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Manganese- and Platinum-Driven Oxidative and Nitrosative Stress in Oxaliplatin-Associated CIPN with Special Reference to Ca<inf>4</inf>Mn(DPDP)<inf>5</inf>, MnDPDP and DPDP
No full textPlatinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative-nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca4Mn(DPDP)5; PledOx®], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca4Mn(DPDP)5 in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca4Mn(DPDP)5, a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca4Mn(DPDP)5. The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca4Mn(DPDP)5 may be explained by redox interactions between Pt2+ and Mn2+ and subtle oxidative-nitrosative chain reactions. In peripheral sensory nerves, Pt2+ presumably leads to oxidation of the Mn2+ from Ca4Mn(DPDP)5 as well as from Mn2+ in MnSOD and other endogenous sources. Thereafter, Mn3+ may be oxidized by peroxynitrite (ONOO-) into Mn4+, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O2•-) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt2+-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca4Mn(DPDP)5 mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt2+-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt2+ outcompetes Mn2+ and endogenous Zn2+ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt2+ by DPDP, which in turn suggests that Mn2+ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.publishedVersio
Morbidity among Adolescent Hypnotic Drug Users in Norway: An Observational Population-Based Study
Full text linkWe have previously shown that the use of hypnotic drugs increased among young Scandinavians during 2012-2018. This study aimed to explore psychiatric and somatic morbidity among adolescent hypnotic drug users in a cohort study of 13-17-year-old individuals during 2008-2018 in Norway. Data sources were (i) prescription data from the Norwegian Prescription Database linked to specialist health care diagnoses from the Norwegian Patient Registry and (ii) sleep disorder diagnoses from the Primary Health Care Database. Hypnotic drugs were defined as the sedative antihistamine alimemazine and the ATC group "Hypnotics and Sedatives" (N05C), excluding midazolam. In 2017, 2519 girls (16.5/1000) and 1718 boys (10.7/1000) were incident (new) users of hypnotic drugs. Most of these new users (82% of girls, 77% of boys) were referred to secondary health care, where the most frequent diagnoses were mental and behavioral disorders (51.8% of girls, 46.2% of boys), while only 3.2% received a specific sleep disorder diagnosis. The most common mental and behavioral disorders were "Neurotic stress-related disorders" among girls (27.4%) and "Behavioral and emotional disorders" among boys (23.6%). In conclusion, the trend of increasing hypnotic drug use among adolescents reflects the initiation of hypnotic drugs in a subgroup of the population with a higher disease burden, mainly due to psychiatric disorders, than the general population.publishedVersio
Reference Ranges and Determinants of Thyroid Function and TSH Receptor Antibodies During Early Pregnancy in Nepal
Full text linkObjective: Different definitions of thyroid dysfunction during pregnancy may lead to under or overtreatment. The aims of this study were to (1) define population-based pregnancy-specific reference ranges for thyroid dysfunction during early pregnancy in Nepal and assess the impact of antibody positivity, (2) quantify the diagnostic impact of population-based reference ranges compared with current practice and (3) assess the determinants of thyroid function and antibody positivity. Methods: A total of 800 healthy pregnant women aged 20-40 years in the Bhaktapur municipality were included. Population-based reference ranges for thyroid hormones levels were defined as 2.5th and 97.5th percentiles using competitive immunoluminometric assay design. Thyroid disease cases and those with recommended treatment indications were calculated using current non-pregnancy new reference ranges. Multivariate regression analyses were performed to identify the determinants of thyroid hormones and antibody levels. Results: Median gestational age was 11 weeks. The reference interval was 0.05-3.69 µLU/mL for thyroid stimulating hormone (TSH) and 8.89-15.28 pg/mL for free tetraiodothyronine (fT4) after excluding thyroid peroxidase antibody-positive women. Compared with the current non-pregnancy reference ranges, the new calculations increased the number of women who required treatment from 5 to 12 (0.9% increase). We identified 19 women (2.4%) who were positive for TSH receptor antibody (TRAb). We could not identify the determinants of TRAb positivity, and TRAb positivity was not associated with TSH or fT4 levels. Conclusions: We found meaningful changes using population-based pregnancy-specific TSH and fT4 reference intervals and encourage further studies in other low- and middle-income settings. Our findings suggest that population screening for TRAb is not clinically meaningful. Trial registration: Clinical Trial Registration: U1111-1183-4093.publishedVersio
Identifying excessive chronic alcohol use with phosphatidylethanol in patients with suspected severe injury-results from the IDART study
