Determining cut-off points in functional assessment scales in stroke

[EN] BACKGROUND: A wide variety of well-validated assessment scales of functioning and disability have been developed for stroke population. However, these instruments have limitations in their interpretation. Therefore, determining cut-off points for their categorization becomes necessary. OBJECTIVES: To determine cut-off points for the BI, FIM and FAM scales to differentiate clinical disability categories and to establish the relationship between mRS and DOS scales. METHODS: One hundred and six adults with ischemic or haemorrhagic stroke were mainly recruited from a rehabilitation facility (Hospitales Nisa, Valencia, Spain). RESULTS: A high correlation was observed between the DOS and mRS scales (Kendall's tau-b = 0.475; p = 0.000) although a certain amount of disagreement between the two scales was detected. The cut-off points were 62.90 (95% CI, 57.26-69.29) and 21.30 (95% CI, 16.34-26.03) for the BI; 70.62 (95% CI, 66.65-75.22) and 38.29 (95% CI, 34.07-42.25) for the FIM; and 116.07 (95% CI, 110.30-122.68) and 66.02 (95% CI, 59.20-72.35) for the FAM. CONCLUSION(S): DOS was observed to be more demanding than the mRS, in terms of patient independence. Additionally, the lower cut-off points separating the levels of severe and moderate disability in the BI, FIM and FAM were determined. These findings would facilitate practitioners clinical interpretation of disability levels in post-stroke patients.Balasch I Bernat, M.; Balasch Parisi, S.; Noe Sebastian, E.; Dueñas Moscardo, L.; Ferri Campos, J.; Lopez Bueno, L. (2015). Determining cut-off points in functional assessment scales in stroke. NeuroRehabilitation. 37(2):165-172. doi:10.3233/NRE-151249S16517237

Tissue-specific suppression of thyroid hormone signaling in various mouse models of aging

DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNAdamaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging

Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection

Decreased serum thyroid hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in thyroid hormone levels, together known as nonthyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of thyroid hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in thyroid hormone metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum thyroid hormone levels and potentially relevant for disease progressio

Thyroid Hormone Receptor alpha Modulates Lipopolysaccharide-Induced Changes in Peripheral Thyroid Hormone Metabolism

Acute inflammation is characterized by low serum T-3 and T-4 levels accompanied by changes in liver type 1 deiodinase (D1), liver D3, muscle D2, and muscle D3 expression. It is unknown at present whether thyroid hormone receptor alpha (TR alpha) plays a role in altered peripheral thyroid hormone metabolism during acute illness in vivo. We induced acute illness in TR alpha-deficient (TR alpha(0/0)) mice by administration of a sublethal dose of LPS. Compared with wild-type, TR alpha(0/0) mice have lower basal serum T-4 and lower liver D1 activity and muscle D3 mRNA expression, whereas liver D3 activity is higher. These changes are gender specific. The inflammatory response to LPS was similar in WT and TR alpha(0/0) mice. The decrease in serum thyroid hormones and liver D1 was attenuated in TR alpha(0/0) mice, whereas the LPS induced fall in liver D3 mRNA was more pronounced in TR alpha(0/0) mice. Muscle D2 mRNA increased similarly in both strains, whereas muscle D3 mRNA decreased less pronounced in TR alpha(0/0) mice. We conclude that alterations in peripheral thyroid hormone metabolism induced by LPS administration are partly regulated via TR alpha. (Endocrinology 151: 1959-1969, 2010

Impaired bacterial clearance in type 3 deiodinase deficient mice infected with Streptococcus pneumoniae

The activation of type 3 deiodinase (D3) has been postulated to play a role in the reduction of thyroid hormone levels during illness. Using a mouse model of acute bacterial infection, we have recently demonstrated marked D3 immunostaining in neutrophils infiltrating infected organs. These observations suggest a possible additional role for this enzyme in the innate immune response. To further assess the role of D3 in the response to acute bacterial infection, we used null D3 (D3KO) and wild type (WT) mice and infected them with Streptococcus (S). pneumoniae. Marked reductions in serum thyroid hormone levels were observed both in D3KO and WT mice. Infection resulted also in a decrease in liver D1 activity in WT, but not in infected D3KO mice. Upon infection, pulmonary neutrophilic influx (measured by MPO levels), IL-6 and TNF concentrations increased equally in D3KO and WT mice and histological examination of infected mice showed similar pulmonary inflammation in both strains. However, D3KO animals demonstrated significantly higher bacterial load in blood, lung and spleen compared to WT mice. We conclude that: 1) D3 is not required to generate the systemic manifestations of the nonthyroidal illness (NTI) syndrome in this model. 2) The lack of D3 does not affect the extent of pulmonary inflammation and 3) Bacterial outgrowth in blood, spleen and lung of D3KO mice is significantly higher than in WT mice. Our results suggest a protective role for D3 in the defence against acute bacterial infection probably by reinforcing the microbial killing capacity of neutrophil

