IMXQB-80: A Quillaja brasiliensis saponin-based nanoadjuvant enhances Zika virus specific immune responses in mice

Vaccine adjuvants are compounds that enhance/prolong the immune response to a co-administered antigen. Saponins have been widely used as adjuvants for many years in several vaccines – especially for intracellular pathogens – including the recent and somewhat revolutionary malaria and shingles vaccines. In view of the immunoadjuvant potential of Q. brasiliensis saponins, the present study aimed to characterize the QB-80 saponin-rich fraction and a nanoadjuvant prepared with QB-80 and lipids (IMXQB-80). In addition, the performance of such adjuvants was examined in experimental inactivated vaccines against Zika virus (ZIKV). Analysis of QB-80 by DI-ESI-ToF by negative ion electrospray revealed over 29 saponins that could be assigned to known structures existing in their congener Q. saponaria, including the well-studied QS-21 and QS-7. The QB-80 saponins were a micrOTOF able to self-assembly with lipids in ISCOM-like nanoparticles with diameters of approximately 43 nm, here named IMXQB-80. Toxicity assays revealed that QB-80 saponins did present some haemolytical and cytotoxic potentials; however, these were abrogated in IMXQB-80 nanoparticles. Regarding the adjuvant activity, QB-80 and IMXQB-80 significantly enhanced serum levels of anti-Zika virus IgG and subtypes (IgG1, IgG2b, IgG2c) as well as neutralized antibodies when compared to an unadjuvanted vaccine. Furthermore, the nanoadjuvant IMXQB-80 was as effective as QB-80 in stimulating immune responses, yet requiring fourfold less saponins to induce the equivalent stimuli, and with less toxicity. These findings reveal that the saponin fraction QB-80, and particularly the IMXQB-80 nanoadjuvant, are safe and capable of potentializing immune responses when used as adjuvants in experimental ZIKV vaccines.     

A spectral framework for sperm shape characterization

A novel methodology for characterization of animal sperm shape involving the use of a spectral approach to multiscale curvature estimation is proposed. By using the derivative property of the Fourier transform, allied to Gaussian smoothing, accurate estimates of the curvature along the sperm contour can be obtained in such a way that the curvature peaks corresponding to the sperm head vertices can be effectively identified. The measurements derived from such a processing, namely the width of the basal region of the head, the centralization of tail implantation, and the multiscale bending energy, provide valuable resources for fertility and phylogenetic studies.     

Fluoroquinolones in bronchopulmonary infections

In recent years, Streptococcus pneumoniae and Haemophilus influenzae, two of the most common pathogens causing bronchopulmonary infections, have developed resistance towards beta-lactam antibiotics in many areas of the globe. In some countries, resistance rates are so high that treatment with penicillin can not be recommended as the therapy of choice. Unfortunately, many S. pneumoniae strains resistant to penicillins are also resistant to co-trimoxazole and erythromycin, and even to the novel macrolides. Present fluoroquinolones may have to be used in such resistant cases. The fluoroquinolones possess a superior activity against H. influenzae and other pathogens causing bronchitis and pneumonia. Fluoroquinolones have a favourable pharmacokinetic profile including penetration into sputum, bronchial fluid, alveolar lining fluid and alveolar macrophages, and therapeutic concentrations and ratios are superior to those of the beta-lactams. Fluoroquinolones have been shown to produce better results than the comparative agents in bronchitis and, in cystic fibrosis, they achieve a definite clinical amelioration in paediatric patients without substantial additional toxicity. Their use in legionnaires' disease has not been confirmed and their place in the treatment of community-acquired pneimonias - particularly those caused by Mycoplasma pneumoniae and Chlamydia trachomatis and the TWAR agent - deserves further investigation.     

Clinical toxicity associated with tiazofurin

Summary Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23–36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity ( grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3%), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 uM) and prolonged exposure to plasma levels exceeding 50 uM may result in a higher incidence of serious non-hematologic toxicity.     

