Clearance of triglyceride-rich lipoproteins (TRLs) is mediated by several receptors, including heparan sulfate proteoglycans (HSPGs). Sulfate glucosamine-6-O-endosulfatase-2 is a gene related to the ...regulation of HSPG. A variant in this gene, rs2281279, has been shown to be associated with triglycerides and insulin resistance.
To determine the relationship between rs2281279, metabolic parameters and vascular events, and type 2 diabetes mellitus (T2DM) in patients at high cardiovascular risk and whether
genotype modifies this relationship.
Patients (
= 4386) at high cardiovascular risk from the Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease study were stratified according to their imputed rs2281279 genotype: AA (
= 2438), AG (
= 1642) and GG (
= 306). Effects of rs2281279 on metabolic parameters, vascular events and T2DM were analyzed with linear regression and Cox models.
There was no relationship between imputed rs2281279 genotype and triglycerides, non-high-density lipoprotein (HDL)-cholesterol, insulin and quantitative insulin sensitivity check index. During a median follow-up of 11.8 (IQR, 9.3-15.5) years, 1026 cardiovascular events and 320 limb events occurred. The presence of the G allele in rs2281279 did not affect the risk of vascular events hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.94-1.14 or limb events (HR, 0.92; 95% CI, 0.77-1.10). The presence of the G allele in rs2281279 did not affect the risk of T2DM (HR, 1.09; 95% CI, 0.94-1.27). The presence of the minor G allele of rs2281279 was associated with a beneficial risk profile in ε2ε2 patients, but not in ε3ε3 patients.
Imputed rs2281279 genotype is not associated with metabolic parameters and does not increase the risk of vascular events or T2DM in patients at high risk for cardiovascular disease.
Abstract Tendon xanthoma are most commonly associated with Familial Hypercholesterolemia, but the differential diagnosis includes sitosterolemia and cerebrotendinous xanthomatosis (CTX). The case ...presented here is of a 48-year old male with large tendon xanthomas attributable to CTX. CTX is a rare, recessive disorder caused by mutations in the CYP27A1 gene. The resultant defect in bile acid synthesis leads to cholestanol deposition in different tissues in the body, including tendons. CTX is associated with neurologic symptoms and a reduced life expectancy. Treatment consists of bile acid supplementation in combination with a statin. When patients present with tendon xanthomas and FH is ruled out, clinicians should consider CTX as a possible diagnosis.
We report on recent results froma target-of-opportunity program to obtain spectropolarimetry observations with the Southern African Large Telescope (SALT) on flaring gamma-ray blazars. SALT ...spectropolarimetry and contemporaneous multi-wavelength spectral energy distribution (SED) data are being modelled self-consistently with a leptonic single-zone model. Such modeling provides an accurate estimate of the degree of order of the magnetic field in the emission region and the thermal contributions (from the host galaxy and the accretion disk) to the SED, thus putting strong constraints on the physical parameters of the gamma-ray emitting region. For the specific case of the γ -ray blazar 4C+01.02, we demonstrate that the combined SED and spectropolarimetry modeling constrains the mass of the central black hole in this blazar to M BH ∼ 10 9 M ⊙ .
Chylomicronaemia accompanies hypertriglyceridaemia, usually due to a polygenic predisposition in combination with secondary risk factors. Monogenic chylomicronaemia represents a small subgroup of ...patients with hypertriglyceridaemia. This article describes three patients and illustrates the heterogeneity in the presentation of monogenic chylomicronaemia. The first case is a man with mild hypertriglyceridaemia who is a compound heterozygote for two variants in the LMF1 gene, without relevant medical history. The second case is a woman who is a double heterozygote of variants in the LPL and APOA5 genes. She experienced pancreatitis. The third case is a man, with recurrent pancreatitis attributed to severe hypertriglyceridaemia and homozygous for a variant in the APOC2 gene. This article highlights that in patients with hypertriglyceridaemia, the absence of pancreatitis or the presence of mild hypertriglyceridaemia does not exclude monogenic chylomicronaemia. Genetic screening should be considered in patients with unexplained or severe hypertriglyceridaemia, to determine appropriate treatment and follow-up.
COVID-19 is a new multi-organ disease causing considerable worldwide morbidity and mortality. While many recognized pathophysiological mechanisms are involved, their exact causal relationships remain ...opaque. Better understanding is needed for predicting their progression, targeting therapeutic approaches, and improving patient outcomes. While many mathematical causal models describe COVID-19 epidemiology, none have described its pathophysiology.
In early 2020, we began developing such causal models. The SARS-CoV-2 virus's rapid and extensive spread made this particularly difficult: no large patient datasets were publicly available; the medical literature was flooded with sometimes conflicting pre-review reports; and clinicians in many countries had little time for academic consultations. We used Bayesian network (BN) models, which provide powerful calculation tools and directed acyclic graphs (DAGs) as comprehensible causal maps. Hence, they can incorporate both expert opinion and numerical data, and produce explainable, updatable results. To obtain the DAGs, we used extensive expert elicitation (exploiting Australia's exceptionally low COVID-19 burden) in structured online sessions. Groups of clinical and other specialists were enlisted to filter, interpret and discuss the literature and develop a current consensus. We encouraged inclusion of theoretically salient latent (unobservable) variables, likely mechanisms by extrapolation from other diseases, and documented supporting literature while noting controversies. Our method was iterative and incremental: systematically refining and validating the group output using one-on-one follow-up meetings with original and new experts. 35 experts contributed 126 hours face-to-face, and could review our products.
