Mutations in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy

Objective: Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. TRIM63 has been suggested as a candidate gene for the development of cardiomyopathies, although evidence for a causative role in HCM is limited. We sought to investigate the relationship between rare variants in TRIM63 and the development of HCM. Methods: TRIM63 was sequenced by next generation sequencing in 4867 index cases with a clinical diagnosis of HCM and in 3628 probands with other cardiomyopathies. Additionally, 3136 index cases with familial cardiovascular diseases other than cardiomyopathy (mainly channelopathies and aortic diseases) were used as controls. Results: Sixteen index cases with rare homozygous or compound heterozygous variants in TRIM63 (15 HCM and one restrictive cardiomyopathy) were included. No homozygous or compound heterozygous were identified in the control population. Familial evaluation showed that only homozygous and compound heterozygous had signs of disease, whereas all heterozygous family members were healthy. The mean age at diagnosis was 35 years (range 15-69). Fifty per cent of patients had concentric left ventricular hypertrophy (LVH) and 45% were asymptomatic at the moment of the first examination. Significant degrees of late gadolinium enhancement were detected in 80% of affected individuals, and 20% of patients had left ventricular (LV) systolic dysfunction. Fifty per cent had non-sustained ventricular tachycardia. Twenty per cent of patients suffered an adverse cerebrovascular event (20%). Conclusion: TRIM63 appears to be an uncommon cause of HCM inherited in an autosomal-recessive manner and associated with concentric LVH and a high rate of LV dysfunction

Sustained Low Serum Substance P Levels in Non-Surviving Septic Patients

Previously, researchers found higher serum substance P (SP) concentrations in survivors of severe sepsis than in non-survivors at the time of severe sepsis diagnosis. The objectives of our current study were to determine whether there is an association between serum SP levels during the first week and sepsis mortality, sepsis severity, serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-10, and whether serum SP levels during the first week could be used as a biomarker of sepsis mortality. We determined serum concentration of SP, TNF-α, and IL-10 at days 1, 4, and 8. The end-point of the study was mortality at 30 days. We found that non-survivor (n = 104) compared to survivor patients (n = 206) showed lower serum SP levels at days 1, 4, and 8 (p < 0.001). Multiple logistic regression analyses showed an association between 30-day mortality and serum SP levels at days 1, 4, and 8 (p < 0.001) controlling for SOFA score, diabetes mellitus, age, and lactic acid levels. The most interesting findings of our study were that there is an association between serum SP levels during the first week and sepsis mortality, and that serum SP levels during the first week could be used as a biomarker of sepsis mortality

Serum Levels of Substance P and Mortality in Patients with a Severe Acute Ischemic Stroke

Substance P (SP), a member of tachykinin family, is involved in the inflammation of the central nervous system and in the appearance of cerebral edema. Higher serum levels of SP have been found in 18 patients with cerebral ischemia compared with healthy controls. The aim of our multi-center study was to analyze the possible association between serum levels of SP and mortality in ischemic stroke patients. We included patients with malignant middle cerebral artery infarction (MMCAI) and a Glasgow Coma Scale (GCS) lower than 9. Non-surviving patients at 30 days (n = 31) had higher serum concentrations of SP levels at diagnosis of severe MMCAI than survivors (n = 30) (p < 0.001). We found in multiple regression an association between serum concentrations of SP higher than 362 pg/mL and mortality at 30 days (Odds Ratio = 5.33; 95% confidence interval = 1.541–18.470; p = 0.008) after controlling for age and GCS. Thus, the major novel finding of our study was the association between serum levels of SP and mortality in patients suffering from severe acute ischemic stroke

High serum levels of caspase-cleaved cytokeratin-18 are associated with malignant middle cerebral artery infarction patient mortality

Abstract Background There have been found apoptotic changes in brain tissue samples from humans after cerebral ischemia. Caspase-cleaved cytokeratin (CCCK)-18 could appears in blood during apoptosis. High circulating levels of CCCK-18 have been associated with a poor prognosis in patients with cerebral process, such as traumatic brain injury and spontaneous cerebral hemorrhage. However, they have not been explored in patients with ischemic stroke. Thus, the aim of this study was to determine whether there is an association between serum CCCK-18 levels and mortality in patients with severe malignant middle cerebral artery infarction (MMCAI). Methods This was an observational, prospective and multicentre study. We included patients with severe MMCAI. We considered MMCAI as severe when Glasgow Coma Scale (GCS) was lower than 9. We measured serum CCCK-18 levels at the diagnosis moment of the severe MMCAI. Results We found that non-surviving severe MMCAI patients (n = 33) showed lower GCS and platelet count, and higher serum CCCK-18 levels than survivor ones (n = 33). We found an area under the curve (AUC) of serum CCCK-18 levels to predict 30-day mortality of 82% (95% CI = 71%–91%; p < 0.001). In the multiple logistic regression analysis was found that serum CCCK-18 levels were associated with 30-day mortality (OR = 1.023; 95% CI = 1.010–1.037; p = 0.001) after to control for platelet count and GCS. Conclusions To our knowledge, this is the first series reporting data on serum CCCK-18 levels in ischemic stroke patients. The novel findings of our study were that non-surviving severe MMCAI patients had higher serum CCCK-18 levels than surviving patients, and that there is an association between high serum CCCK-18 levels and MMCAI patients mortality

Prognostic Value of Serum Caspase-Cleaved Cytokeratin-18 Levels before Liver Transplantation for One-Year Survival of Patients with Hepatocellular Carcinoma

