Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of systemic autoinflammatory disorders in which the majority of patients have mutations in the cold-induced autoinflammatory syndrome (CIAS)1 gene. Despite having indistinguishable clinical features, some patients lack CIAS1 mutations by conventional nucleotide sequencing. We recently reported a CAPS patient with mosaicism of mutant CIAS1, and raised the possibility that CIAS1 mutations were overlooked in "mutation-negative" patients, due to a low frequency of mosaicism. To determine whether there were latent mutant cells in "mutation-negative" patients, we sought to identify mutation-associated biologic phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 up-regulation, was dependent on cathepsin B, and was independent of caspase-1. Cell death was intrinsic to CIAS1-mutated monocytes, was not mediated by the inflammatory milieu, and was independent of disease severity or anti-IL-1 therapy. By collecting dying monocytes after lipopolysaccharide treatment, we succeeded in enriching CIAS1-mutant monocytes and identifying low-level CIAS1-mosaicism in 3 of 4 "mutation-negative" CAPS patients. Our findings reveal a novel effect of CIAS1 mutations in promoting necrosis-like cell death, and demonstrate that CIAS1 mosaicism plays an important role in mutation-negative CAPS patients.     

Release of gastric inhibitory polypeptide in totally pancreatectomized patients

The role of insulin in controlling gastric inhibitory polypeptide (GIP) release was assessed in seven totally pancreatectomized patients, in whom inhibitory effects of endogenous pancreatic hormones on GIP secretion were excluded. In these patients, glucose was ingested on two occasions, once alone and once during insulin infusion using an artificial endocrine pancreas to maintain blood glucose at levels similar to those in normal subjects. Plasma levels of GIP, the maximum response of plasma GIP, and the integrated incremental GIP for 180 min were similar. We conclude that insulin does not alter the secretion of GIP in response to oral glucose when the influence of endogenous pancreatic hormones is excluded.     

Low phagocytic activity of resident peritoneal macrophages in diabetic mice: relevance to the formation of advanced glycation end products.

Formation of advanced glycation end products (AGEs) is accelerated in diabetic subjects along with hyperglycemia. Although several lines of evidence indicate that AGEs stimulate macrophages to secrete several cytokines and growth factors, little is known about the effect of AGEs on the primary function of macrophages, such as phagocytosis. On the other hand, impairment of the phagocytic function of monocytes/macrophages is suggested to contribute to the low resistance to infection in diabetic subjects. In the present study, we examined the effect of AGEs on the phagocytic function of macrophages. Using flow cytometric analysis of mouse resident peritoneal macrophages, we showed that AGEs suppress phagocytosis of fluorescent microspheres by cultured macrophages. In addition, experiments using streptozotocin-induced diabetic mice demonstrated a significant decrease in the phagocytic activity of resident peritoneal macrophages 12 weeks after induction of diabetes compared with age-matched control mice. The phagocytic activity of peritoneal macrophages correlated inversely with AGE content in the adjacent peritoneal tissue. Furthermore, reduced phagocytic activity of macrophages was associated with a reduction in intracellular ATP content. Because phagocytosis is an important component of the defense system, suppression of such activity by AGEs may explain, at least in part, the increased susceptibility of diabetic patients to infection.     

Histological analysis of the ligamentum flavum of patients with dialysis-related spondyloarthropathy

Dialysis-related spondyloarthropathy (DRS) is a severe complication of long-term hemodialysis that ultimately leads to functional disability of the upper and lower extremities. Although the cause of this disease is still unknown, it is thought that amyloid deposits are involved. 2-Microglobulin (2M) is a major component of amyloid fibrils, some of which are modified with the advanced glycation end-product (AGE). To clarify the pathophysiology of DRS we histologically examined the ligamentum flavum of the cervical spine in 15 patients with DRS. The mean duration of hemodialysis was 20 years (12–27 years). In addition to the congo red stain for amyloid, 2M and AGE were detected by immunohistochemical methods. Macrophages were stained with CD68 antibody. Amyloid deposits were found in tissues, although the extent of the stained area differed among the patients. Part of the amyloid deposit area was positively immunostained for 2M and AGE. In 10 cases macrophages positive for CD68 infiltrated around the amyloid deposits. Comparing these histological findings with the dialysis duration, more positive staining areas for 2M and AGE were found in the tissue from patients with long-term dialysis. These findings suggest that both 2M and AGE play roles in the pathogenesis of DRS.     

