Is Metabolic Syndrome Predictive of Prevalence,Extent, and Risk of Coronary Artery Disease beyond Its Components? Results from the Multinational Coronary CT Angiography Evaluation for Clinical Outcome: An International Multicenter Registry (CONFIRM)

Although metabolic syndrome is associated with increased risk of cardiovascular disease and events, its added prognostic value beyond its components remains unknown. This study compared the prevalence, severity of coronary artery disease (CAD), and prognosis of patients with metabolic syndrome to those with individual metabolic syndrome components. The study cohort consisted of 27125 consecutive individuals who underwent ≥64-detector row coronary CT angiography (CCTA) at 12 centers from 2003 to 2009. Metabolic syndrome was defined as per NCEP/ATP III criteria. Metabolic syndrome patients (n=690) were matched 1:1:1 to those with 1 component (n=690) and 2 components (n=690) of metabolic syndrome for age, sex, smoking status, and family history of premature CAD using propensity scoring. Major adverse cardiac events (MACE) were defined by a composite of myocardial infarction (MI), acute coronary syndrome, mortality and late target vessel revascularization. Patients with 1 component of metabolic syndrome manifested lower rates of obstructive 1-, 2-, and 3-vessel/left main disease compared to metabolic syndrome patients (9.4% vs 13.8%, 2.6% vs 4.5%, and 1.0% vs 2.3%, respectively; p<0.05), while those with 2 components did not (10.5% vs 13.8%, 2.8% vs 4.5% and 1.3% vs 2.3%, respectively; p>0.05). At 2.5 years, metabolic syndrome patients experienced a higher rate of MACE compared to patients with 1 component (4.4% vs 1.6%; p=0.002), while no difference observed compared to individuals with 2 components (4.4% vs 3.2% p=0.25) of metabolic syndrome. In conclusion, Metabolic syndrome patients have significantly greater prevalence, severity, and prognosis of CAD compared to patients with 1 but not 2 components of metabolic syndrome.     

Impaired Recruitment of Grk6 and β-Arrestin2 Causes Delayed Internalization and Desensitization of a WHIM Syndrome-Associated CXCR4 Mutant Receptor

WHIM (warts, hypogammaglobulinemia, infections, and myelokatexis) syndrome is a rare immunodeficiency syndrome linked to heterozygous mutations of the chemokine receptor CXCR4 resulting in truncations of its cytoplasmic tail. Leukocytes from patients with WHIM syndrome display impaired CXCR4 internalization and enhanced chemotaxis in response to its unique ligand SDF-1/CXCL12, which likely contribute to the clinical manifestations. Here, we investigated the biochemical mechanisms underlying CXCR4 deficiency in WHIM syndrome. We report that after ligand activation, WHIM-associated mutant CXCR4 receptors lacking the carboxy-terminal 19 residues internalize and activate Erk 1/2 slower than wild-type (WT) receptors, while utilizing the same trafficking endocytic pathway. Recruitment of β-Arrestin 2, but not β-Arrestin 1, to the active WHIM-mutant receptor is delayed compared to the WT CXCR4 receptor. In addition, while both kinases Grk3 and Grk6 bind to WT CXCR4 and are critical to its trafficking to the lysosomes, Grk6 fails to associate with the WHIM-mutant receptor whereas Grk3 associates normally. Since β-Arrestins and Grks play critical roles in phosphorylation and internalization of agonist-activated G protein-coupled receptors, these results provide a molecular basis for CXCR4 dysfunction in WHIM syndrome.     

Is the Neutrophil-to-Lymphocyte Ratio an Exceptional Indicator for Metabolic Syndrome Disease and Outcomes?

ObjectivesTo show that there is relation between neutrophil-to-lymphocyte ratio (NLR) and metabolic syndrome and also, its components.FindingsMetabolic syndrome is associated with elevated fasting blood glucose, increased blood pressure, central obesity, decreased high-density lipoprotein, and increased triglyceride levels. Because of its growing incidence and prevalence and the effect that it has on developing other noncommunicable diseases, the importance gets even more value. The prediction and control of this disease in its early stages and in the most inexpensive way is of crucial need. Due to the role of chronic low-grade inflammation in metabolic syndrome, cytokines and inflammatory factors (like interleukin-6 and tumor necrosis factor-α) play a critical role on this phenomenon. The NLR is an inflammatory marker that has an unchallenging availability and has a reasonable cost. The NLR is related to obesity, type 2 diabetes, hypertension, and blood cholesterol levels.ConclusionThis suggests that there may be a relationship between the NLR and metabolic syndrome. The NLR, as a low-grade inflammation marker, indicates a positive relationship with central obesity. Also, studies indicate that the incidence of diabetes, its severity, and its control are related to the NLR. Hypertension and hyperlipidemia can both be noticed with higher NLRs. This rapid review assesses the association between metabolic syndrome and the NLR.     

