External fixation of airway stents for upper tracheal stenosis and tracheoesophageal fistula

 Open in a separate windowOBJECTIVESStent migration is a common complication of airway stent placement for upper tracheal stenosis and tracheoesophageal fistula. Although several researchers have reported that external fixation is effective in preventing stent migration, the usefulness and safety of external fixation have not been proved because their cohorts were small. We therefore investigated the efficacy and safety of external fixation during upper tracheal stenting.METHODSRecords of patients who underwent airway stent placement from May 2007 to August 2018 in a single centre were retrospectively reviewed. We included only patients whose stent had been placed in the upper trachea with external fixation to the tracheal wall. The primary endpoint of this study was the rate of stent migration.RESULTSAltogether, 51 procedures were performed in 45 patients (32 males, 13 females; median age 60 years, range 14–91 years). The median follow-up period was 9 months (range 0.3–90 months). Among the procedures, 15 were performed for benign disease and 36 for malignancy. Stents were composed of either silicone (n = 42) or metal (n = 9). Stent migration occurred in 3 (6%) patients. The stents with migration were all composed of silicone. Other sequelae were granulation tissue formation in 10 (20%) patients, sputum obstruction in 6 (12%), cellulitis in 3 (6%) and pneumonia in 1 (2%).CONCLUSIONSExternal fixation was an effective method for preventing migration of airway stents placed for upper tracheal stenosis and tracheoesophageal fistula. The complications were acceptable in terms of safety.     

Expression,mutation, and methylation of cereblon‐pathway genes at pre‐ and post‐lenalidomide treatment in multiple myeloma

Cereblon (CRBN) is a target for immunomodulatory drugs. This study investigated the prognostic value of the expression of CRBN‐pathway genes on the clinical relevance of lenalidomide (Len) treatment and evaluated the levels of CRBN‐binding proteins and mutations in these genes after Len treatment. Forty‐eight primary multiple myeloma cells were collected prior to treatment with Len and dexamethasone (Ld) and 25 paired samples were obtained post‐Ld therapy. These tumor cells were used to determine the expression and mutated forms of the CRBN‐pathway genes. Following normalization with CRBN levels, there was a significantly reduced IKZF1/CRBN ratio in samples that responded poorly to Ld therapy. Moreover, patients with low ratios of IKZF1/CRBN showed a significantly shorter progression‐free survival (PFS) and overall survival (OS) than those with higher ratios. However, patients with high ratios of KPNA2/CRBN showed a significantly shorter PFS and OS than patients with lower ratios. Of the 25 paired samples analyzed, most samples showed a reduction in the expression of CRBN and an increase in IKZF1 gene expression. No mutations were observed in CRBN, IKZF1, or CUL4A genes in the post‐Ld samples. In conclusion, a decreased expression of IKZF1 and increased expression of KPNA2 compared to that of CRBN mRNA predicts poor outcomes of Ld therapy.     

Phorbol ester stimulates acetylcholine synthesis in cultured endothelial cells isolated from porcine cerebral microvessels

Acetylcholine (ACh) is one of the factor which induces vasodilation through the release of endothelium-derived relaxing factor. The aim of this study was to clarify whether endothelial cells can synthesize ACh and the types of substance which regulate the synthesis of ACh in endothelial cells. We determined the ACh content of endothelial cells isolated from porcine cerebral microvessels and of the culture medium. ACh was detected in the medium after 12 h incubation in the presence of diisopropylfluorophosphate, a non-specific cholinesterase inhibitor, and increased linearly up to 24 h. Phorbol 12-myristate 13-acetate (PMA, 10⁻⁷ M) increased the ACh content of the medium in a dose-dependent manner. The effect of PMA was most apparent between 12 and 24 h after treatment, and was inhibited by cycloheximide. Calphostin C, a specific inhibitor of protein kinase C (PKC), did not inhibit the effect of PMA. Dioctanoyl glycerol, a specific activator of PKC, did not increase the intracellular ACh content or the amount released into the culture medium. ACh synthesis was not inhibited by bromoacetylcholine, a specific inhibitor of choline acetyltransferase (ChAT). PMA treatment did not affect the specific activity of ACh synthesis in endothelial cells. These data show that endothelial cells are able to synthesize ACh, and that ACh synthesis is up-regulated by PMA through the PKC independent mechanism via protein induction. The enzyme which synthesizes ACh in endothelial cells is not ChAT. The increase in ACh synthesis induced by PMA may not be due to induction of the ACh synthetic enzyme.     

