The complement system is linked to insulin resistance in patients with systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients more commonly have insulin resistance (IR) than control subjects. Recent studies have revealed that the complement (C) system is not only a mediator of the immune system but is also related to the pathogenesis of atherosclerosis in the general population. Given that the C alteration is a characteristic of SLE, in the present work we set out to analyse if there is a relationship between the C system and IR in patients with SLE. METHODS: New generation functional assays of the three pathways of the C system were performed in 225 non-diabetic patients with SLE. In addition, the serum levels of inactive (C1q, C2, C3, C4, factor D), activated (C3a) and regulators (C1 inhibitor and factor H) molecules of the C system were evaluated. Insulin and C-peptide serum levels were measured, and insulin resistance and indices of beta cell function were calculated using the homeostatic model assessment (HOMA). Metabolic syndrome criteria fulfillments were applied. Multivariable linear regression analysis was performed to assess the relationship between C system and IR indices and the presence of metabolic syndrome. RESULTS: After adjusting for covariates that included traditional cardiovascular risk factors associated with IR and prednisone, serum C3a and factor H levels were positively related to higher levels of the HOMA2-IR index. Besides, in the multivariable analysis, after adjustment for covariates, serum levels of C1q and C3 associated with a higher odds ratio for the presence of metabolic syndrome. CONCLUSIONS: IR and metabolic syndrome are positively and independently related to higher serum levels of some serum C elements in patients with SLE with a predominant role of the alternative pathway elements.

Evaluation of antibody-based preventive alternatives for respiratory syncytial virus: a novel multi-criteria decision analysis framework and assessment of nirsevimab in Spain.

BACKGROUND: Respiratory syncytial virus (RSV) is a highly infectious disease that poses a significant clinical and medical burden, as well as social disruption and economic costs, recognized by the World Health Organization as a public health issue. After several failed attempts to find preventive candidates (compounds, products, including vaccines), new alternatives might be available, one being nirsevimab, the first and only option approved for RSV prevention in neonates and infants during their first RSV season. The objective of this study was to develop a novel multi-criteria decision analysis (MCDA) framework for RSV antibody-based preventive alternatives and to use it to assess the value of nirsevimab vs. placebo as a systematic immunization approach to prevent RSV in neonates and infants during their first RSV season in Spain. METHODS: Based on a pre-established model called Vaccinex, an ad-hoc MCDA framework was created to reflect relevant attributes for the assessment of current and future antibody-based preventive measures for RSV. The estimated value of nirsevimab was obtained by means of an additive linear model combining weights and scores assigned by a multidisciplinary committee of 9 experts. A retest and three sensitivity analyses were conducted. RESULTS: Nirsevimab was evaluated through a novel framework with 26 criteria by the committee as a measure that adds value (positive final estimated value: 0.56 ± 0.11) to the current RSV scenario in Spain, by providing a high efficacy for prevention of neonates and infants. In addition, its implementation might generate cost savings in hospitalizations and to the healthcare system and increase the level of public health awareness among the general population, while reducing health inequities. CONCLUSIONS: Under a methodology with increasing use in the health field, nirsevimab has been evaluated as a measure which adds value for RSV prevention in neonates and infants during their first RSV season in Spain.

Amylin serum levels are upregulated in patients with systemic lupus erythematosus.

