Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo

The circulating level of the inflammatory cytokine interleukin (IL)-6 is elevated in various insulin-resistant states including type 2 diabetes, obesity, cancer, and HIV-associated lipodystrophy. To determine the role of IL-6 in the development of insulin resistance, we examined the effects of IL-6 treatment on whole-body insulin action and glucose metabolism in vivo during hyperinsulinemic-euglycemic clamps in awake mice. Pretreatment of IL-6 blunted insulin's ability to suppress hepatic glucose production and insulin-stimulated insulin receptor substrate (IRS)-2-associated phosphatidylinositol (PI) 3-kinase activity in liver. Acute IL-6 treatment also reduced insulin-stimulated glucose uptake in skeletal muscle, and this was associated with defects in insulin-stimulated IRS-1-associated PI 3-kinase activity and increases in fatty acyl-CoA levels in skeletal muscle. In contrast, we found that co-treatment of IL-10, a predominantly anti-inflammatory cytokine, prevented IL-6-induced defects in hepatic insulin action and signaling activity. Additionally, IL-10 co-treatment protected skeletal muscle from IL-6 and lipid-induced defects in insulin action and signaling activity, and these effects were associated with decreases in intramuscular fatty acyl-CoA levels. This is the first study to demonstrate that inflammatory cytokines IL-6 and IL-10 alter hepatic and skeletal muscle insulin action in vivo, and the mechanism may involve cytokine-induced alteration in intracellular fat contents. These findings implicate an important role of inflammatory cytokines in the pathogenesis of insulin resistance.     

Pulsed holmium:yttrium-aluminum-garnet laser-induced liquid jet as a novel dissection device in neuroendoscopic surgery

OBJECT: A pressure-driven continuous jet of water has been reported to be a feasible tool for neuroendoscopic dissection owing to its superiority at selective tissue dissection in the absence of thermal effects. With respect to a safe, accurate dissection, however, continuous water flow may not be suitable for intraventricular use. The authors performed experiments aimed at solving problems associated with continuous flow by using a pulsed holmium:yttrium-aluminum-garnet (Ho:YAG) laser-induced liquid jet (LILJ). They present this candidate neuroendoscopic LILJ dissection system, having examined its mechanical characteristics and evaluated its controllability both in a tissue phantom and in a rabbit cadaveric ventricle wall. METHODS: The LILJ generator was incorporated into the tip of a No. 4 French catheter so that the LILJ could be delivered via a neuroendoscope. Briefly, the LILJ was generated by irradiating an internally supplied column of physiological saline with a pulsed Ho:YAG laser (pulse duration time 350 microsec; laser energy 250-700 mJ/pulse) within a No. 4 French catheter (internal diameter 1 mm) and ejecting it from a metal nozzle (internal diameter 100 microm). The Ho:YAG laser energy pulses were conveyed by an optical fiber (core diameter 400 microm) at 3 Hz, whereas physiological saline (4 degrees C) was supplied at a rate of 40 ml/hour. The mechanical characteristics of the pulsed LILJ were investigated using high-speed photography and pressure measurements; thermal effects and controllability were analyzed using an artificial tissue model (10% gelatin of 1 mm thickness). Finally, the ventricle wall of a rabbit cadaver was dissected using the LILJ. Jet pressure increased in accordance with laser energy from 0.1 to 2 bar; this translated into a penetration depth of 0.08 to 0.9 mm per shot in the ventricle wall of the rabbit cadaver. The gelatin phantom could be cut into the desired shape without significant thermal effects and in the intended manner, with a good surgical view. CONCLUSIONS: The present results show that the pulsed LILJ has the potential to become a safe and reliable dissecting method for endoscopic procedures.     

