Electronic health records (EHRs) coupled with large-scale biobanks offer great promises to unravel the genetic underpinnings of treatment efficacy. However, medication-induced biomarker trajectories stemming from such records remain poorly studied. Here, we extract clinical and medication prescription data from EHRs and conduct GWAS and rare variant burden tests in the UK Biobank (discovery) and the All of Us program (replication) on ten cardiometabolic drug response outcomes including lipid response to statins, HbA1c response to metformin and blood pressure response to antihypertensives (N = 740-26,669). Our findings at genome-wide significance level recover previously reported pharmacogenetic signals and also include novel associations for lipid response to statins (N = 26,669) near LDLR and ZNF800. Importantly, these associations are treatment-specific and not associated with biomarker progression in medication-naive individuals. Furthermore, we demonstrate that individuals with higher genetically determined low-density and total cholesterol baseline levels experience increased absolute, albeit lower relative biomarker reduction following statin treatment. In summary, we systematically investigated the common and rare pharmacogenetic contribution to cardiometabolic drug response phenotypes in over 50,000 UK Biobank and All of Us participants with EHR and identified clinically relevant genetic predictors for improved personalized treatment strategies.
ABSTRACT The present study reports a promising antioxidant protection by a recently developed micellar propolis formulation, against oxidative stress in in vitro and in vivo models of toxicity. The formulation, based on poplar propolis encapsulated in poly(ethylene oxide)-β-poly(propylene oxide)-β-poly(ethylene oxide) triblock copolymer (PEO26-PPO40-PEO26) micelles is characterized by small size (D h = 20 nm), enhances aqueous solubility and good colloidal stability. In vitro, propolis-loaded PEO26-PPO40-PEO26 micelles (20-100 µg/ml) significantly increased the cell viability of human hepatoma HepG2 cells, subjected to H2O2-induced cell injury (0.1 mM, 1 h). Antioxidant activity and protection of the micellar propolis were evaluated in a model of carbon tetrachloride-induced hepatotoxicity in rats (10% CCl4 solution, 1.25 ml/kg, p.o.) by measurement of non-enzyme (malondialdehyde and glutathione) and enzyme (catalase and superoxide dismutase) biomarkers of oxidative stress. Clinic observations, hematological, biochemical parameters and histological analysis were also performed. In vivo, micellar propolis (20 mg/kg b.w., p.o., 14 days) ameliorated CCl4-induced acute liver injury in rats. The oral administration of micellar propolis significantly prevented serum transaminase increases, as well as brought the levels of malondialdehyde, glutathione, and antioxidant enzymes catalase and superoxide dismutase toward the controls levels. Therefore, PEO26-PPO40-PEO26 micelles could be considered as a promising oral delivery system of propolis against oxidative stress injury in liver cells.
The trigeminal ganglion (TG), a cluster of pseudounipolar neurons, is located in the trigeminal impression of the temporal pyramid. It is covered by a sheath of the dura mater and arachnoid and is near the rear end of the cavernous sinus. The peripheral processes of the pseudounipolar cells are involved in the formation of the first and second branch and the sensory part of the third branch of the fifth cranial nerve, and the central ones form the sensory root of the nerve, which penetrates at the level of the middle cerebellar peduncle, aside from the pons, and terminate in the sensory nuclei of the trigeminal complex. We found that the primary sensory neurons involved in sensory innervation of the orofacial complex are a diverse group. Although they possess the general structure of pseudounipolar neurons, there are significant differences among them, seen in varying intensities of staining. Based on our investigations we classified the neurons into 7 groups, i.e. large, subdivided into light and dark, medium, also light and dark, and small light and dark, and, moreover, neurons with an irregular shape of their perikarya. Further research by applying various immunohistochemical methods will clarify whether differences in the morphological patterns of the neurons are associated with differences in the neurochemical composition of various neuronal types.
The digastric muscle is composed by two muscle bellies: an anterior and a posterior, joined by an intermediate tendon. This muscle is situated in the anterior region of the neck. The region between the hyoid bone and the mandible is divided by an anterior belly into two triangles: the submandibular situated laterally and the submental triangle which is located medially. We found that the anatomical variations described in the literature relate mainly to the anterior belly and consist of differences in shape and attachment of the muscle. During routine dissection in February 2013 in the section hall of the Department of Anatomy and Histology in Medical University - Sofia we came across a very interesting variation of the digastric muscle. The digastric muscles that presented anatomical variations were photographed using a Sony Cyber-shot DSC-T1 camera, with a Carl Zeiss Vario-Tessar lens. We found out bilateral variation of the digastric muscle in one cadaver. The anterior bellies were very thin and insert to the hyoid bone. Two anterior bellies connect each other and thus they formed a loop. The anatomical variations observed of our study related only to the anterior belly, as previously described by other authors. It is very important to consider the occurrence of the above mentioned variations in the digastric muscle when surgical procedures are performed on the anterior region of the neck.