OBJECTIVES: Amylin is a pancreatic hormone that participates in glucose homeostasis. We aimed to investigate how serum amylin levels are expressed in patients with systemic lupus erythematosus (SLE) compared to matched controls, and their possible relationship to disease-related characteristics, such as activity or damage. METHODS: 144 SLE patients and 96 non-diabetic sex- (female 96% vs. 91%, p=0.43) and age-matched controls (49±11 vs. 51±8 years, p=0.09) were included. Amylin, insulin and C-peptide serum levels, as well as insulin resistance indexes were assessed in both groups. Multivariable regression analysis was performed to compare amylin between groups and to explore its interrelations with SLE features. The analyses were adjusted for glucocorticoids intake and for insulin resistance classic risk factors. RESULTS: Patients with SLE exhibited significant higher serum levels of amylin when compared to controls after multivariable analysis (beta coef. 1.56 [95%CI 1.01-2.11], p=0.000). Moreover, SLE patients not on prednisone (beat coef. 1.54 [95%CI 0.98-2.10] ng/ml, p=0.000) and those on prednisone (beta coef. 1.51 [95%CI 0.96-2.07] ng/ml, p=0.000) disclosed higher amylin serum levels compared to controls in the fully multivariable analysis. Hyperamylinaemia in SLE patients remained significant even adjusting for differences in the insulin resistance and beta cell production rates between patients and controls. The damage produced by the disease and its severity were independently and positively associated with amylin serum levels. CONCLUSIOINS: Amylin is upregulated in SLE patients compared to controls, regardless of the insulin resistance that SLE may present. The damage produced by the disease and its severity independently explains this upregulation.

A multi-criteria decision analysis on the value of nintedanib for interstitial lung diseases.

OBJECTIVES: Our aim was to assess the value of nintedanib for non-idiopathic progressive fibrosing interstitial lung disease (non-IPF PF-ILD) and systemic sclerosis-associated ILD (SSc-ILD) in the Spanish context, using a multi-criteria decision analysis (MCDA). METHODS: Following an adaptation of the Evidence and Value: Impact on DEcision Making (EVIDEM) MCDA methodology, the estimated value of nintedanib was obtained by means of an additive linear model that combined individual weights (100-points distribution) of criteria with the individual scoring of nintedanib in each criterion for every indication, assigned by a multidisciplinary committee of twelve clinicians, patients, pharmacists, and decision-makers. To assess the reproducibility, an alternative weighting method was applied, as well as a re-test of weights and scores at a different moment of time. RESULTS: The experts committee recognized nintedanib as an intervention with a positive value contribution in comparison to placebo for the treatment of non-IPF PF-ILD (0.50 ± 0.16, on a scale from -1 to 1) and SSc-ILD (0.40 ± 0.12), diseases which were considered as very severe and with high unmet needs. The drug was perceived as a treatment that provides an added therapeutic benefit for patients (0.06-0.07), given its proven clinical efficacy (0.05-0.06), slight improvements in patient-reported outcomes (0.01-0.02), and similar safety profile than placebo (-0.04-0.00), which will likely be positioned as a recommended therapy in the next clinical practice guidelines updates. CONCLUSIONS: Under this increasingly used methodology, nintedanib has shown to provide a positive value estimate for non-IPF PF-ILD and SSc-ILD when compared to placebo in Spain.

Beta-cell function is disrupted in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate how markers of beta-cell secretion (proinsulin-processing metabolites) are expressed in SLE patients and their potential relation to features associated with the disease such as activity or damage. METHODS: One hundred and forty-four SLE patients and 69 nondiabetic sex- and age-matched controls were assessed. Beta-cell secretion molecules, as measured by insulin, split and intact proinsulins, and C-peptide levels were analysed in both groups. Multiple regression analysis was performed to compare proinsulin propeptides between groups and to explore the interrelations with SLE features. Analyses were adjusted for glucocorticoid intake and for insulin resistance classic risk factors. RESULTS: Fully multivariable analysis demonstrated that regardless of glucocorticoid use, SLE patients exhibited higher levels of split proinsulin. Likewise, the split proinsulin-to-insulin ratio was upregulated in patients with SLE undergoing glucocorticoid therapy [beta coeficient 0.19 (95% Confidence Interval 0.07, 0.30), P = 0.002] or not [beta coef. 0.09 (95% CI: 0.01, 0.17), P = 0.025]. Similar results were found for the intact proinsulin-to-insulin ratio, although differences were only statistically significant for patients taking glucocorticoids [beta coef. 0.08 (95% CI: 0.03, 0.12), P = 0.001]. SLE damage score was associated with higher serum levels of intact [beta coef. 0.51 (95% CI 0.17, 0.86) pmol/l, P = 0.004] and split proinsulins [beta coef. 1.65 (95% CI 0.24, 3.06) pmol/l, P = 0.022] after multivariable analysis, including disease duration and prednisone use. CONCLUSION: Among patients with SLE, proinsulin-processing metabolites, a marker of beta-cell disruption, are upregulated compared with matched controls. This disproportionate hyperproinsulinemia can be explained by the damage produced by the disease and occurs independently of prednisone use.