Full text linkIntroduction: Acute and chronic alcohol use are well-known risk factors for accidents and injuries, and concurrent psychoactive drug use can increase injury risk further. Phosphatidylethanol (PEth) 16:0/18:1 is a biomarker used to determine alcohol consumption the previous 3-4 weeks. The aim was to investigate the prevalence of chronic alcohol use in trauma patients, as determined by PEth 16:0/18:1 concentrations, and how excessive chronic alcohol use relate to demographic variables, injury mechanisms and drug use. Setting: Patients received at Norwegian trauma hospitals from March 2019 to February 2020. The study is part of the Impairing Drugs and Alcohol as Risk factors for Traumatic Injuries study. Methods: All patients aged ≥ 16 years received with trauma team were included in the study. Data on injury date and mechanism, gender and age was registered. Blood samples were analyzed for 22 psychoactive medicinal and illicit drugs, ethanol and phosphatidylethanol 16:0/18:1. Regression analyses were conductepublishedVersio
Social withdrawal behaviour in Nepalese infants and the relationship with future neurodevelopment; a longitudinal cohort study
Full text linkBackground Social withdrawal in infants may be a signal of distress and a precursor for non-optimal development. Objective To examine the relationship between infant social withdrawal and neurodevelopment up to 4 years in Nepalese children. Methods A total of 597 Nepalese infants 6–11 months old were assessed with the modified Alarm Distress Baby Scale (m-ADBB), and of these, 527 with the Bayley Scales of Infant and Toddler Development 3rd edition (Bayley-III) during early childhood, and the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) and NEPSY-II subtests at 4 years. We examined whether social withdrawal defined by the m-ADBB was associated with neurodevelopmental scores in regression models. Results Children socially withdrawn in infancy had lower Bayley-III language scores (-2.6 (95% CI -4.5, -0.7)) in early childhood. This association seems to be driven by the expressive communication subscale (-0.7 (95% CI -1.0, -0.3)), but not the receptive communication subscale (-0.2 (95% CI -0.6, 0.1)). There were no differences in the other Bayley-III scores or the WPPSI-IV and NEPSY-II scores at 4 years in children who were socially withdrawn or not. Conclusion Social withdrawal in infancy was reflected in early language development but not cognitive functioning at 4 years.Open access funding provided by University of Bergen. The study was funded by Thrasher Research fund (award 11512).publishedVersio
Reference intervals for 23 common biochemical parameters during pregnancy and the first six postpartum months
Full text linkThe concentration of many biochemical parameters changes significantly during pregnancy and the postpartum period, causing a need for specific reference values for biochemical parameters in these life periods. We have collected blood samples in pregnancy week 18, 28 and 36 and six weeks, four months and six months postpartum from 139 healthy women. Blood samples from 59 healthy never-pregnant women were included as controls. Serum samples were analyzed for 23 common biochemical parameters and reference intervals for pregnancy and postpartum periods were computed with the non-parametric method in accordance with recommendations from IFCC and CLSI. The dynamics of different biochemical parameters during and after pregnancy vary considerably between parameters. Some analytes like serum amylase and HDL cholesterol do not differ from never-pregnant values. Of the 23 parameters, serum alkaline phosphatase, chloride, gamma-glutamyl transferase and sodium and urea which were still significantly changed at six months postpartum compared to never-pregnant women. The physiological changes related to pregnancy and lactation have profound effects on biochemical parameters, denoting the use of specific reference intervals for both pregnancy and the postpartum period.publishedVersio
Impact of an integrated health, nutrition, and early child stimulation and responsive care intervention package delivered to preterm or term small for gestational age babies during infancy on growth and neurodevelopment: study protocol of an individually randomized controlled trial in India (Small Babies Trial)
Full text linkBackground: Preterm and term small for gestational age (SGA) babies are at high risk of experiencing malnutrition and impaired neurodevelopment. Standalone interventions have modest and sometimes inconsistent effects on growth and neurodevelopment in these babies. For greater impact, intervention may be needed in multiple domains-health, nutrition, and psychosocial care and support. Therefore, the combined effects of an integrated intervention package for preterm and term SGA on growth and neurodevelopment are worth investigating. Methods: An individually randomized controlled trial is being conducted in urban and peri-urban low to middle-socioeconomic neighborhoods in South Delhi, India. Infants are randomized (1:1) into two strata of 1300 preterm and 1300 term SGA infants each to receive the intervention package or routine care. Infants will be followed until 12 months of age. Outcome data will be collected by an independent outcome ascertainment team at infant ages 1, 3, 6, 9, and 12 months and at 2, 6, and 12 months after delivery for mothers. Discussion: The findings of this study will indicate whether providing an intervention that addresses factors known to limit growth and neurodevelopment can offer substantial benefits to preterm or term SGA infants. The results from this