摘要： Introduction. Staphylococcus spp. represent the leading cause of hospital-acquired infections and second-most frequent pathogen in bloodstream infections. Methicillin-susceptible S. aureus (MSSA) comprise approximately half of all S. aureus isolates. Standard-of-care therapies (SOCTs) display high treatment success but require frequent dosing, are problematic in penicillin allergic patients, and are nephrotoxic. Ceftriaxone may represent an alternative treatment option. Methods. Adult patients hospitalized from January 2015 through June 2016 with positive MSSA blood cultures and treated with SOCT or ceftriaxone for >= 48 hours were included. Exclusion criteria were receipt of vancomycin or concomitant systemic antimicrobials with activity against MSSA, polymicrobial infections, and pregnant patients. Additional data collected included demographics, source/site of infection, and treatment. The primary endpoint was clinical cure (normalization of white blood cell count and temperature within 7 days and clearance of bloodstream within 7 days). Readmission within 60 days, length of stay, and discharge disposition were collected. Results. A total of 43 patients were included: 23 receiving SOCT and 20 receiving ceftriaxone group. Sixteen patients received SOCT prior to ceftriaxone while 4 patients were initiated on ceftriaxone. Clinical cure was observed in 18/23 (78%) and 10/20 (50%), respectively (P = 0.052). Clinical failure was driven by leukocytosis despite clearance of their bloodstream infection in 3/23 (13%) SOCT group compared to 8/20 (40%) in the ceftriaxone group (P = 0.043). Six patients (SOCT: 2, ceftriaxone: 4;p = 0.669) had infection-related readmissions, and 1 death per group was observed. Conclusion. Ceftriaxone poses a reasonable alternative to consider for MSSA bacteremia when cost and feasibility are concerns for outpatient parenteral therapy after initial clearance of bloodstream infections.

关键词： complementary and alternative therapies   network meta-analysis   protocol   Tension-type headache  

摘要： Background: Tension-type headache (TTH) is the most common form of primary headache with high prevalence, which affects the quantity of life seriously. The pharmacological treatment of TTH is not the most effective. Meanwhile, complementary therapies and alternative therapies play an essential role in the treatment of TTH, and there is an absence of comparison between various interventions. Therefore, we propose the network meta-analysis protocol to compare the efficacy and safety of various complementary therapies and alternative therapies for TTH. Methods: From the beginning to February 2021, we will search the database to collect randomized controlled trials of complementary and alternative therapies for TTH. Two researchers will be responsible for screening retrieve documents, extracting data. The risk of bias will be assessed based on the Cochrane bias risk tool. We will use STATA16.0 and WinBUGS1.4.3 for paired meta-analysis and Bayesian network meta-analysis. The quality of evidence will be assessed using the grading of recommendations assessment development and evaluation. Results: This study will compare and rank the efficacy and safety of various complementary and alternative treatments for TTH. Conclusions: This study will provide more extensive evidence for the complementary and alternative therapies of TTH. We expect to assist clinicians and patients in choosing the optimum treatment. Protocol registration number: INPLASY202130088.

关键词： Asteraceae   databases   in silico   Leishmaniasis   natural products  

摘要： Leishmaniasis is a complex disease caused by over 20 Leishmania species that primarily affects populations with poor socioeconomic conditions. Currently available drugs for treating leishmaniasis include amphotericin B, paromomycin, and pentavalent antimonials, which have been associated with several limitations, such as low efficacy, the development of drug resistance, and high toxicity. Natural products are an interesting source of new drug candidates. The Asteraceae family includes more than 23 000 species worldwide. Secondary metabolites that can be found in species from this family have been widely explored as potential new treatments for leishmaniasis. Recently, computational tools have become more popular in medicinal chemistry to establish experimental designs, identify new drugs, and compare the molecular structures and activities of novel compounds. Herein, we review various studies that have used computational tools to examine various compounds identified in the Asteraceae family in the search for potential drug candidates against Leishmania.

