PEARL: A Non-interventional Study of Real-World Alirocumab Use in German Clinical Practice.

BACKGROUND: Several lipid guidelines recommend that proprotein convertase subtilisin/kexin type 9 inhibitors should be considered for patients with atherosclerotic cardiovascular disease who are inadequately treated with maximally tolerated lipid-lowering treatment. OBJECTIVES: The PEARL study assessed the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in patients with hypercholesterolemia in a real-world setting. METHODS: PEARL was an open, prospective, multicenter, non-interventional study conducted in Germany. Patients (n = 619) for whom treating physicians decided to use alirocumab 75 or 150 mg every 2 weeks according to German guidelines (low-density lipoprotein cholesterol > 1.8/2.6 mmol/L [> 70/100 mg/dL], depending on cardiovascular risk, despite maximally tolerated statin therapy with/without other non-alirocumab lipid-lowering therapy) were enrolled and followed for 24 weeks. Physicians could adjust the alirocumab dose based on their clinical judgment. The primary efficacy endpoint was low-density lipoprotein cholesterol reduction from baseline (prior to alirocumab therapy) to week 24. RESULTS: Overall, 72.8% of patients reported complete or partial statin intolerance. Mean low-density lipoprotein cholesterol was 4.7 mmol/L (180.5 mg/dL) and 2.3 mmol/L (89.8 mg/dL) at baseline and week 24, respectively. Least-squares mean percentage change from baseline to week 24 in low-density lipoprotein cholesterol was - 48.6%. Initial alirocumab dose was 75 mg in 72.9% of patients and 150 mg in 24.5% of patients; 19.6% of patients received an alirocumab dose increase (75 to 150 mg) and 1.6% of patients received a dose decrease. Adverse events were reported in 10.3% of patients, with myalgia being the most common. CONCLUSIONS: In a real-world setting in Germany, alirocumab was used in patients who had high baseline low-density lipoprotein cholesterol levels with/without statin intolerance. Efficacy and safety were consistent with findings observed in the ODYSSEY Phase III program.

Food Intolerance: Immune Activation Through Diet-associated Stimuli in Chronic Disease.

The immune response is a very complex interplay of specific and nonspecific branches that have evolved to distinguish between nondangerous and dangerous or nontolerated factors. In the past, research has focused on the specific immune system much more than the host's innate defense. Studies have shown that a key component of the immune response involves activation of the inflammasome. A direct relationship between the presence of the inflammasome and the onset of disease has already been characterized for a variety of chronic and food-related diseases, including arthrosclerosis, metabolic syndrome, and chronic bowel diseases, such as Crohn's disease and ulcerative colitis. The leukocyte activation (ALCAT test), an immunological blood test for food intolerance reactions, is ideal to identify and eliminate individual food stimuli that may act as triggers for the cellular nonspecific immune response. Although the test is not diagnostic, studies have established that it can be a useful screening tool for the identification of foreign substances that may trigger immune cell activation, particularly of neutrophils, leading to inflammatory disorders. The ALCAT test, coupled with a targeted diet that is individually tailored according to the test's results, may support immune homeostasis and provide a valuable complementary approach for therapy and overall health.

Selenoprotein P is the essential selenium transporter for bones.

Selenium (Se) plays an important role in bone physiology as best reflected by Kashin-Beck disease, an endemic Se-dependent osteoarthritis. Bone development is delayed in children with mutations in SECIS binding protein 2 (SBP2), a central factor for selenoprotein biosynthesis. Circulating selenoprotein P (SePP) is positively associated with bone turnover in humans, yet its function for bone homeostasis is not known. We have analysed murine models of altered Se metabolism. Most of the known selenoprotein genes and factors needed for selenoprotein biosynthesis are expressed in bones. Bone Se is not associated with the mineral but exclusively with the organic matrix. Genetic ablation of Sepp-expression causes a drastic decline in serum (25-fold) but only a mild reduction in bone (2.5-fold) Se concentrations. Cell-specific expression of a SePP transgene in hepatocytes efficiently restores bone Se levels in Sepp-knockout mice. Of the two known SePP receptors, Lrp8 was detected in bones while Lrp2 was absent. Interestingly, Lrp8 mRNA concentrations were strongly increased in bones of Sepp-knockout mice likely in order to counteract the developing Se deficiency. Our data highlight SePP as the essential Se transporter to bones, and suggest a novel feedback mechanism for preferential uptake of Se in Se-deprived bones, thereby contributing to our understanding of hepatic osteodystrophy and the consistent bone phenotype observed in subjects with inherited selenoprotein biosynthesis mutations.

Selenoprotein P in seminal fluid is a novel biomarker of sperm quality.

Hepatically-derived selenoprotein P (SePP) transports selenium (Se) via blood to other tissues including the testes. Male Sepp-knockout mice are infertile. SePP-mediated Se transport to Sertoli cells is needed for supporting biosynthesis of the selenoenzyme glutathione peroxidase-4 (GPX4) in spermatozoa. GPX4 becomes a structural component of sperm midpiece during sperm maturation, and its expression correlates to semen quality. We tested whether SePP is also present in seminal plasma, potentially correlating to fertility parameters. Semen quality was assessed by sperm density, morphology and motility. SePP was measured by an immunoluminometric assay, and trace elements were determined by X-ray fluorescence spectroscopy. SePP levels were considerably lower in seminal plasma as compared to serum (0.4±0.1 mg/l vs. 3.5±1.0 mg/l); Se concentrations showed a similar but less pronounced difference (48.9±20.7 µg/l vs. 106.7±17.3 µg/l). Se and Zn correlated positively in seminal fluid but not in serum. Seminal plasma SePP concentrations were independent of serum SePP concentrations, but correlated positively to sperm density and fraction of vital sperm. SePP concentrations in seminal plasma of vasectomized men were similar to controls indicating that accessory sex glands are a testes-independent source of SePP. This notion was corroborated by histochemical analyses localizing SePP in epithelial cells of seminal vesicles. We conclude that SePP is not only involved in Se transport to testes supporting GPX4 biosynthesis but it also becomes secreted into seminal plasma, likely important to protect sperm during storage, genital tract passage and final journey.