Digenic traits under population admixture and inbreeding

The population genetics of digenic genotypes in diploid populations, genotypes based on alleles at two loci, have been studied theoretically for decades with relevant digenic traits of medical interest being known for over 25 years. Given the effects of linkage and linkage disequilibrium on two locus genotypes, it should be expected that these factors can change the expected frequencies of digenic genotypes in many, sometimes unexpected, ways. In particular, the combination of linkage disequilibrium and inbreeding can combine to increase the frequencies of double homozygotes and double heterozygotes significantly over outbred comparisons. Given the prevalence of linkage disequilibrium in recently admixed populations, this can lead to large shifts in trait prevalence such that it can sometimes exceed that of either original pre-admixed population with the combined effects of linkage disequilibrium and inbreeding. Here we investigate the frequencies of digenic genotypes under the combined effects of linkage, linkage disequilibrium, and inbreeding to analyze how these interact to increase or decrease the frequency of the genotypes across two loci.

How Fibrinolysis was Defeated by PCI

Fibrinolysis refers to the natural enzymatic system responsible for dissolving a blood clot or thrombus. Since an intravascular thrombus is responsible for almost all heart attacks and most strokes, interest in fibrinolysis, the only medical treatment, dominated medical interest in the 60’s-90’s. Since that time, the incidence of heart attacks and strokes has not changed much, but interest in fibrinolysis has faded. Instead, interest has shifted to catheter removal of clots, called percutaneous coronary intervention (PCI) which is a time-consuming that delays reperfusion considerably, and is much more costly than fibrinolysis. It is also a cruder treatment that can only remove clots larger than the catheter, but it is very well reimbursed.

Safety of Cyproheptadine, an Orexigenic Drug. Analysis of the French National Pharmacovigilance Data-Base and Systematic Review

Objectives: Cyproheptadine is a first-generation H1-antihistamine drug first that was distributed in the 1960s. While its orexigenic effect was observed early, cyproheptadine is not yet authorized for this indication in all countries today. There is an increasing medical interest and demand for the orexigenic effect of cyproheptadine, especially in children with poor appetite. As cyproheptadine might be evaluated in future clinical trials, we wanted to assess its safety profile.Methods: Using the French national pharmacovigilance database, we retrospectively analyzed all pediatric and adult reports of adverse effects of cyproheptadine recorded since its first distribution in France. Next, we performed a systematic review of the literature of cyproheptadine adverse effects.Results: Since 1985, 93 adverse effects were reported in the French pharmacovigilance database (adults 81.7%, children 18.3%); these were mainly neurological symptoms (n = 38, adults 71%, children 28.9%), and hepatic complications (n = 15, adults 86.7%, children 13.3%). In the literature, the most frequent adverse effect reported was drowsiness in adults or children, and five case reports noted liver complications in adults. We estimated the frequency of hepatic adverse effects at 0.27 to 1.4/1000, regardless of age.Conclusion: Cyproheptadine can be considered a safe drug. Mild neurological effects appear to be frequent, and hepatotoxicity is uncommon to rare. Randomized controlled trials are needed to evaluate the safety and efficacy of cyproheptadine before authorization for appetite stimulation, especially in young children as studies at this age are lacking. Possible hepatic complications should be monitored, as very rare cases of liver failure have been reported.

Evaluation of thermo-chemical conversion temperatures of cannabinoid acids in hemp (Cannabis sativa L.) biomass by pressurized liquid extraction