Action of Specific Thyroid Hormone Receptor alpha(1) and beta(1) Antagonists in the Central and Peripheral Regulation of Thyroid Hormone Metabolism in the Rat

Background: The iodine-containing drug amiodarone (Amio) and its noniodine containing analogue dronedarone (Dron) are potent antiarrhythmic drugs. Previous in vivo and in vitro studies have shown that the major metabolite of Amio, desethylamiodarone, acts as a thyroid hormone receptor (TR) alpha(1) and beta(1) antagonist, whereas the major metabolite of Dron debutyldronedarone acts as a selective TR alpha(1) antagonist. In the present study, Amio and Dron were used as tools to discriminate between TR alpha(1) or TR beta(1) regulated genes in central and peripheral thyroid hormone metabolism. Methods: Three groups of male rats received either Amio, Dron, or vehicle by daily intragastric administration for 2 weeks. We assessed the effects of treatment on triiodothyronine (T-3) and thyroxine (T-4) plasma and tissue concentrations, deiodinase type 1, 2, and 3 mRNA expressions and activities, and thyroid hormone transporters monocarboxylate transporter 8 (MCT8), monocarboxylate transporter 10 (MCT10), and organic anion transporter 1C1 (OATP1C1). Results: Amio treatment decreased serum T-3, while serum T-4 and thyrotropin (TSH) increased compared to Dron-treated and control rats. At the central level of the hypothalamus-pituitary-thyroid axis, Amio treatment decreased hypothalamic thyrotropin releasing hormone (TRH) expression, while increasing pituitary TSH beta and MCT10 mRNA expression. Amio decreased the pituitary D2 activity. By contrast, Dron treatment resulted in decreased hypothalamic TRH mRNA expression only. Upon Amio treatment, liver T3 concentration decreased substantially compared to Dron and control rats (50%, p <0.01), but liver T-4 concentration was unaffected. In addition, liver D1, mRNA, and activity decreased, while the D3 activity and mRNA increased. Liver MCT8, MCT10, and OATP1C1 mRNA expression were similar between groups. Conclusion: Our results suggest an important role for TR alpha(1) in the regulation of hypothalamic TRH mRNA expression, whereas TR beta plays a dominant role in pituitary and liver thyroid hormone metabolis

Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis

Objective: Proinflammatory cytokines are involved in the pathogenesis of non-thyroidal illness (NTI), its shown by studies with IL-6(-/-) and IL-12(-/-) mice. Interleukin (IL)-6 changes peripheral thyroid hormone metabolism, and IL-12 seems to be involved in the regulation of the central part of the hypothalamic-pituitary-thyroid (HPT) axis during illness. IL-18 is a proinflammatory cytokine which shares important biological properties with IL-12, such as interferon (IFN)-gamma-inducing activity. Design: By studying the changes in the HPT axis during bacterial lipopolysaccharide (LPS)-induced illness in IL-18(-/-), IFNgammaR(-/-) and wild-type (WT) mice, we wanted to unravel the putative role of IL-18 and IFNgamma in the pathogenesis of NTI. Results: LPS induced a decrease in pituitary type 1 deiodinase (D1) activity (P <0.05, ANOVA) in WT mice, but not in IL-18(-/-) mice, while the decrease in D2 activity was similar in both strains. LPS decreased serum thyroid hormone levels and liver D1 mRNA within 24h similarly in IL-18(-/-), and WT mice. The expression of IL-1, IL-6 and IFNgamma mRNA expression was sipificantly lower in IL-18(-/-) mice than in WT, while IL-12 mRNA expression was similar. IFNgammaR(-/-) mice had higher basal D1 activity in the pituitary than WT mice (P <0.05); LPS induced a decrease of D2, but not of D1, activity in the pituitary which was similar in both strains. In the liver, the LPS-induced increase in cytokine expression was not different between IFNgammaR(-/-) mice and WT mice, and the decrease in serum T-3 and T-4 levels and hepatic D1 mRNA was also similar. Conclusions: The relative decrease in serum T-3 and T-4 and liver D1 mRNA in response to LPS is similar in IL-18(-/-), IFNgammaR(-/-) and WT mice despite significant changes in hepatic cytokine induction. However, the LPS-induced decrease in D1 activity in the pituitary of WT mice is absent in IL-18(-/-) mice; in contrast, LPS did not decrease pituitary D1 activity in the IFNgammaR(-/-) mice or their WT, which might be due to the genetic background of the mice. Our results suggest that IL-18 is also involved in the regulation of the central part of the HPT axis during illnes