Evidence for the involvement of the nitric oxide–cGMP pathway in the antinociception of morphine in the formalin test

The effect of inhibition of nitric oxide synthesis and guanylate cyclase on the peripheral antinociceptive effect of morphine was assessed by using the formalin test in the rat. Saline, N^G-monomethyl-

Full-size image

-arginine, a nitric oxide synthesis inhibitor (50 μg) and methylene blue, a guanylate cyclase inhibitor (500 μg), did not exhibit any antinociceptive activity. However, morphine (10 μg) produced a significant antinociceptive effect in phases 2a and 2b, which was reduced by pretreatment with either N^G-monomethyl-

Full-size image

-arginine or methylene blue. These results suggest that the local administration of morphine induces antinociception by the activation of the

Full-size image

-arginine–nitric oxide–cGMP pathway.     

COVID-19 Treatment: Drug Safety Prior to Conception and During Pregnancy and Breastfeeding

In December 2019, a new viral respiratory infection known as coronavirus disease 2019 (COVID-19) was first diagnosed in the city of Wuhan, China. COVID-19 quickly spread across the world, leading the World Health Organization to declare it a pandemic on March 11, 2020. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a similar virus to those involved in other epidemics such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Epidemiological studies have shown that COVID-19 frequently affects young adults of reproductive age and that the elderly and patients with chronic disease have high mortality rates. Little is known about the impact of COVID-19 on pregnancy and breastfeeding. Most COVID-19 cases present with mild flu-like symptoms and only require treatment with symptomatic relief medications, whereas other cases with COVID-19 require treatment in an intensive care unit. There is currently no specific effective treatment for COVID-19. A large number of drugs are being used to fight infection by SARS-CoV-2. Experience with this therapeutic arsenal has been gained over the years in the treatment of other viral, autoimmune, parasitic, and bacterial diseases. Importantly, the search for an effective treatment for COVID-19 cannot expose pregnant women infected with SARS-CoV-2 to the potential teratogenic risks of these drugs. Therefore, it is necessary to determine and understand the safety of anti-COVID-19 therapies prior to conception and during pregnancy and breastfeeding.Key words: COVID-19, SARS-CoV-2, antiviral, pregnancy, breastfeeding     

Regional analysis of functions and demographics of health information managers

Based on the findings of this study, HIM professionals' tasks or functions tend to vary across regions and in relation to levels of experience. As experience increased for RRAs, the task performed by them tended to be more management related. All other HIM professionals performed tasks that were more related to data collection than management. The most frequent title for the RRA (Director/manager/chief of medical records or HIM) was also more related to management activities while the title for the ART (Coder) was directly related to data collection. The majority of all HIM professionals work in acute care with approximately 3-8 percent working in long term care, ambulatory care, mental health care, and other healthcare settings such as software companies or health departments. The two most important predictors of salary across all regions were years of experience and educational level. When experience and education were controlled for, there was a slight salary advantage for males in the Midwest and West regions.     

Comparison of the cytotoxicity of two nitroheterocyclic drugs (NHCD) towards transformed and non-transformed cells.

The cytotoxicity of two nitroheterocyclic compounds (NHCD), Nitracrine, 1-nitro-9(3'3'-dimethylaminopropylamino) acridine (Polfa, Poland) and Quinifuryl, 2-(5'-nitro-2'-furanyl) ethenyl-4-[N-[4-(N,N-diethylamino)-1'-methylbutyl] carbamoyl] quinoline (Dr. N. M. Sukhova, Institute of Organic Synthesis, Riga, Latvian Republic), towards two lines of leukaemic cells and a line of non-transformed cells, was determined under normoxia conditions. Although both drugs showed significant cytotoxicity to all cell lines (LC(50) for 24h, < or = 2 microM) with that of Nitracrine exceeding Quinifuryl, their toxicity towards murine leukaemia P388 was substantially higher, compared to murine fibroblasts NIH3T3. In addition, the rate of cell death was also two- to three-fold higher in case of P388 cells versus NIH3T3. Interestingly, human erythroleukaemia K562 cells were shown to uptake the drugs 10 min after their addition to the tissue culture medium, while the LC(50) values were reached after a substantial delay of 3h. This delay might be due to the intracellular transformation of drugs required for cell killing.