Background Cannabinoids are increasingly becoming compounds of medical interest. However, cannabis plants only produce carboxylated cannabinoids. In order to access the purported medical benefits of these compounds, the carboxylic acid moiety must be removed. This process is typically performed by heating the plant material or extract; however, cannabinoids being thermolabile can readily degrade, evaporate, or convert to undesired metabolites. Pressurized liquid extraction (PLE) operates using a pseudo-closed system under pressure and temperature. While pressure is maintained at 11 MPa, temperature can be varied from ambient to 200 °C. Methods Temperatures were evaluated (80 to 160 °C) using PLE for the thermo-chemical conversion of cannabinoid acids utilizing water as the solvent in the first step of extraction with subsequent extraction with ethanol. Optimum temperatures were established for the conversion of 6 cannabinoid acids to their neutral cannabinoid forms. Cannabinoid acid conversion was monitored by HPLC. Results The use of PLE for thermo-chemical decarboxylation has resulted in a rapid decarboxylation process taking merely 6 min. The temperatures established here demonstrate statistically significant maxima and minima of cannabinoids and their parent cannabinoid acids. One-way ANOVA analysis shows where individual cannabinoids are statistically different, but the combination of the maxima and minima provides temperatures for optimum thermo-chemical conversion. CBC, CBD, CBDV, and CBG have an optimum temperature of conversion of 140 °C, while THC was 120 °C for 6 min. Discussion Decarboxylation of cannabinoid acids is necessary for conversion to the bioactive neutral form. The pseudo-closed chamber of the PLE makes this an ideal system to rapidly decarboxylate the cannabinoid acids due to pressure and temperature, while minimizing loss typically associated with conventional thermal-decarboxylation. This study established the optimum temperatures for thermo-chemical conversion of the cannabinoid acids in water and provides the groundwork for further development of the technology for industrial scale application.

Antimicrobial and cytotoxic activity of fungal mycelial extracts from aquatic environments in the Amazon

Fungi are a prolific source of biologically active metabolites, including a wide range of clinically important drugs. Therefore, this study aims to evaluate the antimicrobial and cytotoxic activity of secondary metabolites extracted from fungal mycelia isolated from freshwater samples in the state of Amazonas. Mycelial extracts from 12 fungal were used, extracted with MeOH/AcOEt (1:1) according to the criteria established by Souza et al. (2004). For antimicrobial activity, the extracts were tested against the pathogens Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Enterococcus feacalis, Candida albicans and C. tropicalis. To identify the minimum inhibitory dosage (MID) the microdilution method was used. To perform the cytotoxicity assay, the VERO strain (ATCC® CCL-81TM) was used. The assays were determined by the Alamar Blue method according to Ahmed et al. (1994). The tested extracts did not show antibacterial activity. Five extracts (41.7%), obtained from the fungi Aspergillus - 1283, Chrysoporther - 1169, Diaporther – 1203, Fusarium – 1085, and Trichoderma, showed antifungal activity against C. albicans. Diaporther extract (8.3%) - 1203 was active against C. tropicalis. In the cytotoxicity assay, 58.3% of the evaluated extracts showed no significant toxic effect. Five extracts, Cladosporium - 1135, Chrysoporther - 1169, Cytospora - 1098, Fusarium - 1085, and Talaromyces - 1244, showed cytotoxic potential, exhibiting viability lower than 70%. The results obtained suggest that mycelial extracts of fungi isolated from water samples from the Amazon region have potential against yeasts of medical interest. Only two of the active extracts were revealed potentially cytotoxic.

Malaria in Europe: A Historical Perspective

Endemic malaria, which claimed 229 million new cases and 409,000 deaths in 2019 mainly in Africa, was eradicated from Europe by the mid-20th century. Historical descriptions of intermittent tertian and quartan fever reported in texts of Hippocrates in Greece and Celsus in Italy suggest malaria. A few paleomicrobiology investigations have confirmed the presence of malarial parasite Plasmodium falciparum in 1st, 2nd, and 5th century infected individuals in diverse regions of Italy, and Plasmodium sp. later in Bavaria. The causative Plasmodium pathogens, discovered in the 19th century in Algeria, were controversially used as therapeutic agents in the European pharmacopeia more than two centuries after effective quinine-based treatments had been introduced in Europe. How Europe managed to eradicate malaria and what the history of malaria was in Europe are of medical interest, and this review traces research pathways for a renewed understanding of malaria eradication in Europe through combined historical and paleomicrobiological investigations.