miR-125b controls apoptosis and temozolomide resistance by targeting TNFAIP3 and NKIRAS2 in glioblastomas.

Diffusely infiltrating gliomas are among the most prognostically discouraging neoplasia in human. Temozolomide (TMZ) in combination with radiotherapy is currently used for the treatment of glioblastoma (GBM) patients, but less than half of the patients respond to therapy and chemoresistance develops rapidly. Epigenetic silencing of the O(6)-methylguanine-DNA methyltransferase (MGMT) has been associated with longer survival in GBM patients treated with TMZ, but nuclear factor κB (NF-κB)-mediated survival signaling and TP53 mutations contribute significantly to TMZ resistance. Enhanced NF-κB is in part owing to downregulation of negative regulators of NF-κB activity, including Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and NF-κB inhibitor interacting RAS-like 2 (NKIRAS2). Here we provide a novel mechanism independent of TP53 and MGMT by which oncogenic miR-125b confers TMZ resistance by targeting TNFAIP3 and NKIRAS2. GBM cells overexpressing miR-125b showed increased NF-κB activity and upregulation of anti-apoptotic and cell cycle genes. This was significantly associated with resistance of GBM cells to TNFα- and TNF-related inducing ligand-induced apoptosis as well as resistance to TMZ. Conversely, overexpression of anti-miR-125b resulted in cell cycle arrest, increased apoptosis and increased sensitivity to TMZ, indicating that endogenous miR-125b is sufficient to control these processes. GBM cells overexpressing TNFAIP3 and NKIRAS2 were refractory to miR-125b-induced apoptosis resistance as well as TMZ resistance, indicating that both genes are relevant targets of miR-125b. In GBM tissues, high miR-125b expression was significantly correlated with nuclear NF-κB confirming that miR-125b is implicated in NF-κB signaling. Most remarkably, miR-125b overexpression was clearly associated with shorter overall survival of patients treated with TMZ, suggesting that this microRNA is an important predictor of response to therapy.

Urinary retention after spinal anaesthesia with hyperbaric prilocaine 2% in an ambulatory setting.

BACKGROUND: Hyperbaric prilocaine 2% is a medium long-acting spinal anaesthetic. There are few data on time to recovery and rate of urinary retention after spinal administration of hyperbaric prilocaine 2%. This prospective study was carried out to evaluate the time to spontaneous micturition, quantify the rate of necessary bladder catheterizations, and identify the risk factors for urinary retention after intrathecal prilocaine administration. METHODS: ASA I/II patients (16-80 yr) undergoing ambulatory lower limb surgery were enrolled and received spinal anaesthesia using hyperbaric prilocaine 2% (60 mg). Ringer's lactate was administered for peroperative volume replacement. Bladder ultrasound was performed hourly until spontaneous micturition or catheterization, when bladder filling reached 600 ml, and they were unable to urinate spontaneously. RESULTS: Eighty-six patients completed the study (49 males and 37 females). Mean (sd) fluid administration was 1200 (499) ml until either micturition or catheterization; 37.8% of the women and 12.2% of the men required catheterization (P=0.009). Mean (sd) time between spinal anaesthesia and catheterization was 190 (88) min, and 260 (61) min to micturition (P<0.0001). Age <40 or >60 yr and female gender were predisposing factors for urinary retention. CONCLUSIONS: After spinal anaesthesia with hyperbaric prilocaine 2% (60 mg) for ambulatory lower limb surgery, 23% of patients required postoperative urinary catheterization. Postoperative bladder ultrasound and early catheterization are essential to avoid bladder distension and facilitate discharge in patients after intrathecal prilocaine 2% administration in ambulatory surgery.

Non-invasive gene-expression-based detection of well-developed collateral function in individuals with and without coronary artery disease.

