Golgi Complex form and Function: A Potential Hub Role Also in Skeletal Muscle Pathologies?

A growing number of disorders has been associated with mutations in the components of the vesicular transport machinery. The early secretory pathway consists of Endoplasmic Reticulum, numerous vesicles, and the Golgi Complex (GC), which work together to modify and package proteins to deliver them to their destination. The GC is a hub organelle, crucial for organization of the other secretory pathway components. As a consequence, GC's form and function are key players in the pathogenesis of several disorders. Skeletal muscle (SKM) damage can be caused by defective protein modifications and traffic, as observed in some Limb girdle muscular dystrophies. Interestingly, in turn, muscle damage in Duchenne dystrophic SKM cells also includes the alteration of GC morphology. Based on the correlation between GC's form and function described in non-muscle diseases, we suggest a key role for this hub organelle also in the onset and progression of some SKM disorders. An altered GC could affect the secretory pathway via primary (e.g., mutation of a glycosylation enzyme), or secondary mechanisms (e.g., GC mis-localization in Duchenne muscles), which converge in SKM cell failure. This evidence induces considering the secretory pathway as a potential therapeutic target in the treatment of muscular dystrophies.

Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy.

Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the cornerstone of atherosclerotic cardiovascular disease (ASCVD) in both primary and secondary prevention. Despite the statin-therapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statin-associated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. There are many risk factors associated with patient features and hypolipidemic agents that seem to increase the risk of developing SAMS. Due to the lack of a "gold standard", the diagnostic test for SAMS is based on a clinical criteria score, which is independent of creatine kinase (CK) elevation. Mechanisms that underlie the pathogenesis of SAMS remain almost unclear, though a high number of risk factors may increase the probability of myotoxicity induced by statin therapy. Some of these, related to pharmacokinetic properties of statins and to concomitant therapies or patient characteristics, may affect statin bioavailability and increase vulnerability to high-dose statins.

Contraction and nutrition interaction promotes anabolism in cachectic muscle.

PURPOSE OF REVIEW: Cachexia is a disease-related multifactorial syndrome characterized by inflammation, massive muscle protein catabolism and carbohydrate and lipid metabolism disorder.Several studies tried to define the impact of either nutrition or physical exercise (single approach strategy) or their combination (multimodal approach strategy) on prevention and/or treatment of muscle wasting in cachectic patients. RECENT FINDINGS: Single approach strategies (i.e. nutrition or physical exercise) have the potential of preventing and improving features of the cachexia syndrome possibly with a differential impact according to the underlying disease. Limited information is available on the beneficial effect of multimodal approach strategies. SUMMARY: Multimodal approaches appear to be more effective than those based on single interventions in physiological condition and in cachectic patients with COPD or chronic kidney disease. Further studies, however, are required in cachexia induced by heart failure, cancer and critical illness.

Derivation and Validation of a Biomarker-Based Clinical Algorithm to Rule Out Sepsis From Noninfectious Systemic Inflammatory Response Syndrome at Emergency Department Admission: A Multicenter Prospective Study.

OBJECTIVES: To derive and validate a predictive algorithm integrating a nomogram-based prediction of the pretest probability of infection with a panel of serum biomarkers, which could robustly differentiate sepsis/septic shock from noninfectious systemic inflammatory response syndrome. DESIGN: Multicenter prospective study. SETTING: At emergency department admission in five University hospitals. PATIENTS: Nine-hundred forty-seven adults in inception cohort and 185 adults in validation cohort. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A nomogram, including age, Sequential Organ Failure Assessment score, recent antimicrobial therapy, hyperthermia, leukocytosis, and high C-reactive protein values, was built in order to take data from 716 infected patients and 120 patients with noninfectious systemic inflammatory response syndrome to predict pretest probability of infection. Then, the best combination of procalcitonin, soluble phospholipase A2 group IIA, presepsin, soluble interleukin-2 receptor α, and soluble triggering receptor expressed on myeloid cell-1 was applied in order to categorize patients as "likely" or "unlikely" to be infected. The predictive algorithm required only procalcitonin backed up with soluble phospholipase A2 group IIA determined in 29% of the patients to rule out sepsis/septic shock with a negative predictive value of 93%. In a validation cohort of 158 patients, predictive algorithm reached 100% of negative predictive value requiring biomarker measurements in 18% of the population. CONCLUSIONS: We have developed and validated a high-performing, reproducible, and parsimonious algorithm to assist emergency department physicians in distinguishing sepsis/septic shock from noninfectious systemic inflammatory response syndrome.