Discovery of Orally Active and Nonsteroidal Farnesoid X Receptor (FXR) Antagonist with Propensity for Accumulation and Responsiveness in Ileum

We describe the discovery of analog 15 (FLG249), which is an orally active and nonsteroidal farnesoid X receptor (FXR) antagonist in mice with unique profiles, such as a propensity for ileum distribution and the significant control in the expression level of three FXR target genes in mouse ileum. Key design features incorporated in 15 were the introduction of metabolically stable groups in potent and metabolically labile antagonist 9. Our pursuit ultimately identified FXR antagonist 15, which has enabled its assessment in a drug discovery program.     

Characteristics of the salivary alpha‐amylase level in resting sublingual saliva as an index of psychological stress

The salivary alpha‐amylase (sAA) level is widely considered a marker of psychological stress. For clinical applicability, its characteristics should be examined under normal conditions. The aims of this study were to investigate the circadian rhythm, daily variation in a week and sex difference of the sAA level in sublingual saliva under a resting condition, for which 6 individuals, 11 individuals and 30 age‐matched women and men, respectively, were enrolled. The individual sAA levels were measured once every hour from 10:00 to 16:00 (7 times/day); at 10:00 on Monday, Wednesday and Friday (thrice/week); and without any restriction in the respective experiments by using a hand‐held sAA monitor. Repeated‐measures analysis of variance and the Student's t‐test were used for statistical analyses (p < 0.05). No significant differences in the sAA levels were observed among the different times of the day (p = 0.311) or different days of the week (p = 0.291), nor was a significant sex difference found (p = 0.962). These results suggest that the sAA level in sublingual saliva remains relatively stable under normal conditions and is not influenced by gender. It would be a useful tool to evaluate the effect of psychological stress in the clinical setting. Copyright © 2010 John Wiley & Sons, Ltd.     

Association of renal function with ambulation in mild acute stroke patients

Background: Renal dysfunction has affected the functional outcome after stroke. However, the association of renal function with walking endurance after stroke is poorly understood.

Objectives: This study aimed to investigate the relationship between renal function and walking endurance and speed in mild acute stroke patients.

Methods: Eighty-nine patients with mild acute stroke were enrolled. Walking endurance and speed were assessed by the 6-minute walk test (6MWT) and comfortable and maximal 10-meter walk tests (10MWT) within 7 days of hospital admission. Stroke severity was assessed using the National Institutes of Health stroke scale (NIHSS) on admission. The estimated glomerular filtration rate (eGFR) was calculated based on creatinine levels as a renal function. Pearson’s correlation coefficients were calculated between eGFR and walking ability. Multivariate regression analysis was used to investigate the relationship between eGFR and walking ability in mild acute stroke patients.

Results: The 6MWT distance was significantly correlated with eGFR (r = 0.212, p = .046). On multivariate regression analysis, the 6MWT was significantly associated with age (p = .029), body mass index (p = .020), NIHSS score (p = .016), and eGFR (p = .028), whereas the comfortable 10MWT was significantly associated with the NIHSS score alone (p = .009) and the maximal 10MWT was significantly associated with age (p = .032) and NIHSS score (p = .007).

Conclusion: The eGFR based on creatinine levels of acute stroke patients may be important factor to predict the walking endurance in mild acute stroke patients.     