study will increase our understanding of growth and development and guide the design of public health programs in low- and middle-income settings for vulnerable infants. Trial registration: The trial has been registered prospectively in Clinical Trial Registry - India # CTRI/2021/11/037881, Registered on 08 November 2021. Keywords: Child health; Early child stimulation; Growth failure; Intrauterine growth restriction; Responsive stimulation; Small for gestational age; Small vulnerable newborns; preterm. © 2024. The Author(s).The study was funded by Centre for Intervention Science in Maternal and Child Health at the University of Bergen (Bergen, Norway). The funding agency did not play any role in the design of the study and is neither involved in nor has any influence over the collection of analysis or interpretation of data.publishedVersio
Investigation of the Impact of Defective Ultrasound Transducers on Clinical Image Quality in Grayscale 2-D Still Images
Full text linkObjective: There are several studies that show high defect rates of transducers in clinical use. The purpose of the present study was to investigate whether image quality and the risk for misdiagnosis is affected by using defective transducers. Methods: Four defective transducers with varying degrees of defect severity, still in clinical use, were selected. Forty artifact-affected clinical images from each transducer were compared with images acquired from fully functional transducers, of the same model, in an observer study where four experienced radiologists rated each of the 320 images. The rating tasks included if the artifacts were detectable, if the possible artifacts might affect the diagnosis, how well structural details were reproduced and, finally, an assessment of overall image quality. Results: The artifacts in the images were detectable for three of the four transducers (p < 0.05), and in 121 of 640 assessments of the images from the defective transducers the observers were confident that the artifacts could affect the diagnosis. All four faulty transducers were assessed to have decreased ability to resolve structural details (p < 0.05), and three of the four transducers were assessed to have worse overall image quality (p < 0.05). Conclusion: The present study shows that image quality and the risk of misdiagnosis can be affected by using defective transducers. This highlights the importance of frequent quality control of the transducers to avoid decreased image quality and even misdiagnosis.publishedVersio
Adolescence internalizing problems as a mediator between autism diagnosis in childhood and quality of life in emerging adults with and without autism: a 10-year longitudinal study
Full text linkBackground Individuals with autism tend to have a reduced quality of life across their lifespan. This reduced quality of life may be a result of autism traits, mental distress, and poor person/environment fit. In this longitudinal study, we looked at the role of adolescence internalizing and externalizing problems in mediating the relationship between having an autism diagnosis from childhood and perceived quality of life as emerging adults.Methods A total of 66 participants in a group of emerging adults with autism (mean age 22.2 years), and without autism (mean age 20.9 years) were assessed in three assessment waves (T1 at 12 years, T2 at 14 years, and T3 at 22 years of age). Parents filled out the Child Behavior Checklist at T2 and participants filled out the Perceived Quality of Life Questionnaire at T3. Total and indirect effects were tested in serial mediation analysis.Results The results showed that internalizing problems fully mediated the association between childhood autism diagnosis and the quality of life in emerging adulthood, while externalizing problems did not.Conclusion Our findings suggest that attention to adolescent internalizing problems is important to improve the later quality of life for emerging adults with autism.This work was supported by grants from Innlandet Hospital Trust (grant numbers: 150610, 150624, and 150648) and the Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Department of Rare Disorders and Disabilities, Oslo University Hospital (grant number: 150616).publishedVersio
Thiamin (Vitamin B1) – A scoping review for Nordic Nutrition Recommendations 2023
Full text linkOnly a few studies have explored relationships between thiamine intake and function, and a few studies have examined the effects of supplements on various clinical or biochemical outcomes. None of these studies, however, makes a useful contribution to understanding requirements in healthy populations. The requirement of thiamine relates to energy and carbohydrate intake. Clinical signs of deficiency have been observed at intakes below 0.5 mg/day, which corresponds to 0.05 mg/MJ. In other studies, thiamine excretion in the urine and normalisation of enzyme activity were normalised at intakes of 0.07-0.08 mg/MJ. The lower limit of intake thus estimates at 0.05 mg/MJ. It has not been possible to set a safe upper intake level for thiamine due to a lack of data. Studies on pregnant and lactating women indicate a higher requirement as assessed by biochemical parameters. A few studies indicate that thiamine utilisation is impaired among elderly subjects. Keywords: recommendations; thiamine; vitamin B1; vitamins.Thiamin (Vitamin B1) – A scoping review for Nordic Nutrition Recommendations 2023publishedVersio