Multiple sites of vascular dilation or aneurysmal disease and matrix metalloproteinase genetic variants in patients with abdominal aortic aneurysm.

OBJECTIVE: The objective of this study was to assess whether functional genetic polymorphisms of matrix metalloproteinases (MMPs) 1, 3, 9, and 12 are associated with arterial enlargements or aneurysms of the thoracic aorta or popliteal arteries in patients with abdominal aortic aneurysm (AAA). METHODS: The associations between MMP1 (-1607 G in/del, rs1799750), MMP3 (-1171 A in/del rs35068180), MMP9 (13-26 CA repeats around -90, rs2234681, rs917576, rs917577), and MMP12 (G/T missense variation, rs652438) polymorphisms and enlargements or aneurysms of the thoracic aorta and popliteal arteries were tested in 169 consecutive AAA patients. RESULTS: Thoracic aorta enlargement or aneurysm (TE/A; maximum diameter, >35 mm) was detected in 34 patients (20.1% prevalence). MMP9 rs2234681 microsatellite was the only genetic determinant of TE/A in AAA patients (P = .003), followed by hypercholesterolemia and antiplatelet use. Carriers of both alleles with ≥22 CA repeats had a 5.9 (95% confidence interval, 1.9-18.6; P < .0001) increased odds of TE/A, and a score considering all three variables showed 98% negative predictive value and 30% positive predictive value for thoracic aortic aneurysm detection. Eighty-two popliteal artery enlargements or aneurysms (diameter >10 mm) occurred in 55 patients (33.1% prevalence). Carriers of MMP12 rs652438 C allele showed an 18% (P = .006) increased diameter in popliteal arteries and a 2.8 (95% confidence interval, 1.3-6; P = .008) increased odds of popliteal artery enlargement or aneurysm compared with TT genotype. CONCLUSIONS: Among patients with AAA, carriers of homozygous ≥22 CA repeats in MMP9 rs12234681 and of C allele in MMP12 rs652438 have a substantial risk of carrying thoracic and popliteal enlargements, respectively.

Intermittent vs. continuous enteral feeding to prevent catabolism in acutely ill adult and pediatric patients.

PURPOSE OF REVIEW: In clinical management of acutely ill adults and children, continuous enteral feeding (CEF), being considered the most tolerable approach, in comparison to other temporal patterns of nutrient administration (i.e. intermittent, cyclic and bolus), is the most frequently applied method. However, uncertainties remain about the most efficient approach to counteract protein catabolism. RECENT FINDINGS: In critically ill adults, protein loss is mainly driven by increased protein breakdown whereas, in pediatric patients, acute illness is mainly characterized by blunted regulation of protein synthesis and stunted growth. Kinetic studies in fed adult volunteers indicate that protein synthesis can be stimulated for a limited period only. However, continuous feeding persistently improves protein balance through a sustained suppression of protein breakdown. This leads to the hypothesis that CEF could be more anticatabolic than intermittent enteral feeding (IEF) in these patients. Differently from adults, experimental models of acute disease in growing animals have consistently indicated that IEF can improve protein anabolism more efficiently than CEF, mainly through protein synthesis stimulation. The scarce number of clinical studies in acutely ill adults or pediatric patients, mostly performed with inadequate methodology, could not define the best approach to maintain protein balance. SUMMARY: There is a need for pragmatic studies to directly compare the protein anabolic action of CEF and IEF using accurate methodologies, such as stable isotopes of amino acids, in both adult and pediatric patients with acute illness.

Procalcitonin in early rule-in/rule-out of sepsis in SIRS patients admitted to a medical ward.

