Oral Administration of Ginger-Derived Lipid Nanoparticles and Dmt1 siRNA Potentiates the Effect of Dietary Iron Restriction and Mitigates Pre-Existing Iron Overload in Hamp KO Mice

Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including ⁵⁹Fe (as FeCl₃) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40–50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.     

Evaluating Differences in Whole Blood,Serum, and Urine Screening Tests for Zika Virus,Puerto Rico,USA, 2016

We evaluated nucleic acid amplification testing (NAAT) for Zika virus on whole-blood specimens compared with NAAT on serum and urine specimens among asymptomatic pregnant women during the 2015–2016 Puerto Rico Zika outbreak. Using NAAT, more infections were detected in serum and urine than in whole blood specimens.     

Lycium barbarum polysaccharide fraction associated with photobiomodulation protects from epithelium thickness and collagen fragmentation in a model of cutaneous photodamage

Lasers in Medical Science - Ultraviolet radiation (UVR) is the major etiologic agent of cutaneous photoaging, and different strategies are used to prevent and treat this condition. The...     

Impact of Cold Ischemia Time on the Function of Liver Grafts Preserved With Custodiol

ObjectiveThis study aimed to evaluate how cold ischemia time (CIT) interferes with liver graft function in the first 7 days after surgery for Custodiol (HTK) preserved organs.MethodsThis retrospective observational study analyzed the medical records of 38 transplantation patients at Hospital Leforte Liberdade, São Paulo, in 2018. The study population was divided into 2 groups (group A, CIT < 8 hours; group B, CIT > 8 hours). Postoperative parameters—such as international normalized ratio, total bilirubin, aspartate aminotransferase/alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase (GGT), lactate dehydrogenase, lactate, creatinine, red blood cell transfusion, need for hemodialysis, use of vasoactive drugs, endotracheal intubation time, length of stay in the intensive care unit (ICU), and length of hospital stay—were compared.ResultsGroup A (CIT < 8 hours) presented less need for red blood cell transfusions (odds ratio 0.29; confidence interval 0.06-0.98; P = .04), had a shorter hospital stay (P = .024), and had lower levels of total bilirubin (P = .05) and GGT (P = .05) in the first 7 postoperative days. The other variables showed no statistically significant difference.ConclusionIn livers preserved with Custodiol, CIT > 8 hours generated higher levels of total bilirubin and GGT in the postoperative period, in addition to higher hospital costs; greater need for red blood cell transfusions; and longer hospitalization, including longer stays in the ICU.     

500 Consecutive Liver Transplants: The Outcomes of a New Transplantation Program in the Middle West of Brazil

IntroductionLiver transplantation is the standard treatment for end-stage liver disease. Brazil holds the third highest number of liver transplants performed per year, but center maldistribution results in high discrepancies in accessing this treatment. In 2012, an interstate partnership successfully implemented a new liver transplantation program in the middle west of Brazil. Here, we report the results of the first 500 liver transplants performed in this new program and discuss the impacts of a new transplant center in regional transplantation dynamics.MethodsWe reviewed data from the first 500 consecutive deceased donor liver transplants performed in the new program during an 8-year period. We analyzed data on patients’ clinical and demographic profiles, postoperative outcomes, and graft and recipient survival rates. Univariate survival analysis was conducted using log-rank tests to compare the groups.ResultsAlmost half (48%) of the procured organs and 40% of the recipients transplanted in our center were from outside our state. Recipient 30-day mortality was 9%. Overall recipient survival at 1 year and 5 years was 85% and 80%, respectively. Mortality was significantly associated with higher Model for End-Stage Liver Disease (P < .001) but not with the presence of hepatocellular carcinoma (P = .795).DiscussionThe new transplantation program treated patients from different regions of Brazil and became the reference center in liver transplantation for the middle west region. Despite the recent implementation, our outcomes are comparable to experienced centers around the world. This model can inspire the creation of new transplantation programs aiming to democratize access to liver transplantation nationwide.     

“It’s a tool,not a cure”: the preoperative teen perspective on bariatric surgery

BackgroundBariatric surgery is well established in adults as the most effective tool for sustained weight loss and reduction of obesity-related co-morbidities, and is an emerging option for adolescents in whom conservative approaches have failed. Narratives are vital in understanding the motivating reasons and psychosocial profiles of adolescents considering bariatric surgery during a developmental period of evolving self-concept, body image sensitivity, peer pressure, and increased opportunity for risky behaviors.ObjectivesTo explore preoperative adolescent patient perspectives on their decision to pursue bariatric surgery, anticipated physical and psychosocial effects, and preparation process.SettingsThe Hospital for Sick Children (SickKids) in Toronto, Ontario, Canada.MethodsWe conducted 14 semi-structured interviews with adolescents (16–18 yr old) 2–4 months before bariatric surgery. A theoretical thematic analysis was conducted with 3 independent reviewers (interrater reliability, Cronbach’s α= .81) and conflicts were resolved through discussion.ResultsPatients’ perspectives are captured in 4 themes: motivation for surgery, effects on health and habits, psychosocial changes, and support systems during preparation. Participants perceived surgery as a tool but not a solution for weight loss. Most were motivated for health and daily functional improvement rather than aesthetic reasons, and some anticipated improved social interactions while maintaining their self-identity. Participants were selective in sharing news of their surgery, and received varying levels of support from families, friends, and healthcare teams.ConclusionAdolescents seem generally prepared for and informed about surgery, with expectations for weight loss and psychosocial improvements, although uncertainty and contradictory thoughts were prevalent. Insights provided by these adolescent patients will help optimize bariatric surgery assessments and support from clinical teams and inform preoperative education for future patients and families.     

