9-cis-retinoic acid treatment increases serum concentrations of alpha-tocopherol in former smokers.

PURPOSE: Low serum concentrations of antioxidants may be associated with an increased risk of cancer. Based on the accumulated evidence, we hypothesized that retinoids would elevate serum alpha-tocopherol. This study was designed to determine whether 9-cis-retinoic acid (9-cis-RA), the most common chemopreventive agent, could alter serum alpha-tocopherol in former smokers. Because hyperlipidemia is a known side effect of retinoids, we also evaluated the association between serum alpha-tocopherol and lipids in the same population. EXPERIMENTAL DESIGN: Subjects who had stopped smoking at least 12 months before the study were randomly assigned to receive oral 9-cis-RA or placebo daily for 3 months. Clinical information and blood samples were obtained monthly; serum alpha-tocopherol concentrations were measured by high-performance liquid chromatography and lipid levels by enzymatic assays before treatment and every month during the treatment. RESULTS: Of the 149 subjects in the study, 113 completed 3 months of treatment and provided samples for evaluation of serum alpha-tocopherol. Serum alpha-tocopherol levels in the 9-cis-RA group (n = 52) were higher after treatment (r = 0.445, P < 0.01) than before. The incidences of grade > or =2 hypertriglyceridemia and hypercholesterolemia were higher in the 9-cis-RA group than in the placebo group (P = 0.0005 and P = 0.01, respectively), but there were no serious complications related to hyperlipidemia. CONCLUSIONS: Treatment of former smokers with 9-cis-RA significantly increased their serum alpha-tocopherol levels, and this could be a benefit. In addition, serum alpha-tocopherol could serve as a biomarker for 9-cis-RA treatment.     

Risk factors and individual probabilities of melanoma for whites.

PURPOSE: Incidence and mortality of cutaneous melanoma is rising rapidly in the United States; therefore, identifying risk factors for melanoma and integrating them into a clinical and population risk estimation tool may help guide prevention efforts and identify participants for preventive interventions. METHODS: We examined risk factors for melanoma in three large prospective studies of women and men. We observed 152,949 women and 25,206 men free of cancer at baseline for up to 14 years. RESULTS: A total of 535 incident cases of invasive melanoma (444 women and 91 men) were included in the analysis. We combined the three studies to examine risk factors and to build a risk model to calculate melanoma risk score. Older age, male sex, family history of melanoma, higher number of nevi, history of severe sunburn, and light hair color were each associated with significantly elevated risk of melanoma and were included in the final risk prediction. Participants at the highest decile of risk had a more than three-fold increase in risk of melanoma compared with those in the lowest decile (observed relative risk, 3.61; expected relative risk, 4.20). The measure of discriminatory accuracy as summarized by an age-and sex-adjusted concordance statistic of 0.62 (95% CI, 0.58 to 0.65) indicated that the model had reasonable ability to differentiate those who will develop melanoma and those who will remain free from the disease. CONCLUSION: We identified several risk factors for melanoma and developed statistical models with adequate performance and discriminatory accuracy.     

L-Serine Treatment is Associated with Improvements in Behavior,EEG, and Seizure Frequency in Individuals with GRIN-Related Disorders Due to Null Variants

Pathogenic missense variants in GRIN2A and GRIN2B may result in gain or loss of function (GoF/LoF) of the N-methyl-D-aspartate receptor (NMDAR). This observation gave rise to the hypothesis of successfully treating GRIN-related disorders due to LoF variants with co-agonists of the NMDAR. In this respect, we describe a retrospectively collected series of ten individuals with GRIN2A- or GRIN2B-related disorders who were treated with L-serine, each within an independent n-of-1 trial. Our cohort comprises one individual with a LoF missense variant with clinical improvements confirming the above hypothesis and replicating a previous n-of-1 trial. A second individual with a GoF missense variant was erroneously treated with L-serine and experienced immediate temporary behavioral deterioration further supporting the supposed functional pathomechanism. Eight additional individuals with null variants (that had been interpreted as loss-of-function variants despite not being missense) again showed clinical improvements. Among all nine individuals with LoF missense or null variants, L-serine treatment was associated with improvements in behavior in eight (89%), in development in four (44%), and/or in EEG or seizure frequency in four (44%). None of these nine individuals experienced side effects or adverse findings in the context of L-serine treatment. In summary, we describe the first evidence that L-serine treatment may not only be associated with clinical improvements in GRIN-related disorders due to LoF missense but particularly also null variants.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01173-9.     

