Characterization of the LPS and 3OHFA Contents in the Lipoprotein Fractions and Lipoprotein Particles of Healthy Men

Atherosclerosis is a chronic inflammatory disease that is caused by the accumulation of LDL particles in the intima, causing the activation of immune cells and triggering an inflammatory response. LPS is a potent activator of the innate immune response and it can be transported by lipoproteins. Since humans are much more sensitive to LPS than other mammals, and very low amounts of LPS can elicit an immune response, the aim of this study is to characterize the distribution of LPS and its immunogenic portion (3OHFAs) among lipoprotein types of healthy men. We separated lipoprotein fractions by ultracentrifugation and the amount of each 3OHFA was measured by MS in each lipoprotein fraction to calculate LPS concentration. Lipoprotein particle concentration was measured by NMR. LDL and HDL fractions transported the highest concentration of LPS (35.7% and 31.5%, respectively), but VLDL particles carried more LPS molecules per particle (0.55 molecules/particle) than LDL or HDL (p < 0.01). The distribution of LPS and all 3OHFAs among lipoprotein fractions showed high interindividual variability, suggesting that they may be studied as a potential biomarker. This may help understand the role of LPS in atherosclerosis in those cases where the disease cannot be explained by traditional risk factors.

Influence of Haemolysis on the Mineral Profile of Cattle Serum

Haemolysis of serum samples is the leading cause of preanalytical errors in clinical laboratories. Little is known about the potential alterations in the concentrations of mineral elements in haemolyzed serum and the phenomenon has not been specifically studied in bovine serum samples. We investigate how haemolysis affects the mineral content of bovine samples. We used ICP-MS to measure the concentrations of 12 mineral elements (Ca, Co, Cr, Cu, Fe, Mg, Mn, Mo, Ni, P, Se and Zn) in bovine whole blood, serum and gradually haemolyzed samples and observed significant differences between the different types of samples, particularly in the Fe and Zn concentrations. However, in practice, the high interindividual variability makes it difficult to establish whether a given value corresponds to normal or haemolyzed samples. In response to this problem, we propose to consider that a result is significantly biased when the haemolysis threshold (the degree of haemolysis above which the concentration of an element in serum is significantly altered) of a given element is surpassed. The haemolysis threshold values for the different elements considered were found as follows: 0.015 g Hb L−1 for Fe, 2 g for Zn, 4 g for Cr and 8 g for Ca, Se and Mo.

Delayed Respiratory Insufficiency and Extramuscular Abnormalities in Selenoprotein N-Related Myopathies

Background: Selenoprotein N-related myopathies (SEPN1-RMs) are a subset of congenital myopathies caused by mutations of Selenoprotein N gene (SELENON or SEPN1). Clinical phenotype is considered as highly consistent and little attention has been given to the extramuscular abnormalities.Methods: We reported clinical, histopathological, and genetic features of four Chinese patients with SEPN1-RM and performed literature review on delayed respiratory insufficiency and extramuscular involvement.Results: A total of four patients exhibited both the typical and atypical clinical features of SEPN1-RM. The classical manifestations included axial and limb girdle weakness, spinal rigidity, scoliosis, respiratory insufficiency, and multiminicore morphological lesions. However, high interindividual variability was noticed on disease severity, especially the onset of respiratory involvement. Two adult patients postponed respiratory insufficiency to the third decade of life, while two juvenile patients manifested early hypoventilation with puberty exacerbation. As atypical features, extramuscular involvement of weight gain, subcutaneous adipose tissue accumulation, intellectual disability, and mild cardiac changes were observed. Molecular findings revealed three novel mutations of SELENON such as c.1286_1288 del CCT, c.1078_1086dupGGCTACATA, and c.785 G&gt;C. Ten cases with delayed respiratory insufficiency were identified from previous publications. A total of 18 studies described extramuscular abnormalities including joint contractures, alterations of body mass index (BMI), mild cardiac changes, and insulin resistance. Intellectual impairment was extremely rare.Conclusion: SEPN1-RM should be considered as a differential diagnosis in adult patients with delayed respiratory involvement. Extramuscular involvement such as body composition alterations deserves more clinical attention. The novel mutations of SELENON widened the genetic spectrum of patients with SEPN1-RM.