Cytokeratin (CK)-18 is the major intermediate filament protein in the liver and during hepatocyte apoptosis is cleaved by the action of caspases; the resulting fragments are released into the blood as caspase-cleaved cytokeratin (CCCK)-18. Higher circulating levels of CCCK-18 have been found in patients with hepatocellular carcinoma (HCC) than in healthy controls and than in cirrhotic patients. However, it is unknown whether serum CCCK-18 levels before liver transplantation (LT) in patients with HCC could be used as a prognostic biomarker of one-year survival, and this was the objective of our study with 135 patients. At one year after LT, non-survivors showed higher serum CCCK-18 levels than survivors (p = 0.001). On binary logistic regression analysis, serum CCCK-18 levels &gt;384 U/L were associated with death at one year (odds ratio = 19.801; 95% confidence interval = 5.301–73.972; p &lt; 0.001) after controlling for deceased donor age. The area under the receiver operating characteristic (ROC) curve of serum CCCK-18 levels to predict death at one year was 77% (95% CI = 69%–84%; p &lt; 0.001). The new finding of our study was that serum levels of CCCK-18 before LT in patients with HCC could be used as prognostic biomarker of survival

Association between Interleukin-6 Promoter Polymorphism (-174 G/C), Serum Interleukin-6 Levels and Mortality in Severe Septic Patients

The association between interleukin (IL)-6 promoter polymorphism (-174 G/C), circulating IL-6 levels and mortality in septic patients has scarcely been addressed, and then only in studies of small sample size, and a direct association among them has not been previously reported. Therefore, the purpose of our study was to determine whether this association exists. An observational, prospective and multicenter study including severe septic patients was undertaken and serum IL-6 levels at severe sepsis diagnosis and IL-6 promoter polymorphism (-174 G/C) were determined. The end-point of the study was 30-day mortality. The study included 263 patients with the following genotypes of IL-6 promoter polymorphism (-174 G/C): 123 (46.8%) GG, 110 (41.8%) GC and 30 (11.4%) CC. CC homozygous patients showed lower sepsis-related organ failure assessment (SOFA) score, serum IL-6 levels and mortality at 30 days compared to those with other genotypes (GC or GG). On regression analysis, CC homozygous patients showed lower 30-day mortality than those with genotype GG (odds ratio = 0.21; 95% CI = 0.053−0.838; p = 0.03) or GC (hazard ratio = 0.28; 95% CI = 0.074−1.037; p = 0.06). The most important results of our study were that CC might be a favorable genotype in septic patients showing lower serum IL-6 levels and lower risk of death within 30 days

Non-Survivor Ischemic Stroke Patients Maintain High Serum Caspase-Cleaved Cytokeratin-18 Levels

Objective: Caspase-cleaved cytokeratin (CCCK)-18 could appear in blood during apoptosis. In two different studies, on day 1 of cerebral infarction and at 72 h of cerebral infarction, respectively, higher circulating CCCK-18 levels were found in non-surviving than in surviving patients. The objective of this study was to analyze the ability of these levels to predict mortality at any time during the first week of cerebral infarction. Methods: Patients with malignant middle cerebral artery infarction (MMCAI) were included and the diagnosis criteria were the presence, observed in a computed tomography, of an acute cerebral infarction in at least 50% of this territory and midline shift, and an acute neurological deterioration with a Glasgow Coma Scale &le; 8. Serum CCCK-18 levels at days 1, 4 and 8 of MMCAI were determined. Results: Serum concentrations of CCCK-18 at days 1, 4 and 8 of MMCAI were higher in non-surviving (n = 34) than in surviving patients (n = 34). Serum CCCK-18 concentrations at days 1, 4 and 8 of MMCAI had an area under curve (95% CI) used to predict a 30-day mortality of 0.83 (0.72 &ndash;0.91; p &lt; 0.001), 0.78 (0.65&ndash;0.89; p &lt; 0.001) and 0.82 (0.68&ndash;0.92; p &lt; 0.001). Conclusions: The novel finding is that serum levels of CCCK-18 levels at any time after the first week of MMCAI could help predict 30-day mortality

Early Mortality of Brain Infarction Patients and Red Blood Cell Distribution Width

Background: Meta-analysis has found that high baseline red blood cell distribution width (RDW) is associated with increased long-term mortality (mortality at one year or more) in ischemic stroke. The objectives of this study were to determine whether there is an association between RDW and 30-day mortality, and to explore whether RDW during the first week of ischemic stroke could be a 30-day mortality biomarker. Methods: We included patients with malignant middle cerebral artery infarction (MMCAI). RDW at days 1, 4, and 8 of MMCAI were determined. The end-point study was 30-day mortality. Results: We found that survivor (n = 37) in respect to non-survivor patients (n = 37) had lower RDW at days 1 (p &lt; 0.001), 4 (p &lt; 0.001), and 8 (p = 0.02). The area under curve (95% CI) for prediction of 30-day mortality by RDW at days 1, 4, and 8 of MMCAI were 0.80 (0.69&ndash;0.89; p &lt; 0.001), 0.79 (0.66&ndash;0.89; p &lt; 0.001), and 0.73 (0.58&ndash;0.84; p = 0.02). Regression analysis showed an association between RDW (odds ratio = 1.695; 95% CI = 1.230&ndash;2.335; p &lt; 0.001) and 30-day mortality. Conclusions: The association between RDW and early mortality, and the potential role of RDW during the first week of MMCAI as a prognostic biomarker of early mortality were the main novelties of our study

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&ndash;0.834; p = 0.006). We found an association between serum levels of melatonin with serum levels of malondialheyde (rho = &minus;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