OCRL controls trafficking through early endosomes via PtdIns4,5P₂-dependent regulation of endosomal actin

Mutations in the phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P(2)) 5-phosphatase OCRL cause Lowe syndrome, which is characterised by congenital cataracts, central hypotonia, and renal proximal tubular dysfunction. Previous studies have shown that OCRL interacts with components of the endosomal machinery; however, its role in endocytosis, and thus the pathogenic mechanisms of Lowe syndrome, have remained elusive. Here, we show that via its 5-phosphatase activity, OCRL controls early endosome (EE) function. OCRL depletion impairs the recycling of multiple classes of receptors, including megalin (which mediates protein reabsorption in the kidney) that are retained in engorged EEs. These trafficking defects are caused by ectopic accumulation of PtdIns4,5P(2) in EEs, which in turn induces an N-WASP-dependent increase in endosomal F-actin. Our data provide a molecular explanation for renal proximal tubular dysfunction in Lowe syndrome and highlight that tight control of PtdIns4,5P(2) and F-actin at the EEs is essential for exporting cargoes that transit this compartment.     

Metabolic Syndrome and Stroke Recurrence in Chinese Ischemic Stroke Patients – The ACROSS-China Study

Objective

Metabolic syndrome has emerged as a novel risk factor in cardiovascular disease due to its potential for predicting stroke in population-based studies. We investigated the relationship of metabolic syndrome with stroke recurrence.

Methods

This was a retrospective analysis of Chinese patients enrolled in the prospective Abnormal gluCose Regulation in patients with acute strOke acroSS China (ACROSS-China) study after their first ischemic stroke. Metabolic syndrome was defined using the International Diabetes Federation (IDF) criteria. Vascular risk factors were assessed. Outcome was defined as recurrence of stroke within one year after the index ischemic stroke. Cox proportional hazards regression was performed to identify potential predictors of stroke recurrence.

Results

The prevalence of metabolic syndrome among 2639 ischemic stroke patients was 51.35%. During the one-year follow-up, 195 strokes (7.4%) recurred. The multivariate hazard ratio (95% CI) of stroke recurrence was 1.94 (1.39–2.73) for metabolic syndrome. After adjustment for components, metabolic syndrome lost its association with stroke recurrence; in this model, high fasting plasma glucose (IDF definition) was a predictor for stroke recurrence.

Conclusion

Metabolic syndrome may not be predictive for stroke recurrence beyond its component individual factors for Chinese ischemic stroke patients.     

Lipocalin-2: development, analytical characterization, and clinical testing of a new ELISA.

Lipocalin-2 (also known as neutrophil gelatinase-associated lipocalin [NGAL]) has been described as a promising marker of metabolic syndrome associated with inflammation. The aim of our work was to develop an assay for the determination of lipocalin-2 in human serum and to investigate its levels in healthy volunteers and donors suffering from metabolic syndrome. We also conducted a pilot study on individuals with metabolic syndrome and on healthy probands and measured lipocalin-2 in these individuals. We developed and evaluated the sandwich ELISA method for the quantitative determination of human lipocalin-2 in serum samples. We measured blood pressure, waist circumference, serum cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, insulin, glucose, creatinine, hs-CRP, and adiponectin and calculated the BMI and Quicki insulin sensitivity index. In the study on 153 healthy volunteers, we showed that sex and age are not determinative for lipocalin-2 serum values. Furthermore, we tested 45 individuals with metabolic syndrome; values of lipocalin-2 did not differ (78.8 vs. 80.0 microg/l, p =0.56) from the data of healthy individuals from the first study. Neither group differed with regard to sex or age. Lipocalin-2 correlated with alanine aminotransferase (ALT) (r=-0.3, p<0.01) aspartate aminotransferase (AST) (r=-0.3, p<0.01), cholesterol (r=-0.21, p=0.047), creatinine (r=0.19, p=0.05), and high-sensitivity C-reactive protein (hs-CRP) (r=0.22, p=0.036). No significant correlation was found between serum lipocalin-2 and BMI, waist circumference, blood pressure, triglycerides, HDL, Quicki, or the number of metabolic syndrome components. When study patients with metabolic syndrome were further stratified according to the number of components of metabolic syndrome, serum concentrations of lipocalin-2 did not differ. The results presented demonstrate the analytical competence of the lipocalin-2 assay. However, we assumed that lipocalin-2 is not a routinely usable marker of metabolic syndrome or obesity. The association between serum lipocalin-2 and obesity or metabolic syndrome was not validated in our study.     