We present two key models, for the initial infection of the respiratory tract and the possible progression to complications, as causal DAGs and BNs with corresponding verbal descriptions, dictionaries and sources. These are the first published causal models of COVID-19 pathophysiology.
Our method demonstrates an improved procedure for developing BNs via expert elicitation, which other teams can implement to model emergent complex phenomena. Our results have three anticipated applications: (i) freely disseminating updatable expert knowledge; (ii) guiding design and analysis of observational and clinical studies; (iii) developing and validating automated tools for causal reasoning and decision support. We are developing such tools for the initial diagnosis, resource management, and prognosis of COVID-19, parameterized using the ISARIC and LEOSS databases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•In familial dysbetalipoproteinemia (FD), evolocumab reduced non-HDL-C by 49%.•Non-HDL-C treatment goals were achieved by 89% of patients using evolocumab.•Evolocumab likely results in CVD reduction ...in FD.
Familial dysbetalipoproteinemia (FD) is the second most common monogenic lipid disorder (prevalence 1 in 850-3500), characterized by postprandial remnant accumulation and associated with increased cardiovascular disease (CVD) risk. Many FD patients do not achieve non-HDL-C treatment goals, indicating the need for additional lipid-lowering treatment options.
To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in patients with FD.
A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. At the start and end of each treatment period patients received an oral fat load. The primary endpoint was the 8-hour post fat load non-HDL-C area under the curve (AUC). Secondary endpoints included fasting and post fat load lipids and lipoproteins.
In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an Ɛ2Ɛ2 genotype. Evolocumab reduced the 8-hour post fat load non-HDL-C AUC with 49% (95%CI 42-55) and apolipoprotein B (apoB) AUC with 47% (95%CI 41-53). Other fasting and absolute post fat load lipids and lipoproteins including triglycerides and remnant-cholesterol were also significantly reduced by evolocumab. However, evolocumab did not have significant effects on the rise above fasting levels that occurred after consumption of the oral fat load.
Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and absolute post fat load concentrations of non-HDL-C, apoB and other atherogenic lipids and lipoproteins in FD patients. The clinically significant decrease in lipids and lipoproteins can be expected to translate into a reduction in CVD risk in these high-risk patients.
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Homozygous familial hypercholesterolemia (hoFH), a genetic disorder characterized by markedly impaired hepatic clearance of LDL and LDL cholesterol concentration exceeding 12 mmol/L, causes coronary ...artery and aortic valve disease before adulthood. The hoFH phenotype is mostly due to bi-allelic mutations in the LDL receptor gene.
HoFH as a clinical phenotype has distinct genetic causes which may affect response to treatment. The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism and other physiologic processes including inflammation and sepsis. Strategies that may lower plasma PCSK9 activity so that uptake of plasma LDL into the liver is improved. Inclisiran, a synthetic oligonucleotide, specifically targets the liver to limit production of PCSK9. Adverse effects due to oligonucleotides in general and specific to low PCSK9 concentration are considered.
HoFH requires expert diagnostic work-up for best management and prediction of response to treatment, including inclisiran. Though most hoFH patients will not reach the ideal LDL cholesterol concentration target by adding agents that lower PCSK9 activity to treatment with statins and ezetimibe, additional benefit is expected. Some patients may not respond. The safety to date appears good but patients with hoFH require treatment from childhood and long-term safety remains to be established.
A review of the physiology of fever in birds Gray, David A.; Marais, Manette; Maloney, Shane K.
Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology,
04/2013, Letnik:
183, Številka:
3
Journal Article
Recenzirano
While fever is known to occur in invertebrates and vertebrates, the mechanisms of fever in animals other than mammals have received scant attention. We look initially at the recognition, by the avian ...immune system, of pathogen associated molecular patterns and the likely role of toll-like receptors in signaling the presence of bacteria and viruses. Several mediators of fever are subsequently released by immune cells, including interleukin-6 and interleukin-1β, that eventually reach the brain and alter thermoregulatory function. As is the case in mammals, prostaglandins appear to be the ultimate mediators of fever in birds, since the febrile response is attenuated when prostaglandin synthesis is inhibited. Ambient temperature modulates the fever response, with larger fevers at higher, and smaller fevers at lower ambient temperatures. Glucocorticoid levels are increased during fever and seem to play an important role by modulating the extent of fever generation, possibly playing a role in the attenuation of fever after repeated exposure to a pathogen in a process termed tolerance, suggesting that the fever process can be phenotypically adapted to likely future conditions. While fever has an ancient phylogenetic history and many of the underling mechanisms in birds appear similar to mammals, there are several important differences that suggest fever has evolved quite differently in these two homeothermic classes.
A 44-year-old woman was admitted with pancreatitis caused by hypertriglyceridaemia (fasting triglycerides 28 mmol/L). She used oral contraceptives and ezetimibe 10 mg. She was overweight (body mass ...index 29.7 kg/m2). Diabetes mellitus was ruled out, as were nephrotic syndrome, alcohol abuse, hypothyroidism and dysbetalipoproteinaemia. Genetic analysis revealed mutations in two genes involved in triglyceride metabolism (apolipoprotein A5 and lipoprotein lipase LPL). The LPL activity was 45% compared with pooled healthy controls. The post-heparin triglyceride reduction was 6%, compared with a normal reduction of >20%. The patient was initially treated with gemfibrozil, but this was discontinued due to side effects. Dietary triglyceride restriction and discontinuation of the oral contraceptives lowered the plasma triglycerides within 2 weeks to 3.4 mmol/L. Hypertriglyceridaemia is a risk factor for pancreatitis and cardiovascular disease, and has a broad differential diagnosis including genetic causes. Patients can achieve near-normal triglyceride values with a low-fat diet only.
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