BACKGROUND: A relevant amount of patients with clinical suspect of sepsis is admitted and treated in medical wards (MW). These patients have a better prognosis but are older and with more comorbidities compared to those admitted to intensive care units (ICU). Procalcitonin (PCT) is extensively used in emergency departments for the diagnosis of sepsis, but its accuracy in the setting of a MW has not been thoroughly investigated. Predicted low PCT levels also call for the comparison of immunomagnetic-chemiluminescent (L-PCT) and time-resolved amplified cryptate emission (TRACE, K-PCT) technologies, in PCT determination. METHODS: In 80 patients with systemic inflammatory response syndrome (SIRS) diagnostic criteria and suspect of sepsis newly admitted to a MW, PCT was determined with L- and K-PCT method. RESULTS: Sixty patients were diagnosed as sepsis (20 microbiologically and 40 clinically proven) and 20 with non-infective SIRS. The sepsis group had significantly higher levels of both PCTs, with no differences between the clinically and microbiologically proven subgroups. The areas under ROC curves for L- and K-PCT were 0.72 and 0.78 (p<0.001 for each), respectively. Based on MW customized cut-off values of 0.150 (L-PCT) and 0.143 ng/mL (K-PCT), overall accuracies were 66.8 (95% CI 58.7-78.9) and 78.2% (69.8-87.2), respectively, compared to the 55% (44.2-66) of 0.5 ng/mL canonical cut-off. Neither PCT-L nor -K held prognostic value on survival. CONCLUSIONS: In MW patients, customized PCT cut-off levels provide better accuracy than customary levels adopted from ICU, and TRACE technology seems to offer a wider analysis range.

Metabolic Consequences of Anabolic Steroids, Insulin, and Growth Hormone Abuse in Recreational Bodybuilders: Implications for the World Anti-Doping Agency Passport.

BACKGROUND: Hormonal doping in recreational sports is a public-health concern. The World Anti-Doping Agency (WADA) promoted the creation of the Athlete Biological Passport, aiming to monitor athlete's biological variables over time to facilitate indirect detection of doping. Detection tests for anabolic androgenic steroids (AAS) and growth hormone (GH) are available while insulin abuse cannot be revealed. We have determined in recreational bodybuilders the metabolic effects associated with different patterns of hormone abuse. All analyses were conducted using Statistical Package for Social Sciences (SPSS) 21.0 software (SPSS Chicago, IL). RESULTS: We have assessed plasma concentrations of selected metabolic markers and fatty acid content in erythrocyte membranes of 92 male bodybuilders and in 45 healthy controls. Hormonal abuse was identified by anonymous questionnaires. 43% (%) of recruited bodybuilders regularly abused hormones, i.e., anabolic androgenic steroids (95%) often associated with GH (30%) and/or insulin (38%). HDL-cholesterol was lower in insulin and/or GH abusers. Alanine (ALT) and aspartic (AST) transaminases were greater in hormone abusing bodybuilders than in non-doping bodybuilders and controls. Insulin doping was selectively associated with increased plasma ALT-to-AST ratio. In erythrocyte membranes, elongase activity (i.e., stearic-to-palmitic ratio) was lower in insulin and/or growth hormone doping, whereas increased Δ-9 desaturase activity (i.e., palmitoleic-to-palmitic ratio) was selectively associated with insulin doping. CONCLUSIONS: In conclusion, our study demonstrates that insulin and GH abuse are characterized by multiple alterations of specific metabolic markers. Although further studies are needed to test whether longitudinal monitoring of selected metabolic marker such as muscle contraction time, HDL levels, ALT-AST ratio as well as the activities of selected enzymes (e.g. Δ-9 desaturase and elongase), could contribute to the detection of insulin and GH abuse in sport.

Opinion paper on innovative approach of biomarkers for infectious diseases and sepsis management in the emergency department.