Does Postoperative Complication Have a Negative Impact on Long-Term Outcomes Following Hepatic Resection for Colorectal Liver Metastasis?: A Meta-Analysis

Background

The negative impact of postoperative complications (POCs) on long-term outcomes is well documented for several cancer surgeries, but conclusive evidence has yet to be provided on the influence of POCs on long-term oncological outcomes after hepatic resection for colorectal liver metastasis (CRLM).

Methods

Studies published through February 2012 evaluating the oncological impact of POCs after hepatectomy for CRLM were identified by an electronic literature search. Finally, 4 studies were identified and included in the meta-analysis. The main outcome measures were 5-year disease-free survival (DFS) and overall survival (OS). A meta-analysis was performed using the DerSimonian-Laird random-effects models to compute odds ratio (OR) along with 95 % confidence intervals (95 % CI).

Results

The outcomes of 2,280 patients were studied. Meta-analysis of 5-year DFS data extracted from three studies demonstrated a significant reduction in 5-year DFS after POCs, with an OR of 1.98 (95 % CI = 1.33–2.96; P = .0008). Meta-analysis of 5-year OS data extracted from four studies demonstrated a significant reduction in 5-year OS after POCs, with an OR of 1.68 (95 % CI = 1.25–2.27; P = .0006). No differences between study heterogeneity were observed in either the DFS or the OS analyses.

Conclusions

This study provides persuasive evidence that POCs following hepatic resection for CRLM have significant adverse oncological outcomes. These findings emphasize the need for meticulous surgical technique and careful perioperative management to minimize POCs.     

High plasma pentosidine level is accompanied with cardiovascular events in hemodialysis patients

Background

Cardiovascular disease is a major complication in patients with end-stage renal disease (ESRD). The accumulation of advanced glycation end products (AGEs) is facilitated in these patients. The aim of this study was to investigate the relationship between circulating AGEs and cardiovascular events in hemodialysis patients.

Methods

The plasma level of pentosidine, a well-defined AGEs, was measured in 110 hemodialysis patients who were prospectively followed for 90?months. The relationship between plasma pentosidine level and cardiovascular events was assessed using Kaplan-Meier and Cox regression analysis.

Results

Thirty-nine cardiovascular events (14 coronary heart disease and 25 strokes) occurred during the follow-up period. Multivariable Cox proportional hazard analysis showed that plasma pentosidine levels (HR 1.040, 95% CI 1.022–1.058, p?p?p?Conclusion The plasma pentosidine level predicts cardiovascular events in hemodialysis patients. The effects of lowering circulating AGE levels on cardiovascular events should be examined in ESRD patients.     

Postoperative neurological complications and risk factors for pre-existing silent brain infarction in elderly patients undergoing coronary artery bypass grafting

Purpose

Elderly patients with multiple infarctions revealed a high prevalence of postoperative stroke after coronary artery bypass grafting (CABG). However, postoperative neurological complications and characteristics of silent brain infarction (SBI) have not been evaluated in elderly patients undergoing CABG.

Methods

Four hundred forty-nine patients (??60 years old) scheduled for CABG underwent cerebral magnetic resonance imaging (MRI) and MR angiography preoperatively to assess cerebral infarctions and carotid and intracranial artery stenosis. Atherosclerosis of the ascending aorta was assessed by epiaortic ultrasound during surgery. Patients were sorted by their history of cerebrovascular disease (CVD) and the presence of infarction by MRI: SBI (infarction without CVD), BI (symptomatic brain infarction; CVD and infarction), and controls (no findings of either CVD or infarction).

