactivating SARS-CoV-2 and Bacterial Pathogens on Filtering Facepiece Respirators

The arrival of SARS-CoV-2 to Aotearoa/New Zealand in February 2020 triggered a massive response at multiple levels. Procurement and sustainability of medical supplies to hospitals and clinics during the then upcoming COVID-19 pandemic was one of the top priorities. Continuing access to new personal protective equipment (PPE) was not guaranteed; thus, disinfecting and reusing PPE was considered as a potential alternative. Here, we describe part of a local program intended to test and implement a system to disinfect PPE for potential reuse in New Zealand. We used filtering facepiece respirator (FFR) coupons inoculated with SARS-CoV-2 or clinically relevant multidrug-resistant pathogens (Acinetobacter baumannii Ab5075, methicillin-resistant Staphylococcus aureus USA300 LAC and cystic-fibrosis isolate Pseudomonas aeruginosa LESB58), to evaluate the potential use of ultraviolet-C germicidal irradiation (UV-C) or dry heat treatment to disinfect PPE. An applied UV-C dose of 1000 mJ/cm2 was sufficient to completely inactivate high doses of SARS-CoV-2; however, irregularities in the FFR coupons hindered the efficacy of UV-C to fully inactivate the virus, even at higher UV-C doses (2000 mJ/cm2). Conversely, incubating contaminated FFR coupons at 65 °C for 30 min or 70 °C for 15 min, was sufficient to block SARS-CoV-2 replication, even in the presence of mucin or a soil load (mimicking salivary or respiratory secretions, respectively). Dry heat (90 min at 75 °C to 80 °C) effectively killed 106 planktonic bacteria; however, even extending the incubation time up to two hours at 80 °C did not completely kill bacteria when grown in colony biofilms. Importantly, we also showed that FFR material can harbor replication-competent SARS-CoV-2 for up to 35 days at room temperature in the presence of a soil load. We are currently using these findings to optimize and establish a robust process for decontaminating, reusing, and reducing wastage of PPE in New Zealand.

Robotic Systems in Radiotherapy and Radiosurgery

Purpose of Review This review provides an overview of robotic systems in radiotherapy and radiosurgery, with a focus on medical devices and recently proposed research systems. We summarize the key motivation for using robotic systems and illustrate the potential advantages. Recent Findings. Robotic systems have been proposed for a variety of tasks in radiotherapy, including the positioning of beam source, patients, and imaging devices. A number of systems are cleared for use in patients, and some are widely used, particularly for beam and patient positioning. Summary The need for precise and safe delivery of focused high doses to the target region motivates the use of robots in radiotherapy. Flexibility in the arrangement of beams and the ability to compensate for target motion are key advantages of robotic systems. While robotic patient couches are widely used and robotic beam positioning is well established, brachytherapy robots are mostly considered in a research context.

Opioids in COVID-19: Two Sides of a Coin

Introduction: The treatment of most severe COVID-19 patients included the large-scale use of sedatives and analgesics–possibly in higher doses than usual–which was reported in the literature. The use of drugs that decrease mortality is necessary and opioids are important agents in procedures such as orotracheal intubation. However, these drugs seem to have been overestimated in the COVID-19 pandemic. We performed a review of the PubMed-Medline database to evaluate the use of opioids during this period. The following descriptors were used to enhance the search for papers: “Opioids”, “COVID-19,” “COVID-19 pandemic,” “SARS-CoV-2,” “Opioid use disorder,” “Opioid dependence” and the names of the drugs used. We also evaluated the distribution of COVID-19 patients in Brazil and the applicability of opioids in our country during the COVID-19 pandemic.Results: Several positive points were found in the use of opioids in the COVID-19 pandemic, for instance, they can be used for analgesia in orotracheal intubation, for chronic pain management, and as coadjutant in the management of acute intensification of pain. However, high doses of opioids might exacerbate the respiratory depression found in COVID-19 patients, their chronic use can trigger opioid tolerance and the higher doses used during the pandemic might result in greater adverse effects. Unfortunately, the pandemic also affected individuals with opioid use disorder, not only those individuals are at higher risk of mortality, hospitalization and need for ventilatory support, but measures taken to decrease the SARS-CoV-2 spread such as social isolation, might negatively affect the treatment for opioid use disorder. In Brazil, only morphine, remifentanil and fentanyl are available in the basic health care system for the treatment of COVID-19 patients. Out of the 5,273,598 opioid units used in this period all over the country, morphine, fentanyl, and remifentanil, accounted for, respectively, 559,270 (10.6%), 4,624,328 (87.6%), and 90,000 (1.8%) units. Many Brazilian regions with high number of confirmed cases of COVID-19 had few units of opioids available, as the Southeast region, with a 0.23 units of opioids per confirmed COVID-19 case, and the South region, with 0.05 units. In the COVID-19 pandemic scenario, positive points related to opioids were mainly the occurrence of analgesia, to facilitate intubation and their use as coadjutants in the management of acute intensification of pain, whereas the negative points were indiscriminate use, the presence of human immunosuppressor response and increased adverse effects due to higher doses of the drug.Conclusion: The importance of rational and individualized use of analgesic hypnotics and sedative anesthetics should be considered at all times, especially in situations of high demand such as the COVID-19 pandemic.

Two Possible Strategies for Drug Modification of Gemcitabine and Future Contributions to Personalized Medicine

Drug repurposing is an emerging strategy, which uses already approved drugs for new medical indications. One such drug is gemcitabine, an anticancer drug that only works at high doses since a portion is deactivated in the serum, which causes toxicity. In this review, two methods were discussed that could improve the anticancer effect of gemcitabine. The first is a chemical modification by conjugation with cell-penetrating peptides, namely penetratin, pVEC, and different kinds of CPP6, which mostly all showed an increased anticancer effect. The other method is combining gemcitabine with repurposed drugs, namely itraconazole, which also showed great cancer cell inhibition growth. Besides these two strategies, physiologically based pharmacokinetic models (PBPK models) are also the key for predicting drug distribution based on physiological data, which is very important for personalized medicine, so that the correct drug and dosage regimen can be administered according to each patient’s physiology. Taking all of this into consideration, it is believed that gemcitabine can be repurposed to have better anticancer effects.