Serum B cell lymphoma-2 concentrations and mortality of patients with spontaneous intracerebral hemorrhage.

OBJECTIVE: There is scarce data on B cell lymphoma 2 (Bcl2), a member of the Bcl-2 family of antiapoptotic molecules of the intrinsic apoptosis pathway, in patients with spontaneous intracerebral hemorrhage (SIH). In one study, higher serum Bcl2 levels were found in patients with SIH than in healthy subjects. Thus, the objective of our study was to compare serum Bcl2 levels in surviving and non-surviving SIH patients. METHODS: Patients with severe supratentorial SIH (defined as Glasgow Coma Scale < 9) admitted from the Intensive Care Units of five Spanish hospitals were included in this observational and prospective study. Serum levels of Bcl2L were determined at the time of diagnosis. Thirty-day mortality was the end-point study. RESULTS: Non-surviving (n = 38) compared to surviving patients (n = 41) had higher intracerebral hemorrhage (ICH) score (p = 0.001), midline shift (p = 0.003), and serum Bcl2 levels (p < 0.001). In addition, non-surviving compared to surviving patients had lower early hematoma evacuation rate (p = 0.03). We found 77% area under curve in mortality prediction for serum Bcl2 levels (95% CI = 0.66-88%; p < 0.001). Patients showing serum Bcl2 levels > 16.5 ng/mL had higher risk of death according to analysis of Kaplan-Meier (HR = 5.2; 95% CI = 2.5-10.6; p < 0.001). An association, after control for ICH score, midline shift, and early hematoma evacuation, was found between serum Bcl2 levels and 30-day mortality (OR = 1.090; 95% CI = 1.030-1.154; p = 0.003) in the multiple logistic regression. CONCLUSIONS: As far as we know, our study is the first one reporting higher serum Bcl2 levels in non-surviving than in surviving SIH patients and the association between serum Bcl2 levels and SIH mortality.

Low blood caspase-8 levels in survivor patients of traumatic brain injury.

OBJECTIVE: High concentrations of caspase-8 (main initiator caspase of the extrinsic pathway of apoptosis) have been found in brain tissue of patients with traumatic brain injury (TBI) and in the blood of patients with different diseases. However, blood caspase-8 concentrations in TBI patients have not been reported. Therefore, our aim was to analyze whether blood caspase-8 concentrations are associated with mortality in TBI patients. METHOD: Patients with isolated and severe TBI were included. TBI was considered isolated if it showed an Injury Severity Score (ISS) <10 points on non-cranial aspects. TBI was considered severe if it showed a Glasgow Coma Scale (GCS) <9 points. This prospective observational study was conducted in 5 Intensive Care Units. Serum caspase-8 concentrations were measured on day 1 of TBI. RESULTS: Surviving patients (n=59) had lower age (p=0.004), higher GCS (p=0.001), lower APACHE-II score (p<0.001), lower high-risk-of-death computed tomography (CT) findings (p=0.02), lower intracranial pressure (ICP) (p=0.01), and lower serum caspase-8 concentrations (p<0.001) than non-surviving patients (n=24). An association was found between serum caspase-8 levels and mortality after controlling for CT findings, GCS, and age (OR=1.037; 95% CI=1.013-1.062; p=0.002), and after controlling for CT findings, APACHE-II, and ICP (OR=1.042; 95% CI=1.013-1.071; p=0.004) in multiple logistic regression. CONCLUSIONS: To our knowledge, this is the first series describing blood caspase-8 concentrations in patients with TBI. The association of high blood caspase-8 concentrations with mortality was the main new finding of the study. However, further investigations are needed to validate the preliminary results of our study.