Results

SBI was found in 35.5% of the 449 patients and increased with age. The prevalence of pre-existing multiple infarctions was less frequent in SBI than in BI. The incidence of postoperative stroke and cognitive dysfunction was 1.3% and 4.9% in controls (n?=?225), 5.7% and 15.2% in SBI (n?=?158), and 9.1% and 18.2% in BI (n?=?66). Patients with SBI were older and had more renal dysfunction and preoperative cognitive impairment. Stepwise logistic regression demonstrated that age, renal dysfunction, preoperative cognitive impairment, atherosclerosis of the ascending aorta, and intracranial arterial stenosis were associated significantly with SBI.

Conclusion

Patients with SBI were ranked at moderate risk of neurological complications after CABG between control and BI. Increased age, renal dysfunction, and preoperative cognitive impairment appeared to be strongly associated with SBI.     

Mitral valve repair for double-orifice mitral valve with flail leaflet: the usefulness of real-time three-dimensional transesophageal echocardiography

We describe a 66-year-old man who required an operation for severe mitral regurgitation associated with a double-orifice mitral valve. Real-time 3-dimensional transesophageal echocardiography clearly demonstrated a double-orifice mitral valve with a central fibrous bridge. A flail posterior leaflet was observed on the anterolateral mitral valve orifice. Mitral valve repair using P1 triangular resection, anterolateral commissure plication, and ring annuloplasty with Duran band (Medtronic, Minneapolis, MN) was successfully performed. Postoperative real-time 3-dimensional transesophageal echocardiography demonstrated a double-orifice mitral valve without regurgitation or stenosis.     

Interaction between ESRα polymorphisms and environmental factors in osteoporosis

We hypothesized that environmental factors might affect the relationship between genetic predisposition and the risk of bone mineral density (BMD) loss. Cases were 114 Japanese women with a confirmed diagnosis of postmenopausal osteoporosis and controls were 171 general Japanese women. Genetic risk of SNPs in the estrogen receptors was analyzed by a case–control study. The interaction between gene and environmental factors for osteoporosis were assessed by a case‐only design. Significant increases in osteoporosis risk were observed with minor alleles of rs2077647 located in the first exon and rs2234693 located in the first intron of estrogen receptor α (ESRα). Haplotype CC at these risk SNPs was strongly associated with osteoporosis risk (odds ratio [OR] = 3.15, 95% confidence interval [CI] = 1.83–5.41). There was a statistically significant interaction between haplotype CC and alcohol drinking; moderate alcohol consumption decreased genetic risk of osteoporosis (OR = 0.22, 95%CI = 0.05–0.83). © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1529–1534, 2012     

Polymorphism of the interleukin-4, interleukin-13, and signal transducer and activator of transcription 6 genes in Indonesian children with minimal change nephrotic syndrome

BACKGROUND/AIMS: Minimal change nephrotic syndrome (MCNS) in children is frequently associated with allergy and immunoglobulin E (IgE) production. T-helper subtype 2 cytokines, such as interleukin (IL)-4 and IL-13, have been implicated in the regulation of IgE production. We investigated the associations of gene polymorphisms of IL-4, IL-13, and signal transducer and activator 6 (STAT6) in Indonesian children with MCNS (n = 84) and controls with neither allergic nor renal disease (n = 61). METHODS: Polymerase chain reaction-restriction fragment length polymorphism was used to determine the IL-4 promoter gene polymorphism (-590C/T) and IL-13 gene polymorphism (4257G/A), and direct sequencing was used for the STAT6 3S untranslated region (2964G/A) polymorphism. RESULTS: There was a significant difference between the MCNS group and the controls in the genotypic distribution of IL-4 and IL-13 gene polymorphism. In the case of the IL-4 promoter gene, the frequency of the CC homozygote was significantly lower in the MCNS group than in the controls, while, in the case of IL-13, the frequency of the GG homozygote was significantly lower in the MCNS group. However, there was no difference between the MCNS group and the controls in the STAT6 gene polymorphism. CONCLUSION: The genetic variations in the IL-4 and IL-13 genes may be associated with predisposition to MCNS.