Feasibility of Therapeutic Drug Monitoring of Sunitinib and its implications on response and toxicity in patients with metastatic renal cell cancer

High interindividual variability in pharmacokinetics coupled with concentration-effect relationship make sunitinib an ideal candidate for therapeutic drug monitoring (TDM). The feasibility of TDM of sunitinib in patients with metastatic renal cell carcinoma (mRCC) was evaluated in this prospective observational study. Seventy patients with mRCC treated with sunitinib 50mg OD were enrolled. Total trough levels (TTL) of sunitinib and N-desethyl sunitinib were measured between days 10-14 of cycle 1. The discriminatory potential of TTL of sunitinib for the prediction of responders and occurrence of grade ≥3 toxicity was determined using receiver operating characteristic (ROC) curve. Threshold concentrations obtained from ROC analysis showed that TTL ≥60.75ng/mL was associated with higher response rates and TTL ≥82.3ng/mL was associated with higher incidence of grade ≥3 toxicity compared with lower exposures (31/34 versus 5/12, P=0.001 and 9/24 versus 4/36; P=0.024 respectively). More than 50% of patients in our cohort attained TTL outside the optimal range of 60.75-82.3 ng/mL demonstrating the feasibility of TDM.

Are Antioxidants Useful in Preventing the Progression of Chronic Kidney Disease?

Chronic kidney disease (CKD) is a progressive impairment of renal function for more than three months that affects 15% of the adult population. Because oxidative stress is involved in its pathogenesis, antioxidants are under study for the prophylaxis of CKD progression. The objective of this work was to meta-analyze the efficacy of antioxidant therapy in CKD patients and to identify the most effective candidate antioxidants. Our meta-analysis showed that, despite being quite heterogeneous, overall antioxidant therapy apparently reduced CKD progression. Pentoxifylline and bardoxolone methyl demonstrated a robust and statistically significant protection, while other products showed a favorable but non-significant tendency, due to a high interindividual variability. Off-target (i.e., antioxidant-independent) effects, such as body weight reduction and heart failure-associated blood dilution, might totally or partially explain the protection provided by effective antioxidants. This potential pleiotropy introduces uncertainty on the role of oxidative stress in CKD progression and on antioxidant therapy in its prevention, which needs to be further investigated. Independently, identification of factors determining the nephroprotective effect of each candidate on each patient is thus necessary for a prospectively personalized antioxidant therapy. Finally, pentoxifylline should be further explored for the prophylaxis of CKD progression.

The Person’s Care Requires a Sex and Gender Approach

There is an urgent need to optimize pharmacology therapy with a consideration of high interindividual variability and economic costs. A sex–gender approach (which considers men, women, and people of diverse gender identities) and the assessment of differences in sex and gender promote global health, avoiding systematic errors that generate results with low validity. Care for people should consider the single individual and his or her past and present life experiences, as well as his or her relationship with care providers. Therefore, intersectoral and interdisciplinary studies are urgently required. It is desirable to create teams made up of men and women to meet the needs of both. Finally, it is also necessary to build an alliance among regulatory and ethic authorities, statistics, informatics, the healthcare system and providers, researchers, the pharmaceutical and diagnostic industries, decision makers, and patients to overcome the gender gap in medicine and to take real care of a person in an appropriate manner.

Axillary microbiota is associated with cognitive impairment in Parkinson's disease patients

Introduction: Cognitive impairment (CI) is among the most common non-motor symptoms of Parkinson's disease (PD) with substantially negative impact on patient management and outcome. The development and progression of CI exhibits high interindividual variability which requires better diagnostic and monitoring strategies. PD patients often display sweating disorders resulting from autonomic dysfunction which has been associated with CI. As the axillary microbiota is known to change with humidity level and sweat composition, we hypothesized that axillary microbiota of PD patients shifts in association with CI progression thus can be used as proxy for classification of CI stages in PD. Methods: We compared the axillary microbiota compositions of 103 PD patients (55 PD patients with dementia (PDD) and 48 PD patients with mild cognitive impairment (PD-MCI)) and 26 cognitively normal healthy controls (HC). Results: We found that axillary microbiota profiles differentiate HC, PD-MCI and PDD groups based on differential ranking analysis and detected an increasing trend in the log ratio of Corynebacterium to Anaerococcus in progression from HC to PDD. In addition, phylogenetic factorization revealed that the depletion of Anaerococcus, Peptoniphilus and W5053 genera is associated with PD-MCI and PDD. Moreover, functional predictions suggested significant increase of myo-inositol degradation, ergothioneine biosynthesis, propionate biosynthesis, menaquinone biosynthesis, and the proportion of aerobic bacteria and biofilm formation capacity in parallel to CI. Conclusion: Our results suggest that alterations in axillary microbiota are associated with CI in PD. Thus, axillary microbiota holds potential to be exploited as a non-invasive biomarker in the development of novel strategies.