High serum levels of TAC and early mortality in patients with spontaneous intracerebral haemorrhage.

OBJECTIVE: Oxidation contributes to secondary brain injury after spontaneous intracerebral haemorrhage (SIH). One study found lower levels of total antioxidant capacity (TAC) in the blood in patients with SIH than in healthy subjects. However, there are no data on blood TAC levels and survival in patients with SIH. Therefore, the objective of our study was to determine if an association exists between serum TAC levels and mortality in patients with SIH. METHODS: We included patients with severe supratentorial SIH. We considered severe when Glasgow Coma Scale (GCS) < 9. Patients from 6 Spanish hospitals were included in this observational and prospective study. Serum TAC levels at days 1, 4 and 8 of SIH were determined. Thirty-day mortality was our end-point study. RESULTS: Non-surviving patients compared with surviving patients showed higher serum TAC levels at day 1 (p < 0.001), 4 (p < 0.001) and 8 (p = 0.001). An area under the curve was found for the prediction of 30-day mortality by serum TAC levels of 0.92 (95% CI = 0.85-96%; p < 0.001). Multiple logistic regression analysis showed an association of serum TAC levels with 30-day mortality (odds ratio = 16.513; 95% CI = 2.548-107.015; p = 0.003) controlling for midline shift, glycemia, early evacuation of SIH, intracerebral haemorrhage (ICH) score, age and volume of SIH. CONCLUSIONS: The new findings of this study are that serum TAC levels are higher in non-surviving than in surviving patients, and that they are associated with mortality and could be used to predict mortality.

High Serum Soluble Fas Ligand Levels in Non-survivor Traumatic Brain Injury Patients.

PURPOSE: Soluble Fas Ligand (sFasL) is one of the main ligands that activates the apoptosis extrinsic pathway. Higher expression of FasL in brain samples and higher cerebrospinal fluid FasL concentrations in traumatic brain injury (TBI) patients than in controls have been found. However, the potential association between blood sFasL concentrations and TBI mortality has not been reported. Therefore, the objective of this study was to determine whether that association exists. METHODS: We included patients with a severe isolated TBI, defined as < 9 points in Glasgow Coma Scale (GCS) and < 10 non-cranial aspects points in Injury Severity Score in this observational and prospective study performed in 5 Intensive Care Units. We measured serum sFasL concentrations on day 1 of TBI. RESULTS: We found that 30-day survivor (n = 59) in comparison to non-survivor patients (n = 24) had higher GCS (p = 0.001), lower age (p = 0.004), lower APACHE-II score (p < 0.001), lower intracranial pressure (ICP) (p = 0.01), lower computer tomography (CT) findings of high risk of death (p = 0.02) and lower serum sFasL concentrations (p < 0.001). The area under the curve for mortality prediction by serum sFasL levels was of 75% (95% CI = 63%-87%; p < 0.001). In Kaplan-Meier analysis was found that patients with serum sFasL levels > 29.2 pg/mL had a higher mortality rate (Hazard ratio = 6.2; 95% CI = 2.6-14.8; p < 0.001). Multiple logistic regression analysis found an association between serum sFasL levels and mortality after controlling for GCS, age and CT findings (OR = 1.055; 95% CI = 1.018-1.094; p = 0.004), and after controlling for APACHE-II, ICP and CT findings (OR = 1.048; 95% CI = 1.017-1.080; p = 0.002). CONCLUSIONS: The association between serum sFasL levels and 30-day mortality in TBI patients was the major novel finding of our study; however, future validation could be interesting to confirm those results.

