Relationship among low T3 levels, type 3 deiodinase, oxidative stress, and mortality in sepsis and septic shock : defining patient outcomes

Low T3 syndrome occurs frequently in patients with sepsis. Type 3 deiodinase (DIO3) is present in immune cells, but there is no description of its presence in patients with sepsis. Here, we aimed to determine the prognostic impact of thyroid hormones levels (TH), measured on ICU admission, on mortality and evolution to chronic critical illness (CCI) and the presence of DIO3 in white cells. We used a prospective cohort study with a follow-up for 28 days or deceased. Low T3 levels at admission were present in 86.5% of the patients. DIO3 was induced by 55% of blood immune cells. The cutoff value of 60 pg/mL for T3 displayed a sensitivity of 81% and specificity of 64% for predicting death, with an odds ratio of 4.89. Lower T3 yielded an area under the receiver operating characteristic curve of 0.76 for mortality and 0.75 for evolution to CCI, thus displaying better performance than commonly used prognostic scores. The high expression of DIO3 in white cells provides a novel mechanism to explain the reduction in T3 levels in sepsis patients. Further, low T3 levels independently predict progression to CCI and mortality within 28 days for sepsis and septic shock patients

Uncovering actions of type 3 deiodinase in the metabolic dysfunction-associated fatty liver disease (MAFLD)

Metabolic dysfunction-associated fatty liver disease (MAFLD) has gained worldwide attention as a public health problem. Nonetheless, lack of enough mechanistic knowledge restrains effective treatments. It is known that thyroid hormone triiodothyronine (T3) regulates hepatic lipid metabolism, and mitochondrial function. Liver dysfunction of type 3 deiodinase (D3) contributes to MAFLD, but its role is not fully understood. Objective: To evaluate the role of D3 in the progression of MAFLD in an animal model. Methodology: Male/adult Sprague Dawley rats (n = 20) were allocated to a control group (2.93 kcal/g) and high-fat diet group (4.3 kcal/g). Euthanasia took place on the 28th week. D3 activity and expression, Uncoupling Protein 2 (UCP2) and type 1 deiodinase (D1) expression, oxidative stress status, mitochondrial, Krebs cycle and endoplasmic reticulum homeostasis in liver tissue were measured. Results: We observed an increase in D3 activity/expression (p < 0.001) related to increased thiobarbituric acid reactive substances (TBARS) and carbonyls and diminished reduced glutathione (GSH) in the MAFLD group (p < 0.05). There was a D3-dependent decrease in UCP2 expression (p = 0.01), mitochondrial capacity, respiratory activity with increased endoplasmic reticulum stress in the MAFLD group (p < 0.001). Surprisingly, in an environment with lower T3 levels due to high D3 activity, we observed an augmented alpha-ketoglutarate dehydrogenase (KGDH) and glutamate dehydrogenase (GDH) enzymes activity (p < 0.05). Conclusion: Induced D3, triggered by changes in the REDOX state, decreases T3 availability and hepatic mitochondrial capacity. The Krebs cycle enzymes were altered as well as endoplasmic reticulum stress. Taken together, these results shed new light on the role of D3 metabolism in MAFLD

Short-term exercise training improves cardiac function associated to a better antioxidant response and lower type 3 iodothyronine deiodinase activity after myocardial infarction

Aims: We assessed the effects of a short-term exercise training on cardiac function, oxidative stress markers, and type 3 iodothyronine deiodinase (D3) activity in cardiac tissue of spontaneously hypertensive rats (SHR) following experimental myocardial infarction (MI). Methods: Twenty-four SHR (aged 3 months) were allocated to 4 groups: sham+sedentary, sham+trained, MI+sedentary and MI+trained. MI was performed by permanent ligation of the coronary artery. Exercise training (treadmill) started 96 hours after MI and lasted for 4 weeks (~60% maximum effort, 4x/week and 40 min/day). Cardiac function (echocardiography), thioredoxin reductase (TRx), total carbonyl levels, among other oxidative stress markers and D3 activity were measured. A Generalized Estimating Equation was used, followed by Bonferroni’s test (p<0.05). Results: MI resulted in an increase in left ventricular mass (p = 0.002) with decreased cardiac output (~22.0%, p = 0.047) and decreased ejection fraction (~41%, p = 0.008) as well as an increase in the carbonyl levels (p = 0.001) and D3 activity (~33%, p<0.001). Exercise training resulted in a decrease in left ventricular mass, restored cardiac output (~34%, p = 0.048) and ejection fraction (~20%, p = 0.040), increased TRx (~85%, p = 0.007) and reduced carbonyl levels (p<0.001) and D3 activity (p<0.001). Conclusions: Our short-term exercise training helped reverse the effects of MI on cardiac function. These benefits seem to derive from a more efficient antioxidant response and lower D3 activity in cardiac tissue

Non-thyroidal illness syndrome predicts outcome in adult critically ill patients : a systematic review and meta-analysis