Cbl-b Is a Critical Regulator of Macrophage Activation Associated With Obesity-Induced Insulin Resistance in Mice

We previously reported the potential involvement of casitas B-cell lymphoma-b (Cbl-b) in aging-related murine insulin resistance. Because obesity also induces macrophage recruitment into adipose tissue, we elucidated here the role of Cbl-b in obesity-related insulin resistance. Cbl-b^+/+ and Cbl-b^−/− mice were fed a high-fat diet (HFD) and then examined for obesity-related changes in insulin signaling. The HFD caused recruitment of macrophages into adipose tissue and increased inflammatory reaction in Cbl-b^−/− compared with Cbl-b^+/+ mice. Peritoneal macrophages from Cbl-b^−/− mice and Cbl-b–overexpressing RAW264.7 macrophages were used to examine the direct effect of saturated fatty acids (FAs) on macrophage activation. In macrophages, Cbl-b suppressed saturated FA-induced Toll-like receptor 4 (TLR4) signaling by ubiquitination and degradation of TLR4. The physiological role of Cbl-b in vivo was also examined by bone marrow transplantation and Eritoran, a TLR4 antagonist. Hematopoietic cell-specific depletion of the Cbl-b gene induced disturbed responses on insulin and glucose tolerance tests. Blockade of TLR4 signaling by Eritoran reduced fasting blood glucose and serum interleukin-6 levels in obese Cbl-b^−/− mice. These results suggest that Cbl-b deficiency could exaggerate HFD-induced insulin resistance through saturated FA-mediated macrophage activation. Therefore, inhibition of TLR4 signaling is an attractive therapeutic strategy for treatment of obesity-related insulin resistance.Obesity is sometimes associated with a chronic inflammatory state, insulin resistance, and type 2 diabetes (1,2). One feature of obesity-induced inflammation is the recruitment of macrophages into white adipose tissue (WAT). These activated macrophages secrete proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), and induce localized insulin resistance (3–5). Furthermore, the cytokines, adipokines, and free fatty acids (FAs) released from the WAT also act on the endocrine system, liver, and muscles and may reduce insulin sensitivity within these organs (6).Casitas B-cell lymphoma-b (Cbl-b) is a unique ubiquitin ligase involved in the maturation and activation of macrophages and T lymphocytes (7,8). Expression of Cbl-b is upregulated with macrophage differentiation of the HL60 and U937 cell lines (7). We have already reported that recruitment of macrophages into the WAT is markedly augmented in elderly Cbl-b–deficient (Cbl-b^−/−) mice and that their accumulation is associated with systemic insulin resistance and glucose intolerance (9). The current study demonstrated that a high-fat diet (HFD) induced accumulation of macrophages in WAT and insulin resistance in Cbl-b^−/− mice at an earlier stage than in Cbl-b^−/− mice fed a normal diet (ND). Feeding an HFD for 5 weeks induces macrophage accumulation and insulin resistance even in young Cbl-b^−/− mice, whereas at least a 20-week period is often required to induce a similar phenomenon in Cbl-b^−/− mice fed an ND (9).Free FAs, especially saturated FAs, induce activation of macrophages and aggravate the inflammatory process in WAT (6,10,11). Saturated FAs can activate Toll-like receptor 4 (TLR4), which is a receptor for lipopolysaccharides (LPS), and trigger the activation of its adaptor protein myeloid differentiation factor 88 (MyD88) and a downstream signaling cascade, leading to upregulation of cytokine expression through the nuclear factor-κB (NF-κB) inflammatory signaling pathway (12–14). Recent experiments showed that Cbl-b binds to TLR4 and MyD88 in neutrophils and TLR4-overexpressing HEK293 cells (15). We therefore hypothesized that Cbl-b is a critical regulator of saturated FA-induced cytokine expression in macrophages and neutrophils.The aim of this study was to elucidate the pathophysiological role of Cbl-b in the mechanism of macrophage activation by saturated FAs. The results showed that Cbl-b deficiency was associated with recruitment of macrophages into the WAT at the early stages of HFD-induced obesity. Cbl-b is an important molecule in diet-induced obesity and insulin resistance, especially through the activation of macrophages.