High Serum Levels of Caspase-3 and Early Mortality in Patients with Severe Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Apoptotic cell death leads to secondary brain injury after spontaneous intracerebral hemorrhage (SIH). There is an association between serum caspase-3 levels and late mortality (at 6 months) in patients with SIH in basal ganglia. The new objective of this study was to determine whether there exists an association between serum caspase-3 levels and early mortality (at 30 days) in patients with SIH at different sites and not only in basal ganglia. METHODS: Patients with severe supratentorial SIH (defined as Glasgow Coma Scale < 9) admitted in 6 Spanish hospitals were included in this observational and prospective study. Patients with SIH due to aneurysm, arteriovenous malformation, and anticoagulant or fibrinolytic treatment were excluded. Serum caspase-3 levels at days 1, 4, and 8 of SIH were determined. Thirty-day mortality was the end-point study. RESULTS: Non-surviving (n = 53) showed higher serum caspase-3 levels at days 1 (p < 0.001), 4 (p < 0.001), and 8 (p < 0.001) than survivor patients (n = 64). Multiple logistic regression analysis showed an association of serum caspase-3 levels > 0.167 ng/mL with 30-day mortality (Odds Ratio = 47.007; 95% CI = 4.838-456.727; p = 0.001). CONCLUSIONS: The new findings of our study are that serum caspase-3 levels are associated with early mortality in patients with severe supratentorial SIH at different sites and that those levels during the first week of SIH are higher in non-survivors than in survivors.

Serum Levels of B-cell Lymphoma-2 Anti-Apoptotic Protein and Malignant Middle Cerebral Artery Infarction Mortality.

INTRODUCTION AND GOAL: There is scarce and contradictory data on B-cell lymphoma 2 (Bcl2), member of the Bcl-2 antiapoptotic molecules family of intrinsic apoptosis pathway, in ischemic stroke patients. The objective of this study was to determine whether there is an association between blood Bcl2 concentrations and mortality of ischemic stroke patients. MATERIAL AND METHODS: Five Intensive Care Units participated in this prospective and observational study of patients with severe malignant middle cerebral artery infarction (MMCAI). Severe MMCAI was diagnosed when acute infarction was present in 50% or more of said region and with a Glasgow Coma Scale (GCS) score of less than 9 points. Serum samples were collected at the time of MMCAI diagnosis. FINDINGS: Higher serum Bcl2 concentrations (p = 0.001), lower platelet count (p = 0.01) and lower GCS (p = 0.002) were found in non-survivors (n = 28) than in MMCAI survivors (n = 28). Serum Bcl2 levels had an area under the curve for mortality prediction of 75% (95% CI = 62%-88%; p < 0.001). Patients with serum Bcl2 levels > 43.6 ng/mL had higher mortality rate according to Kaplan-Meier analysis (Hazard ratio=10.0; 95% CI = 3.4-29.5; p < 0.001). Multiple logistic regression showed an association between serum Bcl2 and mortality at 30 days (OR = 1.041; 95% CI = 1.006-1.077; p = 0.02) controlling for GCS and platelet count. CONCLUSIONS: This study reports for the first time the higher blood Bcl2 concentrations in non-surviving ischemic stroke patients than in survivors and the association between elevated blood Bcl2 and mortality in ischemic stroke patients.

Association Between DNA and RNA Oxidative Damage and Mortality of Patients with Traumatic Brain Injury.

BACKGROUND: The hyperoxidative state in traumatic brain injury (TBI) could produce oxidative damage on the ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Oxidative damage to nucleic acids in TBI patients has been studied, and higher concentrations of 8-OHdG were found in postmortem brain samples of subjects who died following TBI than in subjects who died from sudden cardiac death. Thus, the objective of this study was to determine whether there is an association between serum DNA and RNA oxidative damage and mortality in TBI patients. METHODS: We included patients with severe isolated TBI defined as a lower score than 9 points in the Glasgow Coma Scale (GCS) and lower than 9 points in non-cranial aspects in the Injury Severity Score. We determined serum concentrations of the three oxidized guanine species (OGS) (8-OHdG from DNA, 8-hydroxyguanosine from RNA, and 8-hydroxyguanine from DNA or RNA) and malondialdehyde (to estimate lipid peroxidation) on the day of TBI. Mortality at 30 days was the end-point study. RESULTS: We found higher serum concentrations of OGS (p < 0.001) and malondialdehyde (p < 0.001) in non-surviving (n = 34) than in surviving patients (n = 90), an association between serum OGS levels and 30-day mortality after control for CGS, age, and computed tomography findings (OR = 1.397; 95% CI = 1.137-1.716; p = 0.001), and a positive correlation between serum levels of OGS and malondialdehyde (rho = 0.24; p = 0.01). CONCLUSIONS: To our knowledge, our study is the largest series reporting data on DNA oxidative damage in TBI patients and is the first reporting DNA and RNA oxidative damage in TBI patients associating lipid peroxidation and mortality.