Systemic oxidative stress in children with cystic fibrosis with bacterial infection including Pseudomonas Aeruginosa

IntroductionOxidative stress (OS) occurs in cystic fibrosis (CF).ObjectiveThe objective of this work is to evaluate the influence of bacterial infection on biomarkers of OS (catalase [CAT], glutathione peroxidade [GPx], reduced glutathione [GSH]), markers of oxidative damage (protein carbonyls [PC], thiobarbituric acid reactive substances [TBARS]), together with the nutritional status and lung function in children with CF.MethodsCross‐sectional study including CF group (CFG, n = 55) and control group (CG, n = 31), median age: 3.89 and 4.62 years, respectively. CFG was distributed into CFG negative bacteriology (CFGB−, n = 27) or CFG positive bacteriology (CFGB+, n = 28), and CFG negative Pseudomonas aeruginosa (CFGPa−, n = 36) or CFG positive Pseudomonas aeruginosa (CFGPa+, n = 19).ResultsCompared with CG, CFG (P = .034) and CFGB+ (P = .042) had lower body mass index‐for‐age z‐score; forced expiratory volume in the first second was lower in CFGB+ and CFGPa+ (both P < .001). After adjusting for confounders and compared with CG: CFG showed higher TBARS (P ≤ .001) and PC (P = .048), and lower CAT (P = .004) and GPx (P = .003); the increase in PC levels was observed in CFGB+ (P = .011) and CFGPa+ (P = .001) but not in CFGB− (P = .510) and CFGPa− (P = .460).ConclusionsThese results indicate a systemic OS in children with CF. The presence of bacterial infection particularly Pseudomonas aeruginosa seems to be determinant to exacerbate the oxidative damage to proteins, in which PC may be a useful biomarker of OS in CF.     

Revisiting the fetal loss rate after second-trimester genetic amniocentesis: a single center's 16-year experience

OBJECTIVE: To estimate an institution's specific fetal loss rate after a second-trimester genetic amniocentesis. METHODS: This is a retrospective cohort study using our prenatal diagnosis database for all pregnant women presenting for care between 1990 and 2006. We compared the fetal loss rate in women who underwent amniocentesis between 15 and 22 weeks of gestation with those women who did not have any invasive procedure and had a live fetus documented on ultrasound examination between 15 and 22 weeks. Only singleton gestations were included. Logistic regression analysis was used to adjust for potential confounders between the groups. RESULTS: Among 58,436 women meeting the inclusion criteria, complete outcome data were available for 51,557 (88%), 11,746 (91%) in the amniocentesis group and 39,811 (87%) in the group that did not have amniocentesis. The fetal loss (miscarriages and intrauterine fetal death) rate in the amniocentesis group was 0.4% compared with 0.26% in those without amniocentesis (relative risk 1.6, 95% confidence interval [CI] 1.1-2.2). Fetal loss less than 24 weeks (including induction for ruptured membranes and oligohydramnios) occurred in 0.97% of the amniocentesis group and 0.84% of the group with no procedure (P=.33). The fetal loss rate less than 24 weeks attributable to amniocentesis was 0.13% (95% CI -0.07 to 0.20%) or 1 in 769. The only subgroup that had a significantly higher amniocentesis attributable fetal loss rate was women with a normal serum screen (0.17%, P=.03). CONCLUSION: The institutional fetal loss rate attributable to amniocentesis is 0.13%, or 1 in 769 at Washington University School of Medicine. The total fetal loss rate was not significantly different from that observed in patients who had no procedure.