Sepsis is a leading healthcare problem, accounting for the vast majority of fatal events in critically ill patients. Beyond early diagnosis and appropriate treatment, this condition requires a multifaceted approach for monitoring the severity, the potential organ failure as well as the risk of death. Monitoring of the efficacy of treatment is also a major issue in the emergency department (ED). The assessment of critically ill conditions and the prognosis of patients with sepsis is currently based on some scoring systems, which are, however, inefficient to provide definite clues about organ failure and prognosis in general. The discretionary and appropriate use of some selected biomarkers such as procalcitonin, inducible protein 10 (IP10), Group IV phospholipase A2 type II (PLA2 II), neutrophil gelatinase-associated lipocalin (NGAL), natriuretic peptides, mature adrenomedullin (ADM), mid-regional pro-adrenomedullin (MR-proADM), copeptin, thrombopoietin, Mer receptor and even red blood cell distribution width (RDW) represent thereby an appealing perspective in the diagnosis and management of patients with sepsis. Nevertheless, at the moment, it is not still clear if it is better to use a multimarkers approach or if a single, most appropriate, biomarker exists. This collective opinion paper is aimed at providing an overview about the potential clinical usefulness of some innovative biomarkers of sepsis in its diagnosis and prognosis, but also in the treatment management of the disease. This manuscript represents a synopsis of the lectures of Third Italian GREAT Network Congress, that was hold in Rome, 15-19 October 2012.

High-protein diet with excess leucine prevents inactivity-induced insulin resistance in women.

BACKGROUND AND AIMS: Muscle inactivity leads to muscle atrophy and insulin resistance. The branched-chain amino acid (BCAA) leucine interacts with the insulin signaling pathway to modulate glucose metabolism. We have tested the ability of a high-protein BCAA-enriched diet to prevent insulin resistance during long-term bed rest (BR). METHODS: Stable isotopes were infused to determine glucose and protein kinetics in the postabsorptive state and during a hyperinsulinemic-euglycemic clamp in combination with amino acid infusion (Clamp + AA) before and at the end of 60 days of BR in two groups of healthy, young women receiving eucaloric diets containing 1 g of protein/kg per day (n = 8) or 1.45 g of protein/kg per day enriched with 0.15 g/kg per day of BCAAs (leucine/valine/isoleucine = 2/1/1) (n = 8). Body composition was determined by Dual X-ray Absorptiometry. RESULTS: BR decreased lean body mass by 7.6 ± 0.3 % and 7.2 ± 0.8 % in the groups receiving conventional or high protein-BCAA diets, respectively. Fat mass was unchanged in both groups. At the end of BR, percent changes of insulin-mediated glucose uptake significantly (p = 0.01) decreased in the conventional diet group from 155 ± 23 % to 84 ± 10 % while did not change significantly in the high protein-BCAA diet group from 126 ± 20 % to 141 ± 27 % (BR effect, p = 0.32; BR/diet interaction, p = 0.01; Repeated Measures ANCOVA). In contrast, there were no BR/diet interactions on proteolysis and protein synthesis Clamp + AA changes in the conventional diet and the high protein-BCAA diet groups. CONCLUSION: A high protein-BCAA enriched diet prevented inactivity-induced insulin resistance in healthy women.

Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives.

Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1-10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25-30%. Mipomersen decreases Lp(a) levels by 25-40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.

Epidemiology of atherosclerotic cardiovascular disease in polygenic hypercholesterolemia with or without high lipoprotein(a) levels.

Background and aims: Epidemiology of atherosclerotic cardiovascular disease might be different in patients with polygenic hypercholesterolemia plus high levels (≥30 mg/dl) of Lp(a) (H-Lpa) than in those with polygenic hypercholesterolemia alone (H-LDL). We compared the incidence of peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CVD) in patients with H-Lpa and in those with H-LDL. Methods: Retrospective analysis of demographics, risk factors, vascular events, therapy, and lipid profile in outpatient clinical data. Inclusion criteria was adult age, diagnosis of polygenic hypercholesterolemia, and both indication and availability for Lp(a) measurement. Results: Medical records of 258 patients with H-Lpa and 290 H-LDL were reviewed for occurrence of vascular events. The median duration of follow-up was 10 years (IQR 3-16). In spite of a similar reduction of LDL cholesterol, vascular events occurred more frequently, and approximately 7 years earlier (P = 0.024) in patients with H-Lpa than in H-LDL (HR 1.96 1.21-3.17, P = 0.006). The difference was around 10 years for acute events (TIA, Stroke, acute coronary events) and one year for chronic ones (P = 0.023 and 0.525, respectively). Occurrence of acute CAD was higher in H-Lpa men (HR 3.1, 95% CI 1.2-7.9, P = 0.007) while, among women, PAD was observed exclusively in H-Lpa subjects with smoking habits (P = 0.009). Conclusions: Patients with high Lp(a) levels suffer from a larger and earlier burden of the disease compared to those with polygenic hypercholesterolemia alone. These patients are at higher risk of CAD if they are men, and of PAD if they are women.