High Temporal Resolution Measurements of Movement Reveal Novel Early-Life Physiological Decline in C. elegans

Age-related physiological changes are most notable and best-studied late in life, while the nature of aging in early- or middle-aged individuals has not been explored as thoroughly. In C. elegans, studies of movement vs. age generally delineate three distinct phases: sustained, youthful movement; a discrete onset of rapidly progressing impairment; and gross immobility. We investigated whether this first period of early-life adult movement is simply a sustained “healthy” level of high function followed by a discrete “movement catastrophe” — or whether there are early-life changes in movement that precede future physiological declines. To determine how movement varies during early adult life, we followed isolated individuals throughout life with a previously unachieved combination of duration and temporal resolution. By tracking individuals across the first six days of adulthood, we observed declines in movement starting as early as the first two days of adult life, as well as high interindividual variability in total daily movement. These findings suggest that movement is a highly dynamic behavior early in life, and that factors driving movement decline may begin acting as early as the first day of adulthood. Using simulation studies based on acquired data, we suggest that too infrequent sampling in common movement assays limits observation of early-adult changes in motility, and we propose feasible alternate strategies and a framework for designing assays with increased sensitivity for early movement declines.

The Expression Profiles and Deregulation of UDP-Glycosyltransferase (UGT) Genes in Human Cancers and Their Association with Clinical Outcomes

The human UDP-glycosyltransferase (UGTs) superfamily has 22 functional enzymes that play a critical role in the metabolism of small lipophilic compounds, including carcinogens, drugs, steroids, lipids, fatty acids, and bile acids. The expression profiles of UGT genes in human cancers and their impact on cancer patient survival remains to be systematically investigated. In the present study, a comprehensive analysis of the RNAseq and clinical datasets of 9514 patients from 33 different TCGA (the Genome Cancer Atlas) cancers demonstrated cancer-specific UGT expression profiles with high interindividual variability among and within individual cancers. Notably, cancers derived from drug metabolizing tissues (liver, kidney, gut, pancreas) expressed the largest number of UGT genes (COAD, KIRC, KIRP, LIHC, PAAD); six UGT genes (1A6, 1A9, 1A10, 2A3, 2B7, UGT8) showed high expression in five or more different cancers. Kaplan–Meier plots and logrank tests revealed that six UGT genes were significantly associated with increased overall survival (OS) rates [UGT1A1 (LUSC), UGT1A6 (ACC), UGT1A7 (ACC), UGT2A3 (KIRC), UGT2B15 (BLCA, SKCM)] or decreased OS rates [UGT2B15 (LGG), UGT8 (UVM)] in specific cancers. Finally, differential expression analysis of 611 patients from 12 TCGA cancers identified 16 UGT genes (1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2A1, 2A3, 2B4, 2B7, 2B11, 2B15, 3A1, 3A2, UGT8) that were up/downregulated in at least one cancer relative to normal tissues. In conclusion, our data show widespread expression of UGT genes in cancers, highlighting the capacity for intratumoural drug metabolism through the UGT conjugation pathway. The data also suggests the potentials for specific UGT genes to serve as prognostic biomarkers or therapeutic targets in cancers.

Stability of Methylphenidate under Various pH Conditions in the Presence or Absence of Gut Microbiota

Methylphenidate is one of the most widely used oral treatments for attention-deficit/hyperactivity disorder (ADHD). The drug is mainly absorbed in the small intestine and has low bioavailability. Accordingly, a high interindividual variability in terms of response to the treatment is known among ADHD patients treated with methylphenidate. Nonetheless, very little is known about the factors that influence the drug’s absorption and bioavailability. Gut microbiota has been shown to reduce the bioavailability of a wide variety of orally administered drugs. Here, we tested the ability of small intestinal bacteria to metabolize methylphenidate. In silico analysis identified several small intestinal bacteria to harbor homologues of the human carboxylesterase 1 enzyme responsible for the hydrolysis of methylphenidate in the liver into the inactive form, ritalinic acid. Despite our initial results hinting towards possible bacterial hydrolysis of the drug, up to 60% of methylphenidate is spontaneously hydrolyzed in the absence of bacteria and this hydrolysis is pH-dependent. Overall, our results indicate that the stability of methylphenidate is compromised under certain pH conditions in the presence or absence of gut microbiota.