关键词： Anatomy   Inhibition   Peptides and proteins   Genetics   Metabolism  

摘要： Prophylactic antiretroviral therapy (ART) in HIV infected pregnant mothers and their newborns can dramatically reduce mother-to-child viral transmission and seroconversion in the neonate. The ritonavir-boosted lopinavir regimen, known as Kaletra, has been associated with premature birth and transient adrenal insufficiency in newborns, accompanied by increases in plasma dehydroepiandrosterone 3-sulfate (DHEA-S). In the fetus and neonates, cytochrome P450 CYP3A7 is responsible for the metabolism of DHEA-S into 16a-hydroxy DHEA-S, which plays a critical role in growth and development. In order to determine if CYP3A7 inhibition could lead to the adverse outcomes associated with Kaletra therapy, we conducted in vitro metabolic studies to determine the extent and mechanism of CYP3A7 inhibition by both ritonavir and lopinavir and the relative intrinsic clearance of lopinavir with and without ritonavir in both neonatal and adult human liver microsomes (HLMs). We identified ritonavir as a potent inhibitor of CYP3A7 oxidation of DHEA-S (IC50 = 0.0514 mu M), while lopinavir is a much weaker inhibitor (IC50 = 5.88 mu M). Furthermore, ritonavir is a time-dependent inhibitor of CYP3A7 with a K-I of 0.392 mu M and a k(inact) of 0.119 min(-1), illustrating the potential for CYP3A mediated drug-drug interactions with Kaletra. The clearance rate of lopinavir in neonatal HLMs was much slower and comparable to the rate observed in adult HLMs in the presence of ritonavir, suggesting that the addition of ritonavir in the cocktail therapy may not be necessary to maintain effective concentrations of lopinavir in neonates. Our results suggest that several of the observed adverse outcomes of Kaletra therapy may be due to the direct inhibition of CYP3A7 by ritonavir and that the necessity for the inclusion of this drug in the therapy may be obviated by the lower rate of lopinavir clearance in the neonatal liver. These results may lead to a reconsideration of the use of ritonavir in neonatal a

关键词： Protein fining agents   Grape seed protein   Phenolic composition   Color   Red wine  

摘要： Currently, the wine industry has an increasing interest in developing alternative solutions to traditional animal proteins fining agents. In this study, the impact of different protein fining agents on the turbidity, phenolic composition and color of 2-month and 12-month Syrah red wines was assessed. Wines fined with egg albumin and plant-based proteins from potato, pea, and grape seed as recent alternative, were compared to unfined control wines. Changes on turbidity, phenolic composition and color (by Differential Colorimetry) showed that animal and plant proteins differed in their clarifying efficiency and ability to interact with colorless phenolics and anthocyanins, depending on the age of wine, with important consequences on color quality and stability. Plant proteins showed lower effectiveness to reduce wine turbidity than egg albumin but modified in different way the phenolic composition, inducing lower color differences with respect to control wine and similar stability, especially potato and grape seed proteins.

关键词： alternative splicing   C-degron   hypoxia   MAX   protein surveillance  

摘要： Proteome integrity is crucial for cellular homeostasis and adaptation to stress conditions such as hypoxia. One mechanism for rapid adaptation of the proteome in response to changing environmental signals is alternative splicing. In addition to generating different protein isoforms, alternative splicing is also capable of controlling total protein levels by the regulated synthesis of non-productive mRNA isoforms. The hypoxia-induced isoform E of the tumor suppressor MAX is produced by retention and translation of the last intron. This leads to an alternative C-terminus that harbors a potent C-degron, the isoE degron. Strikingly, the isoE degron represents a universal protein degradation signal that is not only functional in mammalian cells, but also in yeast and even in bacteria. Essential for efficient protein decay is a conserved (F/W)xxW motif. Degradation of isoE tagged proteins is mediated by the proteasome in eukaryotes and Lon protease in bacteria. Thus, the isoE degron is a broadly applicable and highly efficient tool in protein analyses. © 2021 Elsevier Ltd