System to decrease length of stay for vascular surgery

OBJECTIVES: Reduction of length of stay (LOS) is critical for optimal use of hospital resources. We developed and evaluated a system to aggressively reduce LOS for vascular surgery. METHOD: Key to this system, which we introduced on January 1, 2001, was appointment of a LOS officer, who communicated daily during hospitalization with patients and families about discharge planning, organized outpatient services for wound care and rehabilitation to transition patients quickly to nonhospital care, and had biweekly meetings with relevant paramedical services. LOS for 509 patients operated on in 2000 (standard group) was compared with LOS for 474 operated on in 2001 and 595 patients operated on in 2002 (LOS reduction groups). Data for all patients with aortic aneurysm, carotid artery stenosis, lower extremity critical ischemia or amputation, and foot debridement were included. RESULTS: LOS in 2000 averaged 8.5 days, compared with 5.9 days in 2001 and 5.6 days in 2002. All decreases in LOS for each diagnostic category in 2001 and 2002 were statistically significant (P = <.001-.03). There was no significant increase in readmission rate (2.2% vs 1.9% and 2.0%, respectively), mortality rate (0.8% vs 0.6% and 0.7%, respectively), or percent of patients who received endovascular treatment (18% vs 16% and 14%, respectively). These decreases in LOS saved the hospital more than US dollars 616200 in 2001, and US dollars 847550 in 2002 (US dollars 500/patient-day). CONCLUSIONS: A committed LOS officer with major specific daily responsibilities for decreasing LOS and discharging patients resulted in a 31% to 33% decrease in LOS, with important cost savings to the hospital and no negative effect on patient care.     

Experimental evaluation of the optimal tidal volume for simultaneous pacing of the diaphragm and respiratory muscles

Because of problems with pacing devices, surgical procedures, and diaphragm fatigue in pacing therapy of the phrenic nerve, we performed simultaneous pacing of the diaphragm alone and of multiple respiratory muscles in dogs and evaluated the optimal tidal volume. After intravenously anesthetizing 20 dogs with an average weight of 11kg, their tidal volume was measured with a spirometer to obtain control values. In the first 4 dogs, electrodes were sutured to the diaphragm and the optimal voltage, pulse width, and output to maximize tidal volume were determined. In the remaining 16 dogs, we stimulated individual canine respiratory muscles, i.e., the diaphragm, the rectus thoracis, and intercostal muscles 3-5 and simultaneously stimulated the diaphragm and the rectus thoracis; the diaphragm and intercostal muscles; the rectus thoracis and the intercostal muscles; or the diaphragm, rectus thoracis, and intercostal muscles. We compared a group in which a counterelectrode was positioned in each muscle group (group A) with a group in which no counterelectrode was used (group B). The best tidal volume was obtained at 10V, 50Hz, and a pulse width of 1.0ms. All the respiratory muscle pacings yielded better tidal volumes in group B than in group A. The greatest tidal volume was obtained with the rectus thoracis and intercostal muscle combination, suggesting the possibility of being able to reduce diaphragm fatigue by alternate pacing of these muscles and the diaphragm.     

Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas

Activating mutations of BRAF have been frequently observed in microsatellite unstable (MSI+) colorectal carcinomas (CRCs), in which mutations of BRAF and KRAS are mutually exclusive. Previously, we reported that hypermethylation of hMLH1 might play an important role in the tumorigenesis of right-sided sporadic CRCs with MSI showing less frequency of KRAS/TP53 alteration. Therefore, we have assumed that BRAF mutations might be highly associated with hMLH1 methylation status rather than MSI status. In this study, mutations of BRAF and KRAS and their relationship with MSI and hMLH1 methylation status were examined in 140 resected specimens of CRC. The methylation status was classified into 3 types: full methylation (FM), partial methylation (PM) and nonmethylation (NM). Only FM closely linked to reduced expression of hMLH1 protein. BRAF mutations were found in 16 cases (11%), all leading to the production of BRAF(V599E). As for MSI status, BRAF mutations were found in 43% of MSI+ and 4% of MSI- cases (p < 0.0001). Among the MSI+ individuals, BRAF mutations were more frequent in cases with hMLH1 deficiency (58%) than those with hMSH2 deficiency (0%; p=0.02). Moreover, they were found in 69% of FM, 4% of PM and 4% of NM, revealing a striking difference between FM and the other 2 groups (FM vs. PM or NM; p < 0.0001). These findings suggest that BRAF activation may participate in the carcinogenesis of sporadic CRCs with hMLH1 hypermethylation in the proximal colon, independently of KRAS activation.     

Significance and usefulness of corticospinal motor evoked potential monitoring for lesions adjacent to primary motor cortex]

This study evaluated the usefulness of intraoperative corticospinal motor evoked potential (MEP) monitoring in preventing postoperative motor deficits, and whether this procedure contributed to surgery on intrinsic brain lesions in the vicinity of the motor area. The subjects were 45 patients with brain tumors located in and around the primary motor area. MEP was recorded through the cervical epidural electrodes in response to stimulation of the motor cortex. The amplitude of D-response of MEP was compared at the beginning and at the end of surgery. Then MEP changes were divided into five groups; "increase", "no change", "diminish", "decrease" and "disappear". We used the DeJong classification for qualitative analysis of motor function, and reviewed these findings in relation to the change in MEP. It was possible to record MEP when the preoperative motor weakness was DeJong 3 or better. There was no postoperative motor deficit when the MEP amplitude was preserved at better than 50% of a control amplitude. If the amplitude decreased to less than 50%, motor deficits were encoutered. When MEP amplitude increased during the surgery, preoperative motor weakness was improved after the surgery. It is concluded that there is little possibility of causing motor deficits even if tumor removal is aggressively pursued, as long as the amplitude of D-response remains at 50% or more of the baseline. This monitoring procedure is expected to improve the overall surgical results in patients with intrinsic brain tumors around the motor area.     

Objective evaluation of infraorbital nerve involvement in maxillary lesions by means of the blink reflex

OBJECTIVE: To objectively evaluate the effects of maxillary lesions on the infraorbital nerve (ION). METHODS: We investigated the latencies (R1, R2) of the blink reflex, stimulating the infraorbital foramen electrically (18 mA, 0.2 millisecond). Twenty-two patients with unilateral maxillary lesions were enrolled. RESULTS: Ten patients showed delayed or absent R1 on the lesion side. Four of 20 patients showed delayed difference in R2 latency. Ten (77%) of 13 patients with lesions along the ION pathway showed an abnormal blink reflex. Only 3 patients demonstrated a normal blink reflex despite a lesion along the pathway of the ION. All patients whose ION pathway was intact showed a normal blink reflex. CONCLUSIONS: These results suggested that lesions along the ION pathway may impair the afferent pathway of the blink reflex. The blink reflex may be valuable to evaluate maxillary lesions objectively. Furthermore, R1 is more effective than R2 in detecting ION defects.     

The regulation of EN-RAGE (S100A12) gene expression in human THP-1 macrophages

EN-RAGE is a ligand for the receptor for advanced glycation end products (RAGE) and may be involved in the development of diabetic macro- and micro-angiopathy. This study is designed to investigate the regulation of EN-RAGE gene expression in human macrophages. The amounts of EN-RAGE mRNA were measured in cultured human THP-1 macrophages after treatment with various stimuli known to modulate atherosclerosis. First, interleukin-6 (IL-6), a proinflammatory cytokine, increased the level of EN-RAGE mRNA by approximately 2-fold in a time- and a dose-dependent fashion. EN-RAGE protein was detected in the cultured medium and increased significantly by the addition of IL-6. The induction was abolished by pretreatment with the JAK kinase inhibitor and cycloheximide, but not with the MEK kinase inhibitor. Second, pioglitazone (PIO), a thiazolidinedione, decreased the level of EN-RAGE mRNA by approximately 25% of the basal in a time- and a dose-dependent fashion. Pioglitazone also inhibited the induction of EN-RAGE mRNA by IL-6. These results indicate the production of EN-RAGE is induced by IL-6 through de novo protein synthesis via the JAK-STAT kinase pathway and inhibited by the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) in human macrophages.     

Vestibular evoked myogenic potentials in ipsilateral delayed endolymphatic hydrops

We recorded vestibular evoked myogenic potentials (VEMPs) in 12 patients diagnosed as having ipsilateral delayed endolymphatic hydrops (DEH). Seventy-five percent (9/12) of the patients showed decreased or absent VEMPs in the affected ears. Almost all patients had normal VEMPs in the unaffected ears. In addition, in 4 patients, VEMPs were recorded before and 3 h after oral glycerol administration (1.3 g/kg body weight). VEMPs improved after glycerol administration in 2 of the 3 patients whose VEMPs had been abnormal in the affected ears before glycerol administration. None of the 4 patients presented significant changes in VEMPs in the unaffected ears after glycerol administration. Improvement of VEMPs after glycerol administration confirmed the existence of endolymphatic hydrops in patients with ipsilateral DEH. In conclusion, VEMPs are useful to evaluate the function of otolith organs in patients with ipsilateral DEH, and the glycerol test using VEMPs may be useful to detect endolymphatic hydrops in ipsilateral DEH.