Oral anticoagulation and VKORC1 polymorphism in patients with a mechanical heart prosthesis: a 6-year follow-up.

Therapy with Vitamin K antagonists (VKA) effectively reduces the thrombosis risk in many clinical conditions. Genetic variants of vitamin K epoxide reductase (VKORC-1) are associated with increased VKA effect and bleeding risk. It is unknown whether these variants could also affect the long-term outcome in patients with high-dosage oral anticoagulation and/or more difficult adherence to the therapeutic INR range. Hundred and twenty-four patients with mechanical heart valve replacement assuming VKA were genotyped for VKORC-1 -1639G>A (Rs9923231) polymorphism. Hemorrhage, venous thrombosis and atherothrombotic events were retrospectively assessed for a 6-year period. Furthermore, stability of their INR in relationship with the VKORC-1 genotype was investigated day-by-day for 3 months. No differences were observed in hemorrhage and venous thrombosis events according to rs 9923231. GG genotype carriers (n = 41) had no atherothrombotic events, while 4 strokes, 4 TIA and 3 AMI were diagnosed in A carriers (n = 83; P = 0.0008). During the daily observation period, A allele carriers had lower VKA requirements (4.7, 3.7, 2.2 mg/day for GG/GA/AA genotype respectively; P = 0.00001), higher mean INR (2.7, 2.8, 2.9; P = 0.05) and a higher number of examinations above the therapeutic range than GG carriers (17 % vs. 0 % in GG genotype, P = 0.036). Conversely, patients with GG genotype had a more stable dosage of VKA (P = 0.006) and a higher percentage of examinations under the therapeutic range (51, 43 and 36 % in GG, GA and AA genotype, respectively, P = 0.040). In patients with high dosage VKA, VKORC-1 polymorphism is associated to a different warfarin dosage, anticoagulation level, time spent outside the therapeutic range and, in the long-term, a different incidence of atherothrombotic events.

Skeletal Muscle in Hypoxia and Inflammation: Insights on the COVID-19 Pandemic.

SARS-CoV-2 infection is often associated with severe inflammation, oxidative stress, hypoxia and impaired physical activity. These factors all together contribute to muscle wasting and fatigue. In addition, there is evidence of a direct SARS-CoV-2 viral infiltration into skeletal muscle. Aging is often characterized by sarcopenia or sarcopenic obesity These conditions are risk factors for severe acute COVID-19 and long-COVID-19 syndrome. From these observations we may predict a strong association between COVID-19 and decreased muscle mass and functions. While the relationship between physical inactivity, chronic inflammation, oxidative stress and muscle dysfunction is well-known, the effects on muscle mass of COVID-19-related hypoxemia are inadequately investigated. The aim of this review is to highlight metabolic, immunity-related and redox biomarkers potentially affected by reduced oxygen availability and/or muscle fatigue in order to shed light on the negative impact of COVID-19 on muscle mass and function. Possible countermeasures are also reviewed.

Remodeling of abdominal aortic aneurysm sac following endovascular aortic repair: association with clinical, surgical, and genetic factors.