关键词： Chronic lymphocytic leukemia   apoptosis   BCL-2   BCL-2 family  

摘要： Venetoclax, a BCL-2 inhibitor, is highly effective for the treatment of patients with chronic lymphocytic leukemia (CLL) and dependence on alternative proteins may result in resistance to BCL-2 inhibition. Patients with CLL treated with venetoclax as monotherapy at MD Anderson Cancer Center between 05/2012 and 01/2016 were included and pretreatment bone marrow was analyzed by immunohistochemistry (IHC) for BCL-W, BCL-XL, BCL2-A1 and MCL-1. Twenty-seven patients were included. BCL-W + and BCL-2A1+ was found in 15% and 7% of the patients, respectively. Both BCL-XL and MCL-1 were negative in all samples. A higher CR and longer PFS rates were observed in patients with BCL-W+ (p = .60, p = .46), BCL-2A1+ (p = .60, p = .29), and either BCL-W + or BCL-2A1+ (p = .33, p = .20), though not statistically significant. Pretreatment IHC expression of BCL-2 alternative proteins does not predict response to venetoclax in CLL, but may be a surrogate for an indolent biology. Sensitive techniques are needed to explore anti-apoptotic pathways.

关键词： Essential oil   GC-MS   Gaultheria longibracteolata   Wintergreen   Traditional medicine  

摘要： Gaultheria longibracteolata (Ericaceae) has been traditionally used by different linguistic groups in Yunnan Province, China, but it has not been well studied. Through our ethnobotanical study in Luchun County of Yunnan, we found that this species has multiple traditional uses including food, medicine, and worship. The essential oils from the root, stem, and leaf were investigated by both GC-MS and anti-bacterial assays. The GC-MS study showed that methyl salicylate is the main (> 90%) component of the essential oil, and the oil composition extracted from different plant parts showed some similarities. The oil of G. longibracteolata displayed antimicrobial activity against Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus, which is likely due to its methyl salicylate content. Gautheria longbracteolata appears to be a useful natural wintergreen oil substitute, but further studies are needed to develop this product.

关键词： COVID-19   multisystem inflammatory syndrome in children   Reye syndrome   COVID-19 pandemic   SARS-CoV-2 (COVID-19)  

摘要： We describe a 7-year-old child with multisystemic inflammatory syndrome that was temporarily associated with the novel coronavirus disease which evolved into serious illness, with coronary aneurysm, using human immunoglobulin and acetylsalicylic acid, in which clinical manifestations including hepatitis, convulsions, and coma were aggravated with Reye's syndrome. To date, there has been no report of the association of multisystemic inflammatory syndrome that is temporarily associated with the novel coronavirus disease and Reye's syndrome.

关键词： X-ray crystallography   Hydrogen transfer   4-Methylbenzyl alcohol   4-Bromobenzyl alcohol   1H,1H-heptafluorobutanol  

摘要： Enzymes typically have high specificity for their substrates, but the structures of substrates and products differ, and multiple modes of binding are observed. In this study, high resolution X-ray crystallography of complexes with NADH and alcohols show alternative modes of binding in the active site. Enzyme crystallized with the good substrates NAD(+) and 4-methylbenzyl alcohol was found to be an abortive complex of NADH with 4-methylbenzyl alcohol rotated to a "non-productive" mode as compared to the structures that resemble reactive Michaelis complexes with NAD(+) and 2,2,2-trifluoroethanol or 2,3,4,5,6-pentafluorobenzyl alcohol. The NADH is formed by reduction of the NAD(+) with the alcohol during the crystallization. The same structure was also formed by directly crystallizing the enzyme with NADH and 4-methylbenzyl alcohol. Crystals prepared with NAD(+) and 4-bromobenzyl alcohol also form the abortive complex with NADH. Surprisingly, crystals prepared with NAD(+) and the strong inhibitor 1H,1H-heptafluorobutanol also had NADH, and the alcohol was bound in two different conformations that illustrate binding flexibility. Oxidation of 2-methyl-2,4-pentanediol during the crystallization apparently led to reduction of the NAD(+). Kinetic studies show that high concentrations of alcohols can bind to the enzyme-NADH complex and activate or inhibit the enzyme. Together with previous studies on complexes with NADH and formamide analogues of the carbonyl substrates, models for the Michaelis complexes with NAD(+)-alcohol and NADH-aldehyde are proposed.