Higher mortality rates associated with rheumatoid arthritis in Saskatchewan,Canada, 2001–2019

ObjectivesTo estimate provincial all-cause mortality rates of Saskatchewan people with rheumatoid arthritis (RA) for comparison with the general population over time and between different geographic regions.MethodsSaskatchewan provincial administrative health databases (2001–2019) were utilized as data sources. Two RA case definitions were employed: (1) ≥ 3 physician billing diagnoses, at least 1 from a specialist (rheumatologist, general internist or orthopaedic surgeon) within 2 years; (2) ≥ 1 hospitalization diagnosis (ICD-9 code 714, and ICD-10-CA codes M05, M06). Data from these definitions were combined to create an administrative data RA cohort. All-cause mortality rates across geographic regions, between rural/urban residences and between sexes were examined.ResultsOver an 18-year span, between fiscal-year 2001–2002 and fiscal-year 2018–2019, age- and sex-adjusted mortality rates ranged from 17.10 to 21.04 (95% CI 14.77, 19.44; 18.03, 24.05)/1000 RA person-years, compared with mortality rates for the general Saskatchewan population without RA, which ranged from 9.37 to 10.88 (95% CI 9.23, 9.51; 10.72, 11.05)/1000 person-years. Fiscal-year mortality rate ratios ranged from 1.82 to 2.13 (95% CI 1.56, 2.13; 1.83, 2.46). Provincial mortality rates were higher in men than in women for both general and RA populations. Northern Saskatchewan mortality rates were significantly higher in the general population but did not achieve significance compared with other provincial regions for the RA population. Regression analysis identified age, male sex, RA and geographic region as factors contributing to increased mortality. A trend towards lower mortality rates over time was observed.ConclusionHigher mortality rates were observed in the RA population overall. Men had higher mortality rates, as did residents of Northern Saskatchewan compared with residents of other regions for the general population.     

Impact of Tdap vaccine during pregnancy on the incidence of pertussis in children under one year in Brazil – A time series analysis

Pertussis is a globally distributed infectious disease that is a significant cause of morbidity and mortality, especially in infants who are too young to be immunized. This disease is common in childhood, and when it occurs during the first few months of life, it leads to hospitalization and, sometimes, death. Brazil has adopted the strategy of maternal immunization against pertussis in late 2014. This study aims to analyze public data on the disease to determine whether there was an impact on the disease burden following the introduction of the vaccine Tdap in pregnant women and its magnitude. We performed a time-series analysis of the incidence of pertussis between October 2010 and January 2019. We stratified the population of interest into three groups: infants aged less than two months old, infants aged two to six months, and infants aged six months to one year, according to Brazil's vaccination schedule. We found a protective effect of maternal vaccination in all age groups, more prominent on the first group. Before the intervention, infants under two months had a higher risk of getting pertussis in comparison with infants two to six months old (HR 1.15, CI 95%: 1.11–1.19). After the intervention, age under two months is a protective factor compared with two to six months (HR 0.90, CI 95%: 0.82–0.98). The pertussis incidence reduced in all age groups and all Brazil's Regions.     

Interaction with 14-3-3 proteins promotes functional expression of the potassium channels TASK-1 and TASK-3

The two-pore-domain potassium channels TASK-1, TASK-3 and TASK-5 possess a conserved C-terminal motif of five amino acids. Truncation of the C-terminus of TASK-1 strongly reduced the currents measured after heterologous expression in Xenopus oocytes or HEK293 cells and decreased surface membrane expression of GFP-tagged channel proteins. Two-hybrid analysis showed that the C-terminal domain of TASK-1, TASK-3 and TASK-5, but not TASK-4, interacts with isoforms of the adapter protein 14-3-3. A pentapeptide motif at the extreme C-terminus of TASK-1, RRx(S/T)x, was found to be sufficient for weak but significant interaction with 14-3-3, whereas the last 40 amino acids of TASK-1 were required for strong binding. Deletion of a single amino acid at the C-terminal end of TASK-1 or TASK-3 abolished binding of 14-3-3 and strongly reduced the macroscopic currents observed in Xenopus oocytes. TASK-1 mutants that failed to interact with 14-3-3 isoforms (V411*, S410A, S410D) also produced only very weak macroscopic currents. In contrast, the mutant TASK-1 S409A, which interacts with 14-3-3-like wild-type channels, displayed normal macroscopic currents. Co-injection of 14-3-3ζ cRNA increased TASK-1 current in Xenopus oocytes by about 70 %. After co-transfection in HEK293 cells, TASK-1 and 14-3-3ζ (but not TASK-1ΔC5 and 14-3-3ζ) could be co-immunoprecipitated. Furthermore, TASK-1 and 14-3-3 could be co-immunoprecipitated in synaptic membrane extracts and postsynaptic density membranes. Our findings suggest that interaction of 14-3-3 with TASK-1 or TASK-3 may promote the trafficking of the channels to the surface membrane.