Therapy of Cushing''s syndrome with steroid biosynthesis inhibitors

Several substances with different inhibitory effects on adrenal steroid biosynthesis were investigated in patients with Cushing's syndrome. It has been shown that trilostane, a 3β-hydroxysteroid-dehydrogenase inhibitor, is not potent enough to block cortisol biosynthesis in patients with hypercortisolism. Aminoglutethimide inhibits side chain cleavage of cortisol synthesis, but it has been demonstrated that the blocking effect on cortisol secretion is not strong enough to normalize urinary cortisol excretion in patients with Cushing's disease. For metyrapone, an inhibitor of adrenal 11β-hydroxylase, promising results were reported for the treatment of Cushing's syndrome. However, the drug has several side effects and depending on the definition of the desired reduction of cortisol secretion a true remission was only found in a minority of patients. The antifungal drug ketoconazole in vitro predominantly blocks 17,20-desmolase (IC₅₀ 1 μM) and to a lesser extent 17-hydroxylase (IC₅₀ 10 μM) and 11β-hydroxylase (IC₅₀ 15–40 μM). Therefore, ketoconazole in vivo most potently suppresses androgen secretion and only to a lesser extent cortisol biosynthesis. Several therapeutic trials with ketoconazole treatment in patients with pituitary Cushing's disease showed various remission rates between 30 and 90%. In contrast, in almost all patients with benign, primary adrenal Cushing's syndrome cortisol levels were normalized. In patients with ectopic ACTH syndrome ketoconazole was effective in about 50% of all reported cases, while cortisol hypersecretion due to adrenocortical carcinoma was only rarely inhibited by ketoconazole. The main side effect of ketoconazole treatment was liver toxicity which occurred in 12% of all treated patients. In contrast to ketoconazole, the narcotic drug etomidate shows a strong inhibitory effect on 11β-hydroxylase (IC₅₀ 0.03–0.15 μM) but only a weak inhibition of 17,20 desmolase (IC₅₀ 380 μM). This correlates with in vivo studies where even low, non-hypnotic doses of etomidate induced a pronounced fall in serum cortisol levels in normals and in patients with Cushing's syndrome. However, its clinical use is limited by its mandatory intravenous application and its sedative effects. In conclusion, ketoconazole remains the only available steroid-inhibitory drug for a therapeutic trial in patients with Cushing's syndrome who cannot be treated definitively by surgery.     

Constitutive Gαi Coupling Activity of Very Large G Protein-coupled Receptor 1 (VLGR1) and Its Regulation by PDZD7 Protein

The very large G protein-coupled receptor 1 (VLGR1) is a core component in inner ear hair cell development. Mutations in the vlgr1 gene cause Usher syndrome, the symptoms of which include congenital hearing loss and progressive retinitis pigmentosa. However, the mechanism of VLGR1-regulated intracellular signaling and its role in Usher syndrome remain elusive. Here, we show that VLGR1 is processed into two fragments after autocleavage at the G protein-coupled receptor proteolytic site. The cleaved VLGR1 β-subunit constitutively inhibited adenylate cyclase (AC) activity through Gα_i coupling. Co-expression of the Gα_iq chimera with the VLGR1 β-subunit changed its activity to the phospholipase C/nuclear factor of activated T cells signaling pathway, which demonstrates the Gα_i protein coupling specificity of this subunit. An R6002A mutation in intracellular loop 2 of VLGR1 abolished Gα_i coupling, but the pathogenic VLGR1 Y6236fsx1 mutant showed increased AC inhibition. Furthermore, overexpression of another Usher syndrome protein, PDZD7, decreased the AC inhibition of the VLGR1 β-subunit but showed no effect on the VLGR1 Y6236fsx1 mutant. Taken together, we identified an independent Gα_i signaling pathway of the VLGR1 β-subunit and its regulatory mechanisms that may have a role in the development of Usher syndrome.     