After successful endovascular aortic repair (EVAR), abdominal aortic aneurysms (AAA) sac will undergo negative remodeling (i.e., shrinkage) as a measure of successful exclusion. Determinants of shrinkage after EVAR are not fully known. In 84 post-EVAR patients, time course of AAA diameter after repair and occurrence of endoleaks (ELs) have been correlated with clinical history, medications, anthropometric data, vascular anatomy, and matrix metalloprotease (MMP) genetic variants (namely MMP-1 rs1799750, MMP-3 rs35068180, MMP-9 rs2234681, rs917576, rs917577, MMP-12 rs652438, and TIMP1 rs4898). During follow-up, 41 ELs were detected in 37 patients (44%, 10.4 events/100 pt./y), accounting for AAA dilation or reduced shrinkage (P < .001). High-flow ELs (type 1 and/or 3) occurrence was associated with warfarin use, MMP9 rs17577 polymorphism, and unfavorable anatomy, while low-flow type 2 ELs occurred more often in TIMP1 rs4898 non-T carriers. In EL-free patients, AAA diameter decreased for the first three years, (-4, -3 and - 2 mm/year respectively) and remained stable thereafter. Shrinkage between two measurements (n = 120) was associated with smaller AAA diameter at the baseline, peripheral arterial disease (PAD), patients' older age at intervention, and G-/G- genotype in MMP1 rs1799750 (binary logistic regression, P = .0001). Aneurysmal sac shrinking occurs for few years after EVAR, only in patients without EL, and is related to older age, PAD, smaller aneurysm size and putative lower MMP1 expression while EL occurrence prevents such a remodeling and is mainly related to local-acting factors like unfavorable anatomy, anticoagulation, and MMP9 and TIMP1 genetic polymorphisms.

Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome.

Bempedoic acid is a new cholesterol-lowering drug, which has recently received US FDA and EMA approval. This drug targets lipid and glucose metabolism as well as inflammation via downregulation of ATP-citrate lyase and upregulation of AMP-activated protein kinase (AMPK). The primary effect is the reduction of cholesterol synthesis in the liver and its administration is generally not associated to unwanted muscle effects. Suppression of hepatic fatty acid synthesis leads to decreased triglycerides and, possibly, improved non-alcoholic fatty liver disease. Bempedoic acid may decrease gluconeogenesis leading to improved insulin sensitivity, glucose metabolism, and metabolic syndrome. The anti-inflammatory action of bempedoic acid is mainly achieved via activation of AMPK pathway in the immune cells, leading to decreased plasma levels of C-reactive protein. Effects of bempedoic acid on atherosclerotic cardiovascular disease, type 2 diabetes and chronic liver disease have been assessed in randomized clinical trials but require further confirmation. Safety clinical trials in phase III indicate that bempedoic acid administration is generally well-tolerated in combination with statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to achieve low-density lipoprotein cholesterol targets. The aim of this narrative review on bempedoic acid is to explore the underlying mechanisms of action and potential clinical targets, present existing evidence from clinical trials, and describe practical management of patients.

Early lean mass sparing effect of high-protein diet with excess leucine during long-term bed rest in women.

Muscle inactivity leads to muscle atrophy. Leucine is known to inhibit protein degradation and to promote protein synthesis in skeletal muscle. We tested the ability of a high-protein diet enriched with branched-chain amino acids (BCAAs) to prevent muscle atrophy during long-term bed rest (BR). We determined body composition (using dual energy x-ray absorptiometry) at baseline and every 2-weeks during 60 days of BR in 16 healthy young women. Nitrogen (N) balance was assessed daily as the difference between N intake and N urinary excretion. The subjects were randomized into two groups: one received a conventional diet (1.1 ± 0.03 g protein/kg, 4.9 ± 0.3 g leucine per day) and the other a high protein, BCAA-enriched regimen (1.6 ± 0.03 g protein-amino acid/kg, 11.4 ± 0.6 g leucine per day). There were significant BR and BR × diet interaction effects on changes in lean body mass (LBM) and N balance throughout the experimental period (repeated measures ANCOVA). During the first 15 days of BR, lean mass decreased by 4.1 ± 0.9 and 2.4 ± 2.1% (p < 0.05) in the conventional and high protein-BCAA diet groups, respectively, while at the end of the 60-day BR, LBM decreased similarly in the two groups by 7.4 ± 0.7 and 6.8 ± 2.4%. During the first 15 days of BR, mean N balance was 2.5 times greater (p < 0.05) in subjects on the high protein-BCAA diet than in those on the conventional diet, while we did not find significant differences during the following time intervals. In conclusion, during 60 days of BR in females, a high protein-BCAA diet was associated with an early protein-LBM sparing effect, which ceased in the medium and long term.