Type 3 Deiodinase Is Highly Expressed in Infiltrating Neutrophilic Granulocytes in Response to Acute Bacterial Infection

Background: Macrophages and polymorphonuclear cells (PMNs) play an important role in the first line of defense against bacteria by infiltrating the infected organ in order to clear the harmful pathogen. Our earlier studies showed that granulocytes express type 3 deiodinase (D3) when activated during a turpentine-induced abscess. We hypothesized that D3 expression by granulocytes may also occur during bacterial infection. Methods: In order to test this hypothesis, we used the following experimental infection models: peritonitis induced by Escherichia coli and acute pneumonia induced by Streptococcus pneumoniae. Results: E. coli-induced peritonitis was characterized by infiltration in the liver by inflammatory cells with abundant immunocytochemical D3 expression while no staining was present in hepatocytes of infected or control mice. Acute pneumonia induced by S. pneumoniae resulted in inflamed lungs characterized by numerous infiltrating granulocytes expressing D3 while no D3 staining was present in lung sections without an infiltrate. Serum thyroid hormones were negatively correlated to bacterial outgrowth in both lung and spleen, and thus to the severity of illness. Conclusion: Infiltrating granulocytes during acute bacterial infection express D3. Our work supports the hypothesis that D3 plays an important role during chemical and bacterial inflammation. Whether the resulting decreased local bioavailability of thyroid hormones or rather the increased local availability of iodide is an important element of the innate immune response remains to be studie

Downregulation of Type 3 Deiodinase in the Hypothalamus During Inflammation

Background: Inflammation is associated with marked changes in cellular thyroid hormone (TH) metabolism in triiodothyronine (T3) target organs. In the hypothalamus, type 2 deiodinase (D2), the main T3 producing enzyme, increases upon inflammation, leading to an increase in local T3 availability, which in turn decreases thyrotropin releasing hormone expression in the paraventricular nucleus. Type 3 deiodinase (D3), the T3 inactivating enzyme, decreases during inflammation, which might also contribute to the increased T3 availability in the hypothalamus. While it is known that D2 is regulated by nuclear factor κB (NF-κB) during inflammation, the underlying mechanisms of D3 regulation are unknown. Therefore, the aim of the present study was to investigate inflammation-induced D3 regulation using in vivo and in vitro models. Methods: Mice were injected with a sublethal dose of bacterial endotoxin (lipopolysaccharide [LPS]) to induce a systemic acute-phase response. A human neuroblastoma (SK-N-AS) cell line was used to test the involvement of the thyroid hormone receptor alpha 1 (TRα1) as well as the activator protein-1 (AP-1) and NF-κB inflammatory pathways in the inflammation-induced decrease of D3. Results: D3 expression in the hypothalamus was decreased 24 hours after LPS injection in mice. This decrease was similar in mice lacking the TRα. Incubation of SK-N-AS cells with LPS robustly decreased both D3 mRNA expression and activity. This led to increased intracellular T3 concentrations. The D3 decrease was prevented when NF-κB or AP-1 was inhibited. TRα1 mRNA expression decreased in SK-N-AS cells incubated with LPS, but knockdown of the TRα in SK-N-AS cells did not prevent the LPS-induced D3 decrease. Conclusions: We conclude that the inflammation-induced D3 decrease in the hypothalamus is mediated by the inflammatory pathways NF-κB and AP-1, but not TRα1. Furthermore, the observed decrease modulates intracellular T3 concentrations. Our results suggest a concerted action of inflammatory modulators to regulate both hypothalamic D2 and D3 activities to increase the local TH concentrations