The many faces of aggressive aortic pathology: Loeys-Dietz syndrome

Background: Loeys-Dietz syndrome (LDS) is a newly recognised disorder of connective tissue which shares overlapping features with Marfan syndrome (MFS) and the vascular type of Ehlers- Danlos syndrome, including aortic root dilatation and skin abnormalities. It is clinically classified into types 1 and 2. LDS type 1 can be recognised by craniofacial characteristics, e.g. hypertelorism, bifid uvula or cleft palate, whereas these are absent in LDS type 2. It is important to recognise LDS because its vascular pathology is aggressive. We describe nine LDS patients from four families, relate their features to published cases, and discuss important aspects of the diagnosis and management of LDS in order to make clinicians aware of this new syndrome. Results: Characteristics found in the majority of these LDS patients were aortic root dilatation, cleft palate and/or a bifid/abnormal uvula. Conclusion: Because aortic dissection and rupture in LDS tend to occur at a young age or at aortic root diameters not considered at risk in MFS, and because the vascular pathology can be seen throughout the entire arterial tree, patients should be carefully followed up and aggressive surgical treatment is mandatory. Clinicians must therefore be aware of LDS as a cause of aggressive aortic pathology and that its distinguishing features can sometimes be easily recognised. (Neth Heart J 2008;16:299-304.)     

Loss-of-Function Mutations in HPSE2 Cause the Autosomal Recessive Urofacial Syndrome

Previously, we localized the defective gene for the urofacial syndrome (UFS) to a region on chromosome 10q24 by homozygosity mapping. We now report evidence that Heparanse 2 (HPSE2) is the culprit gene for the syndrome. Mutations with a loss of function in the Heparanase 2 (HPSE2) gene were identified in all UFS patients originating from Colombia, the United States, and France. HPSE2 encodes a 592 aa protein that contains a domain showing sequence homology to the glycosyl hydrolase motif in the heparanase (HPSE) gene, but its exact biological function has not yet been characterized. Complete loss of HPSE2 function in UFS patients suggests that HPSE2 may be important for the synergic action of muscles implicated in facial expression and urine voiding.     

Tracing the origins of SARS-CoV-2: lessons learned from the past

The origins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain elusive;understanding how,when,and where SARS-CoV-2 was transmitted from its ...     

Mutation analyses in pedigrees and sporadic cases of ethnic Han Chinese Kallmann syndrome patients

Kallmann syndrome, a form of idiopathic hypogonadotropic hypogonadism, is characterized by developmental abnormalities of the reproductive system and abnormal olfaction. Despite association of certain genes with idiopathic hypogonadotropic hypogonadism, the genetic inheritance and expression are complex and incompletely known. In the present study, seven Kallmann syndrome pedigrees in an ethnic Han Chinese population were screened for genetic mutations. The exons and intron–exon boundaries of 19 idiopathic hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism)-related genes in seven Chinese Kallmann syndrome pedigrees were sequenced. Detected mutations were also tested in 70 sporadic Kallmann syndrome cases and 200 Chinese healthy controls. In pedigrees 1, 2, and 7, the secondary sex characteristics were poorly developed and the patients’ sense of smell was severely or completely lost. We detected a genetic mutation in five of the seven pedigrees: homozygous KAL1 p.R191ter (pedigree 1); homozygous KAL1 p.C13ter (pedigree 2; a novel mutation); heterozygous FGFR1 p.R250W (pedigree 3); and homozygous PROKR2 p.Y113H (pedigrees 4 and 5). No genetic change of the assayed genes was detected in pedigrees 6 and 7. Among the 70 sporadic cases, we detected one homozygous and one heterozygous PROKR2 p.Y113H mutation. This mutation was also detected heterozygously in 2/200 normal controls and its pathogenicity is likely questionable. The genetics and genotype–phenotype relationships in Kallmann syndrome are complicated. Classical monogenic inheritance does not explain the full range of genetic inheritance of Kallmann syndrome patients. Because of stochastic nature of genetic mutations, exome analyses of Kallmann syndrome patients may provide novel insights.     

NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes

Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes.     

Integrity of the thyroglobulin locus in tricho-rhino-phalangeal syndrome II

Summary The thyroglobulin gene has been mapped to chromosome band 8q24 by several investigators. This is the band implicated in the causation of Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome II). We have examined a restriction fragment length polymorphism at the thyroglobulin locus in a patient with Langer-Giedion syndrome and 8q deletion in order to: (1) localize the Langer-Giedion deletion more precisely, (2) define the relative map positions of the thyroglobulin gene and the Langer-Giedion locus. The results indicate that the locus of the thyroglobulin gene is intact in the patient with an interstitial deletion of proximal band 8q24.1 which confirms its more distal localization reported earlier by Bergé-Lefranc et al. (1985). It also assigns the critical region for the causation of Langer-Giedion syndrome to the proximal part of band 8q24, viz. 8q24.11q24.13.     

Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?