High Serum DNA and RNA Oxidative Damage in Non-surviving Patients with Spontaneous Intracerebral Hemorrhage.

PURPOSE: One study found higher leukocytes 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in patients with spontaneous intracerebral hemorrhage (ICH) than in healthy subjects due to the oxidation of guanosine from deoxyribonucleic acid (DNA). The objective of this study was to determine whether there is an association between oxidative damage of serum DNA and ribonucleic acid (RNA) and mortality in patients with ICH. METHODS: In this observational and prospective study, patients with severe supratentorial ICH (defined as Glasgow Coma Scale < 9) were included from six Intensive Care Units of Spanish hospitals. At the time of severe ICH diagnosis, concentrations in serum of malondialdehyde (as lipid peroxidation biomarker) and of the three oxidized guanine species (OGS) (8-hydroxyguanosine from RNA, 8-hydroxyguanine from DNA or RNA, and 8-OHdG from DNA) were determined. Thirty-day mortality was considered the end-point study. RESULTS: Serum levels of OGS (p < 0.001) and malondialdehyde (p = 0.002) were higher in non-surviving (n = 46) than in surviving patients (n = 54). There was an association of serum OGS levels with serum malondialdehyde levels (rho = 0.36; p = 0.001) and 30-day mortality (OR = 1.568; 95% CI 1.183-2.078; p = 0.002). CONCLUSIONS: The novel and most important finding of our study was that serum OGS levels in ICH patients are associated with mortality.

Mortality prediction of ischemic stroke patients without thrombectomy by blood total antioxidant capacity.

It has been previously established that total antioxidant capacity concentrations of blood on the first day of ischemic stroke could predict mortality. Therefore, our study objective was to determine whether total antioxidant capacity concentrations in the blood during the first week of a cerebral infarction could help predict mortality. We included severe and malignant middle cerebral artery infarction patients (affecting 50% or more of the territory in computed tomography and a score of nine or fewer points in the Glasgow Coma Scale). Serum total antioxidant capacity concentrations were determined on days first, fourth, and eighth of the diagnosis of a malignant middle cerebral artery infarction. Higher serum total antioxidant capacity concentrations at first (P < 0.001), fourth (P < 0.001), and eighth (P = 0.003) day were found in non-surviving patients than in surviving ones. Serum total antioxidant capacity concentrations on first, fourth and eighth day of malignant middle cerebral artery infarction had an area under curve (95% Confidence Intervals) for 30-day mortality prediction of 0.86 (0.75-0.93; P < 0.001), 0.87 (0.74-0.95; P < 0.001) and 0.79 (0.64-0.90; P = 0.004)), respectively. Thus, the potential use of serum total antioxidant capacity concentrations at any time during the first 7 days of a severe malignant middle cerebral artery infarction without thrombectomy to predict mortality was the main novel finding of our study.

Serum substance P levels and early mortality of spontaneous intracerebral haemorrhage patients.