Candidate Biomarkers for the Detection of Serious Infections in Children: A Prospective Clinical Study.

Serious bacterial infections (SBI) in children are associated with considerable morbidity and mortality, and their early identification remains challenging. The role of laboratory tests in this setting is still debated, and new biomarkers are needed. This prospective, observational, single-center study aims to evaluate the diagnostic role of blood biomarkers in detecting SBI in children presenting with signs of systemic inflammatory response syndrome (SIRS). A panel of biomarkers was performed, including C-reactive protein (CRP), procalcitonin (PCT), white blood cell count (WBC), absolute neutrophil count (ANC), interleukin (IL)-6, IL-8, IL-10, human terminal complement complex (C5b-9), Plasmalemma-Vesicle-associated protein 1 (PV-1), Intercellular Adhesion Molecule-1 (ICAM-1), and Phospholipase A2 (PLA2). Among 103 patients (median age 2.9 years, 60% males), 39 had a diagnosis of SBI (38%). Significant predictors of SBI were CRP (p = 0.001) and ICAM-1 (p = 0.043). WBC (p = 0.035), ANC (p = 0.012) and ANC/WBC ratio (p = 0.015) were also significantly associated with SBI in children without pre-existing neutropenia. ROC curves, however, revealed suboptimal performance for all variables. Nevertheless, a model that combined CRP and ANC/WBC ratio had more in-depth diagnostic accuracy than either of the two variables. Overall, this study confirms the limited usefulness of blood biomarkers for the early diagnosis of SBI. WBC, ANC, ANC/WBC ratio, CRP, and ICAM-1 showed the best, albeit moderate, diagnostic accuracy.

Genetic Variants of Matrix Metalloproteinase and Sepsis: The Need Speed Study.

Many causal mechanisms in sepsis susceptibility are largely unknown and the functional genetic polymorphisms (GP) of matrix metalloproteinases (MMPs) and their natural tissue inhibitor of MMPs (TIMP1) could play a role in its development. GPs of MMPs and TIMP (namely MMP-1 rs1799750, MMP-3 rs3025058, MMP-8 rs11225395, MMP-9 rs2234681, and TIMP-1 rs4898) have been compared in 1058 patients with suspected sepsis to assess the association with susceptibility and etiology of sepsis. Prevalence of MMP8 rs11225395 G/G genotype was higher in sepsis patients than in those with non-infective Systemic Inflammatory Reaction Syndrome (35.6 vs. 26%, hazard ratio, HR 1.56, 95% C.I. 1.04-2.42, p = 0.032). G/G patients developed less hyperthermia (p = 0.041), even after stratification for disease severity (p = 0.003). Patients carrying the 6A allele in MMP3 rs3025058 had a higher probability of microbiologically-proven sepsis (HR 1.4. 95%C.I. 1.01-1.94, p = 0.044), particularly when due to virus (H.R. 2.14, 95% C.I. 1.06-4.31, p = 0.046), while MMP-1 G/G genotype patients carried a higher risk for intracellular bacteria (Chlamydia, Mycoplasma, and Legionella, H.R. 6.46, 95% C.I. 1.58-26.41, p = 0.003). Neither severity of sepsis at presentation, nor 30-day mortality were influenced by the investigated variants or their haplotype. MMP8 rs11225395 G/G carriers have lower temperature at presentation and a more than 50% increased susceptibility to sepsis. Among patients with sepsis, carriers of MMP1 rs1799750 G/G have an increased susceptibility for intracellular pathogen infections, while virus serology is more often positive in those with the MMP3 rs3025058 A/A genotype.