Heterozygous mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause the dominant adult cancer syndrome termed Lynch syndrome or hereditary non-polyposis colorectal cancer. During the past 10 years, some 35 reports have delineated the phenotype of patients with biallelic inheritance of mutations in one of these MMR genes. The patients suffer from a condition that is characterised by the development of childhood cancers, mainly haematological malignancies and/or brain tumours, as well as early-onset colorectal cancers. Almost all patients also show signs reminiscent of neurofibromatosis type 1, mainly café au lait spots. Alluding to the underlying mechanism, this condition may be termed as “constitutional mismatch repair-deficiency (CMMR-D) syndrome”. To give an overview of the current knowledge and its implications of this recessively inherited cancer syndrome we summarise here the genetic, clinical and pathological findings of the so far 78 reported patients of 46 families suffering from this syndrome.     

Canakinumab

Canakinumab (ACZ885, Ilaris) is a human anti-IL-1β monoclonal antibody developed by Novartis. its mode of action is based on the neutralization of 1β signaling, resulting in suppression of inflammation in patients with disorders of autoimmune origin. In June 2009 the drug was approved by the US Food and Drug Administration for the treatment of familial cold auto-inflammatory syndrome and Muckle-wells syndrome, which are inflammatory diseases related to cryopyrin-associated periodic syndromes. The drug is currently being evaluated for its potential in the treatment of rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis, chronic obstructive pulmonary disease, type 1 and 2 diabetes and ocular diseases. Reports from clinical trials suggest that canakinumab is well-tolerated in most patients, and no serious adverse effects have been reported. The drug provides significant advantages over existing competitive therapies, including bimonthly administration and approved use in children.Key words: canakinumab, Ilaris, trials, CAPS, rheumatoid arthritis, IL-1β     

Unusual Case of Multiple Endocrine Neoplasia Type 2A Syndrome Without Medullary Thyroid Carcinoma

ObjectiveTo present an unusual case of multiple endocrine neoplasia type 2A (MEN 2A) syndrome and to describe how this case differs from the typical clinical features and usual genetic variations seen in classic MEN 2A syndrome.MethodsWe describe the work-up, diagnosis, and treatment course of a patient who presented with multifocal pheochromocytomas, parathyroid adenoma, thyroid abnormalities, and a RET mutation.ResultsA 65-year-old man with previously treated pheochromocytoma presented with a parathyroid adenoma, multiple thyroid nodules, and a RET polymorphism. C-cell hyperplasia (CCH) or medullary thyroid carcinoma (MTC) occurs with nearly 100% penetrance in patients with MEN 2A syndrome. Our patient did not have CCH or frank MTC, but he expressed the other manifestations of the MEN 2A syndrome.ConclusionMEN 2A syndrome is characterized by the occurrence of MTC, pheochromocytomas, and parathyroid hyperplasia or adenomas. It is inherited in an autosomal dominant fashion, and more than 80% of patients with MEN 2A have a specific substitution on codon 634 of the RET proto-oncogene. Despite the nearly 100% penetrance of MTC or CCH in patients with MEN 2A, our patient did not have this. Additionally, he exhibited a RET mutation that is uncommonly seen in classic MEN 2A syndrome. Our patient may have a MEN 2A variant or a pseudo-MEN 2A syndrome. (Endocr Pract. 2011;17:e4-e7)     

Central sleep apnoea syndrome in chronic heart failure: an underestimated and treatable comorbidity

Chronic heart failure is a clinical syndrome with a high mortality and morbidity. Despite optimal therapy, five-year survival is still only 50%. Central sleep apnoea syndrome is seen in approximately 40% of patients with congestive heart failure. Sleep apnoea syndrome can be divided into two forms in these patients: obstructive sleep apnoea syndrome (OSAS) and central sleep apnoea syndrome (CSAS, Cheyne-Stokes respiration), of which CSAS is the most common. CSAS is a form of sleep apnoea in congestive heart failure which is driven by changes in pCO₂. As a consequence of apnoea-hypopnoea an imbalance in myocardial oxygen delivery/consumption ratio will develop, sympathetic and other neurohormonal systems will be activated and right and left ventricular afterload will be increased. Sleep apnoea is associated with an increased mortality in patients with systolic heart failure. Treatment of sleep apnoea increases left ventricular ejection fraction and transplant-free survival. Because of its high prevalence, poor quality of life, poor outcome, and the beneficial effects of treatment, physicians treating patients with heart failure should be aware of central sleep apnoea. There are different treatment options, but the exact effects and indications of each option have not yet been fully determined. Further studies should be done to further investigate its prevalence, and to establish the most adequate therapy for the individual patient. (Neth Heart J 2010;18:260-3.)