We performed a systematic review and meta-analysis to comprehensively determine the prevalence and the prognostic role of non-thyroidal illness syndrome (NTIS) in critically ill patients. We included studies that assessed thyroid function by measuring the serum thyroid hormone (TH) level and in-hospital mortality in adult septic patients. Reviews, case reports, editorials, letters, animal studies, duplicate studies, and studies with irrelevant populations and inappropriate controls were excluded. A total of 6869 patients from 25 studies were included. The median prevalence rate of NTIS was 58% (IQR 33.2-63.7). In univariate analysis, triiodothyronine (T3) and free T3 (FT3) levels in non-survivors were relatively lower than that of survivors (8 studies for T3; standardized mean difference (SMD) 1.16; 95% CI, 0.41-1.92; I2 = 97%; P < 0.01). Free thyroxine (FT4) levels in non-survivors were also lower than that of survivors (12 studies; SMD 0.54; 95% CI, 0.31-0.78; I2 = 83%; P < 0.01). There were no statistically significant differences in thyrotropin levels between non-survivors and survivors. NTIS was independently associated with increased risk of mortality in critically ill patients (odds ratio (OR) = 2.21, 95% CI, 1.64-2.97, I2 = 65% P < 0.01). The results favor the concept that decreased thyroid function might be associated with a worse outcome in critically ill patients. Hence, the measurement of TH could provide prognostic information on mortality in adult patients admitted to ICU

Availability and affordability of medicines and cardiovascular outcomes in 21 high-income, middle-income and low-income countries

Objectives: We aimed to examine the relationship between access to medicine for cardiovascular disease (CVD) and major adverse cardiovascular events (MACEs) among people at high risk of CVD in high-income countries (HICs), upper and lower middle-income countries (UMICs, LMICs) and low-income countries (LICs) participating in the Prospective Urban Rural Epidemiology (PURE) study.Methods: We defined high CVD risk as the presence of any of the following: hypertension, coronary artery disease, stroke, smoker, diabetes or age \u3e55 years. Availability and affordability of blood pressure lowering drugs, antiplatelets and statins were obtained from pharmacies. Participants were categorised: group 1-all three drug types were available and affordable, group 2-all three drugs were available but not affordable and group 3-all three drugs were not available. We used multivariable Cox proportional hazard models with nested clustering at country and community levels, adjusting for comorbidities, sociodemographic and economic factors.Results: Of 163 466 participants, there were 93 200 with high CVD risk from 21 countries (mean age 54.7, 49% female). Of these, 44.9% were from group 1, 29.4% from group 2 and 25.7% from group 3. Compared with participants from group 1, the risk of MACEs was higher among participants in group 2 (HR 1.19, 95% CI 1.07 to 1.31), and among participants from group 3 (HR 1.25, 95% CI 1.08 to 1.50).Conclusion: Lower availability and affordability of essential CVD medicines were associated with higher risk of MACEs and mortality. Improving access to CVD medicines should be a key part of the strategy to lower CVD globally

Public attitudes towards automated external defibrillators: results of a survey in the Australian general population

BackgroundSwift defibrillation by lay responders using automated external defibrillators (AEDs) increases survival in out-of-hospital cardiac arrest (OHCA). This study evaluated newly designed yellow–red vs. commonly used green–white signage for AEDs and cabinets and assessed public attitudes to using AEDs during OHCA.MethodsNew yellow–red signage was designed to enable easy identification of AEDs and cabinets. A prospective, cross-sectional study of the Australian public was conducted using an electronic, anonymised questionnaire between November 2021 and June 2022. The validated net promoter score investigated public engagement with the signage. Likert scales and binary comparisons evaluated preference, comfort and likelihood of using AEDs for OHCA.ResultsThe yellow–red signage for AED and cabinet was preferred by 73.0% and 88%, respectively, over the green–white counterparts. Only 32% were uncomfortable with using AEDs, and only 19% indicated a low likelihood of using AEDs in OHCA.ConclusionThe majority of the Australian public surveyed preferred yellow–red over green–white signage for AED and cabinet and indicated comfort and likelihood of using AEDs in OHCA. Steps are necessary to standardise yellow–red signage of AED and cabinet and enable widespread availability of AEDs for public access defibrillation

Manganese deficiency alters the patterning and development of root hairs in Arabidopsis

Manganese (Mn) is the second most prevalent transition metal in the Earth's crust but its availability is often limited due to rapid oxidation and low mobility of the oxidized forms. Acclimation to low Mn availability was studied in Arabidopsis seedlings subjected to Mn deficiency. As reported here, Mn deficiency caused a thorough change in the arrangement and characteristics of the root epidermal cells. A proportion of the extra hairs formed upon Mn deficiency were located in atrichoblast positions, indicative of a post-embryonic reprogramming of the cell fate acquired during embryogenesis. When plants were grown under a light intensity of >50 μmol m−2 s−1 in the presence of manganese root hair elongation was substantially inhibited, whereas Mn-deficient seedlings displayed stimulated root hair development. GeneChip analysis revealed several candidate genes with potential roles in the reprogramming of rhizodermal cells. None of the genes that function in epidermal cell fate specification were affected by Mn deficiency, indicating that the patterning mechanism which controls the differentiation of rhizodermal cells during embryogenesis have been bypassed under Mn-deficient conditions. This assumption is supported by the partial rescue of the hairless cpc mutant by Mn deficiency. Inductively coupled plasma-optical emission spectroscopy (ICP-OES) analysis revealed that, besides the anticipated reduction in Mn concentration, Mn deficiency caused an increase in iron concentration. This increase was associated with a decreased transcript level of the iron transporter IRT1, indicative of a more efficient transport of iron in the absence of Mn

Enhanced Fear Expression in a Psychopathological Mouse Model of Trait Anxiety: Pharmacological Interventions

The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB), or normal (NAB) anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i) for identifying biological factors underlying misguided conditioned fear responses and (ii) for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias