Background
Despite limited evidence about the efficacy and safety of anticoagulation in patients post bariatric surgery, both vitamin K antagonists (VKA) and direct-acting oral anticoagulants (DOACs) ...are commonly prescribed.
Aim
To evaluate plasma anti-Xa levels of DOACs in morbidly obese (MO) patients before and after a Roux-en-Y gastric bypass (RYGB) procedure.
Patients and Methods
Retrospective, cross-sectional, and longitudinal study of anti-Xa activity of apixaban or rivaroxaban in MO patients (
N
= 41).
Results
Preoperative analysis of plasma anti-Xa levels were within the normal range in patients using apixaban (
n
= 29; body mass index BMI 44.5 ± 5.1 kg/m
2
) as well as those using rivaroxaban (
n
= 12; BMI 42.6 ± 5.9 kg/m
2
). Postoperative anti-Xa levels of apixaban were all within the therapeutic range, whereas anti-Xa levels of rivaroxaban were subtherapeutic in nine out of 14 (64%) patients. Perioperative longitudinal follow-up in patients using apixaban (
n
= 18) showed no significant change in anti-Xa levels after RYGB.
Conclusion
Plasma anti-Xa levels of apixaban in MO patients remained within the therapeutic range up to a body weight of 144 kg. In patients using rivaroxaban, no statistically significant relation between anti-Xa levels and bodyweight was found. After RYGB, plasma anti-Xa levels of apixaban were unaffected, whereas plasma anti-Xa levels of rivaroxaban tended to become subtherapeutic.
Obesity and dyslipidemia Franssen, Remco; Monajemi, Houshang; Stroes, Erik S G ...
The Medical clinics of North America,
09/2011, Letnik:
95, Številka:
5
Journal Article
Recenzirano
Dyslipidemia associated with obesity and the metabolic syndrome is one of the central features contributing to the increased CV risk in these patients. In view of the pandemic of the metabolic ...syndrome, it is imperative to fully understand the mechanisms leading to the metabolic lipid phenotype before embarking upon optimal treatment strategies. The traditional concept that insulin resistance causes increased FFA flux via increased TG hydrolysis in adipose tissue is still of a central theme in the general hypothesis. The combination of increased hepatic VLDL secretion with impaired LPL-mediated TG clearance explains the hypertriglyceridemia phenotype of the metabolic syndrome. Hence, central IR may be an important factor contributing to peripheral hypertriglyceridemia. Recently recognized regulatory systems include the profound impact of the hypothalamus on TG secretion and glucose control. In addition, dysfunctional (or inflamed) intra abdominal adipose tissue has emerged as a potent regulator of dyslipidemia and IR. It will be a challenge to design novel treatment modalities that target “dysfunctional” fat or central IR to attempt to prevent the epidemic of CV disease secondary to the metabolic syndrome.
Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly ...modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ's ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.
Genetic lipodystrophies are a group of rare syndromes associated with major metabolic complications - including severe insulin resistance, type 2 diabetes mellitus, and hypertriglyceridemia - which ...are classified according to the distribution of adipose tissue. Lipodystrophies can be present at birth or develop during life and can range from local to partial and general. With at least 18 different genes implicated so far, definite diagnosis can be challenging due to clinical and genetic heterogeneity. In an adult female patient with clinical and metabolic features of partial lipodystrophy we identified via whole genome sequencing (WGS) a single complex
allele V67M;V167A, functionally equivalent to heterozygosity.
encodes for an acyltransferase implicated in the biosynthesis of triacylglycerol and glycerophospholipids. So far homozygous and compound heterozygous mutations in
have only been associated with generalized lipodystrophy. A SNP risk score analysis indicated that the index patient is not predisposed to lipodystrophy based on her genetic background. The partial phenotype in our patient is therefore more likely associated to the genetic variants in
To test whether the resulting double-mutant AGPAT2 protein is functional we analyzed its
enzymatic activity via mass spectrometry. The resulting AGPAT2 double mutant is enzymatically inactive. Our data support the view that the current classification of lipodystrophies as strictly local, partial or generalized may have to be re-evaluated and viewed more as a continuum, both in terms of clinical presentation and underlying genetic causes. Better molecular understanding of lipodystrophies may lead to new therapies to treat adipose tissue dysfunction in common and rare diseases.
The nuclear receptor PPARγ is the master regulator of adipocyte differentiation, distribution, and function. In addition, PPARγ induces terminal differentiation of several epithelial cell lineages, ...including colon epithelia. Loss-of-function mutations in PPARG result in familial partial lipodystrophy subtype 3 (FPDL3), a rare condition characterized by aberrant adipose tissue distribution and severe metabolic complications, including diabetes. Mutations in PPARG have also been reported in sporadic colorectal cancers, but the significance of these mutations is unclear. Studying these natural PPARG mutations provides valuable insights into structure-function relationships in the PPARγ protein. We functionally characterized a novel FPLD3-associated PPARγ L451P mutation in helix 9 of the ligand binding domain (LBD). Interestingly, substitution of the adjacent amino acid K450 was previously reported in a human colon carcinoma cell line.
We performed a detailed side-by-side functional comparison of these two PPARγ mutants.
PPARγ L451P shows multiple intermolecular defects, including impaired cofactor binding and reduced RXRα heterodimerisation and subsequent DNA binding, but not in DBD-LBD interdomain communication. The K450Q mutant displays none of these functional defects. Other colon cancer-associated PPARγ mutants displayed diverse phenotypes, ranging from complete loss of activity to wildtype activity.
Amino acid changes in helix 9 can differently affect LBD integrity and function. In addition, FPLD3-associated PPARγ mutations consistently cause intra- and/or intermolecular defects; colon cancer-associated PPARγ mutations on the other hand may play a role in colon cancer onset and progression, but this is not due to their effects on the most well-studied functional characteristics of PPARγ.
•Mutations in PPARG, encoding for the nuclear receptor PPARγ, underly lipodystrophy.•A novel lipodystrophy-associated PPARγ mutant, L451P, displays impaired activity.•Mutation of the adjacent K450, detected in colon cancer, has no effect.•Other colon cancer-associated PPARγ mutants display diverse phenotypes.•Lipodystrophy but not cancer-associated PPARγ mutants consistently display defects.
We previously isolated APOL3 (CG12-1) cDNA and now describe the isolation of APOL1 and APOL2 cDNA from an activated endothelial cell cDNA library and show their endothelialspecific expression in ...human vascular tissue. APOL1–APOL4 are clustered on human chromosome 22q13.1, as a result of tandem gene duplication, and were detected only in primates (humans and African green monkeys) and not in dogs, pigs, or rodents, showing that this gene cluster has arisen recently in evolution. The specific tissue distribution and gene organization suggest that these genes have diverged rapidly after duplication. This has resulted in the emergence of an additional signal peptide encoding exon that ensures secretion of the plasma high-density lipoprotein-associated APOL1. Our results show that the APOL1–APOL4 cluster might contribute to the substantial differences in the lipid metabolism of humans and mice, as dictated by the variable expression of genes involved in this process.
Summary
Lipodystrophies represent a heterogeneous group of diseases characterized by an abnormal subcutaneous fat distribution, the extent of which can vary from localized, to partial, to generalized ...lipoatrophy. Whereas partial and generalized lipodystrophies are each associated with metabolic abnormalities, the localized form is not. These metabolic changes include insulin resistance with type 2 diabetes, acanthosis nigricans, dyslipidaemia predominantly consisting of hypertriglyceridaemia (associated with the onset of pancreatitis) and depressed HDL cholesterol, liver steatosis and hypertension. Affected women are often hirsute and this can be associated with the presence of polycystic ovarian syndrome (PCOS). Most of these clinical features are present to some extent in patients with the common metabolic syndrome. As the prevalence of metabolic syndrome far outweighs that of lipodystrophy, the diagnosis of this rare disorder may often be overlooked with the affected patient diagnosed as merely being ‘yet’ another case of metabolic syndrome. In this article, we draw attention to the importance of recognizing patients with lipodystrophy who present with metabolic abnormalities, as both the diagnostic as well as the therapeutic approach of these patients differ profoundly from patients with the metabolic syndrome.
Obesity and dyslipidemia Franssen, Remco; Monajemi, Houshang; Stroes, Erik S G ...
Endocrinology and metabolism clinics of North America,
09/2008, Letnik:
37, Številka:
3
Journal Article
Recenzirano
The alarming and still increasing prevalence of obesity and associated cardiovascular risk raises much concern. The increase in cardiovascular risk depends to a significant extent on the changes in ...lipid profiles as observed in obesity. These changes are decreased high-density lipoprotein cholesterol and increased triglyceride levels. Much effort has already been expended into the elucidation of the mechanisms behind these obesity-associated lipid changes. Insulin resistance certainly plays a central role and, in addition, both hormonal and neurologic pathways have recently been found to play an important role. This article focuses on the mechanisms involved in the development of the proatherogenic lipid changes associated with obesity.
We report here the molecular cloning of a novel member of the triglyceride lipase family, a 2.4-kb cDNA encoding human lipase H (
LIPH) and the mouse ortholog (
Liph). The human
LIPH cDNA encodes a ...451-amino-acid protein with a lipase domain. Mouse
Liph shows 85% amino acid identity and 75% nucleotide identity to human
LIPH. Human
LIPH exhibits 47% identity with phosphatidylserine-specific phospholipase A1 (
PS-PLA1) and 46% identity with endothelial lipase (
LIPG) and lipoprotein lipase (
LPL).
LIPH is localized on human chromosome 3q27–q28. Northern blot analysis revealed specific expression of
LIPH mRNA in intestine, lung, and pancreas. Lipase H protein was also detected in human intestine. Lipase H is a secreted protein with an apparent molecular weight of 63 kDa. Although several lipid substrates were tested, the lipid substrate of LIPG was not identified. Like the other members of this gene family,
LIPH may be involved in lipid and energy metabolism.
Abstract
Context
Primary aldosteronism (PA) confers an increased risk of cardiovascular disease (CVD), independent of blood pressure. Animal models have shown that aldosterone accelerates ...atherosclerosis through proinflammatory changes in innate immune cells; human data are scarce.
Objective
The objective of this article is to explore whether patients with PA have increased arterial wall inflammation, systemic inflammation, and reprogramming of monocytes.
Design
A cross-sectional cohort study compared vascular inflammation on 2’-deoxy-2’-(18F)fluoro-D-glucose; (18F-FDG) positron emission tomography–computed tomography, systemic inflammation, and monocyte phenotypes and transcriptome between PA patients and controls.
Setting
This study took place at Radboudumc and Rijnstate Hospital, the Netherlands.
Patients
Fifteen patients with PA and 15 age-, sex-, and blood pressure-matched controls with essential hypertension (EHT) participated.
Main Outcome Measures and Results
PA patients displayed a higher arterial 18F-FDG uptake in the descending and abdominal aorta (P < .01, P < .05) and carotid and iliac arteries (both P < .01). In addition, bone marrow uptake was higher in PA patients (P < .05). Although PA patients had a higher monocyte-to-lymphocyte ratio (P < .05), systemic inflammatory markers, cytokine production capacity, and transcriptome of circulating monocytes did not differ. Monocyte-derived macrophages from PA patients expressed more TNFA; monocyte-derived macrophages of healthy donors cultured in PA serum displayed increased interleukin-6 and tumor necrosis factor-α production.
Conclusions
Because increased arterial wall inflammation is associated with accelerated atherogenesis and unstable plaques, this might importantly contribute to the increased CVD risk in PA patients. We did not observe inflammatory reprogramming of circulating monocytes. However, subtle inflammatory changes are present in the peripheral blood cell composition and monocyte transcriptome of PA patients, and in their monocyte-derived macrophages. Most likely, arterial inflammation in PA requires interaction between various cell types.
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