INTRODUCTION AND GOAL: Substance P, a neuropeptide of the tachykinin family, is involved in the neuroinflammation of different diseases of the central nervous system. To our knowledge, there is no published data on the level of circulating substance P levels in the prognosis of patients with spontaneous intracerebral hemorrhage (ICH). Therefore, the objectives of this observational and prospective study were to determine whether serum substance P levels in ICH patients were associated with early mortality and whether could be used in the mortality prognostic. MATERIAL AND METHODS: We included patients with severe primary supratentorial ICH (defined as Glasgow Coma Scale < 9) from 6 Intensive Care Units of Spanish hospitals. We determined serum substance P levels at the time of severe ICH diagnosis, at fourth and at eighth day. Thirty-day mortality was considered the end-point study. FINDINGS: Non-surviving (n=53) compared to surviving ICH patients (n=64) showed higher serum substance P levels at day 1 (p<0.001), day 4 (p<0.001) and day 8 (p<0.001). The area under the curve for 30-day mortality prediction by serum substance P levels was of 79% (95% CI = 70-86%; p<0.001). Kaplan-Meier analysis showed a higher 30-day mortality in patients with serum substance P levels>503 pg/mL (Hazard ratio=14.7; 95% CI=6.88-31.55; p<0.001). Multiple logistic regression analysis showed an association between serum substance P levels and 30-day mortality (Odds Ratio=1.006; 95% CI=1.002-1.010; p=0.004) controlling for ICH score, midline shift, glycemia, early evacuation of ICH. CONCLUSIONS: Thus, the novel aspects our study include that serum substance P levels in severe primary ICH patients were higher in non-surviving than in surviving patients, that serum substance P levels were associated with early mortality controlling for other variables, and that serum substance P levels could be used as biomarkers of prognosis.

High serum levels of tissue inhibitor of matrix metalloproteinase-1 during the first week of a malignant middle cerebral artery infarction in non-surviving patients.

BACKGROUND: Higher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 early after ischemic stroke have been associated with lower survival. The objectives of this study were to determine serum TIMP-1 levels during the first week of a severe cerebral infarction in surviving and non-surviving patients, and whether those levels during the first week could be used as a mortality biomarker for these patients. METHODS: We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as computer tomography showing ischaemic changes in more than 50% of the middle cerebral artery territory and Glasgow Coma Scale (GCS) ≤ 8. We measured serum levels of matrix metalloproteinases (MMP)-9 and TIMP-1. End-point study was 30-day mortality. RESULTS: We found higher TIMP-1 concentrations at days 1 (p < 0.001), 4 (p = 0.001), and 8 (p = 0.03) of MMCAI in non- urviving (n = 34) than in surviving (n = 34) patients. We found lower serum MMP-9 concentrations at day 1 (p = 0.03) of MMCAI and no significant differences at days 4 and 8. ROC curve analysis of TIMP-1 concentrations performed at days 1, 4, and 8 of MMCAI showed an area under curve to predict 30-day mortality of 81% (p < 0.001), 80% (p < 0.001) and 72% (p = 0.07) respectively. CONCLUSIONS: The new findings of our study were that non-surviving MMCAI patients showed higher serum TIMP-1 levels during the first week of MMCAI that surviving patients, and those levels during the first week of MMCAI could be used as mortality biomarkers.

Serum Caspase-3 Levels and Early Mortality of Patients with Malignant Middle Cerebral Artery Infarction.

PURPOSE: Circulating caspase-3 levels at 24 h of ischemic stroke were found to be associated with poorer functional neurological outcome in a previous study. The aim of this study was to determine whether there is an association between serum caspase-3 levels and early mortality in patients with malignant middle cerebral artery infarction (MMCAI). METHODS: We included patients with MMCAI defined as computer tomography showing ischemic changes in more than 50% of the middle cerebral artery territory and Glasgow Coma Scale ≤ 8. Serum caspase-3 levels at days 1, 4, and 8 of MMCAI were determined. RESULTS: Non-surviving MMCAI (n = 34) showed higher serum caspase-3 levels at days 1 (p < 0.001), 4 (p = 0.001), and 8 (p = 0.01) than surviving patients (n = 34). We found that the area under the curve of serum caspase-3 levels for prediction of mortality at 30 days was 88% (95% CI = 78-95%; p < 0.001). Multiple logistic regression showed that serum caspase-3 levels were associated with 30-day mortality (OR = 51.25; 95% CI = 8.30-316.31; p < 0.001). CONCLUSIONS: The novel and more important findings of our study were that high serum caspase-3 levels were associated with mortality in MMCAI patients.

Low Serum Melatonin Levels Prior to Liver Transplantation in Patients with Hepatocellular Carcinoma are Associated with Lower Survival after Liver Transplantation.

Melatonin administration has been associated with different benefits in animals and patients suffering from liver diseases. However, there is no published data about circulating melatonin levels in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). Thus, the objective of this observational and retrospective study was to determine whether patients with HCC with lower serum melatonin levels prior to LT have a higher risk of one-year mortality after LT. We measured serum levels of melatonin, malondialdehyde (to assess lipid peroxidation), and total antioxidant capacity (to assess antioxidant state) before LT. One-year surviving LT patients (n = 129) showed higher serum levels of melatonin (p = 0.001) and total antioxidant capacity (p = 0.001) and lower serum levels of malondialheyde (p = 0.01) than non-surviving LT patients (n = 16). Logistic regression analysis showed that high serum melatonin levels prior to LT were associated with lower one-year LT mortality (odds ratio = 0.525; 95% confidence interval (CI) = 0.331⁻0.834; p = 0.006). We found an association between serum levels of melatonin with serum levels of malondialheyde (rho = -0.22; p = 0.01) and total antioxidant capacity (rho = 0.21; p = 0.01). Thus, the novel findings of our study were the association between high serum melatonin levels prior to LT and survival at first year after LT and the association between serum levels of melatonin with malondialheyde and total antioxidant capacity.

Proprotein convertase subtilisin/kexin type 9 in rheumatoid arthritis.

OBJECTIVES: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism through low-density lipoprotein receptor degradation and that has been linked with cardiovascular risk. The purpose of the present study was to examine whether PCSK9 levels are related to both abnormalities in the lipid profile and the severe atherosclerosis that occur in rheumatoid arthritis (RA) patients. METHODS: Cross-sectional study that encompassed 520 individuals; 326 patients with RA and 194 age- and sex-matched controls. PCSK9 and lipoproteins serum concentrations, standard lipid profile and carotid intima-media thickness (cIMT) and carotid plaques were assessed in patients and controls. A multivariable analysis, adjusted for standard cardiovascular risk factors, was performed to evaluate the influence of PCSK9 on RA related dyslipidaemia and subclinical carotid atherosclerosis. RESULTS: After adjusting for classical cardiovascular risk factors, lipid profile and statins, RA patients showed lower PCSK9 serum concentrations than controls (beta coefficient -45 95%CI [-53, -38] ng/ml, p=0.00). PCSK9 was associated with both cIMT and the presence of carotid plaques in RA patients. However, this association was lost after adjusting for classical cardiovascular risk factors. CONCLUSIONS: PCSK9 is down-regulated in patients with RA.

Relationship between endothelial dysfunction and osteoprotegerin, vitamin D, and bone mineral density in patients with rheumatoid arthritis.

OBJECTIVES: We aimed to investigate whether the abnormalities in bone mineral density (BMD) that occur in patients with rheumatoid arthritis (RA) are associated with the presence of endothelial dysfunction. METHODS: Cross-sectional study encompassing 216 subjects (111 patients with RA and 105 age- and sex-matched controls) without history of cardiovascular disease. Endothelial function was determined by brachial artery flow-mediated dilatation (FMD) and BMD by dual x-ray absorptiometry (DXA) measurements. Plasma vitamin D and osteoprotegerin serum (OPG) levels were assessed in patients and controls. Multiple regression analysis was performed to study the relationship between BMD with endothelial function, taking into account vitamin D and OPG levels. RESULTS: After adjusting for traditional cardiovascular risk factors, vitamin D and OPG levels, BMD emerged as an independent factor associated with lower FMD values in controls, but not in patients with RA. Although OPG levels were inversely associated with FMD values in both RA patients and controls after adjusting for BMD, vitamin D showed this relationship only in the controls. CONCLUSIONS: Whilst OPG is associated with endothelial function in RA patients and controls, vitamin D levels and BMD are related to endothelial function in controls but not in patients with RA.