BACKGROUND: In patients with coronary artery disease (CAD), a well grown collateral circulation has been shown to be important. The aim of this prospective study using peripheral blood monocytes was to identify marker genes for an extensively grown coronary collateral circulation. METHODS: Collateral flow index (CFI) was obtained invasively by angioplasty pressure sensor guidewire in 160 individuals (110 patients with CAD, and 50 individuals without CAD). RNA was extracted from monocytes followed by microarray-based gene-expression analysis. 76 selected genes were analysed by real-time polymerase chain reaction (PCR). A receiver operating characteristics analysis based on differential gene expression was then performed to separate individuals with poor (CFI<0.21) and well-developed collaterals (CFI>or=0.21) Thereafter, the influence of the chemokine MCP-1 on the expression of six selected genes was tested by PCR. RESULTS: The expression of 203 genes significantly correlated with CFI (p = 0.000002-0.00267) in patients with CAD and 56 genes in individuals without CAD (p = 00079-0.0430). Biological pathway analysis revealed 76 of those genes belonging to four different pathways: angiogenesis, integrin-, platelet-derived growth factor-, and transforming growth factor beta-signalling. Three genes in each subgroup differentiated with high specificity among individuals with low and high CFI (>or=0.21). Two out of these genes showed pronounced differential expression between the two groups after cell stimulation with MCP-1. CONCLUSIONS: Genetic factors play a role in the formation and the preformation of the coronary collateral circulation. Gene expression analysis in peripheral blood monocytes can be used for non-invasive differentiation between individuals with poorly and with well grown collaterals. MCP-1 can influence the arteriogenic potential of monocytes.

Influence of diabetes mellitus on coronary collateral flow: an answer to an old controversy.

OBJECTIVES: To determine the influence of diabetes mellitus on coronary collateral flow by accurate means of collateral flow measurement in a large population with variable degrees of coronary artery disease. METHODS: 200 patients (mean (SD) age 64 (9) years; 100 diabetic and 100 non-diabetic) were enrolled in the study. Coronary collateral flow was assessed in 174 stenotic and in 26 angiographically normal vessels with a pressure guidewire (n = 131), Doppler guidewire (n = 36), or both (n = 33) to calculate pressure or flow velocity derived collateral flow index (CFI). Diabetic patients were perfectly matched with a non-diabetic control group for clinical, haemodynamic, and angiographic parameters. RESULTS: CFI did not differ between the diabetic and the non-diabetic patients (0.21 (0.12) v 0.19 (0.13), not significant). Likewise, CFI did not differ when only angiographically normal vessels (0.20 (0.09) v 0.15 (0.08), not significant) or chronic total coronary occlusions (0.30 (0.14) v 0.30 (0.17), not significant) were compared. Fewer patients in the diabetic group tended to have angina pectoris during the one minute vessel occlusion (60 diabetic v 69 non-diabetic patients, p = 0.15). CONCLUSION: Quantitatively measured coronary CFI did not differ between diabetic and non-diabetic patients with stable coronary artery disease.

[Phytotherapy in cardiovascular medicine]. / Phytotherapie in der kardiovaskulären Medizin.

There is widespread use of herbal medicine in patients suffering from cardiovascular diseases. The discussion about the benefit of these drugs is still controversial because of lack of scientific evidence. Ginkgo biloba, Crataegus and Garlic are often recommended substances for patients with cardiovascular diseases. For these substances there is a lot of data available from experimental and clinical studies, unfortunately not always adhering to the criteria of evidence based medicine. Extracts from ginkgo biloba contain several active constituents, mainly flavonoids and terpens, which have antioxidative properties and an inhibitory effect on platelet aggregation by inhibiting platelet activation factor PAF. Ginkgo is mainly used in vascular dementia and peripheral vascular disease. Garlic shows a modest lipid-lowering effect in the same range as a low-cholesterol diet. Effect on blood pressure seems to be at best minor. Crataegus is often used in patients with heart failure because of its positive inotropic effect. Additionally, crataegus acts as an antiarrhythmic substance by prolonging refractory period of the action potential.

Endothelin-1 induces vasodilation in human skin by nociceptor fibres and release of nitric oxide.

AIMS: Endothelin is a peptide produced by endothelial cells with many biological properties. In the human skin microcirculation endothelin induces neurogenic vasodilation associated with burning pruritus. We investigated the mechanisms involved in this response. METHODS: The effects of prolonged pretreatment with capsaicin, a specific inhibitor of polimodal nociceptor fibres, and of the nitric oxide synthase inhibitor L-NMMA on endothelin-1-induced vasodilation were studied in 15 human subjects. Furthermore, we investigated the effects of the ET(A)-selective antagonist PD147953 on bradykinin-induced vasodilation. RESULTS: After local injection, endothelin-1 caused vasoconstriction at the injection site and a profound vasodilation in the surrounding area (flare reaction, P<0.01). This response was specific and not induced by saline, albumin, acetylcholine or an ET-antagonist. Prolonged capsaicin pretreatment inhibited endothelin-1 induced vasodilation in the area surrounding the injection site, but not the central vasoconstriction at the injection site. Bradykinin also induced a marked vasodilation in the area surrounding the injection site; this was not inhibited by an ETA-selective antagonist, while the flare reaction was. L-NMMA applied at the site of the flare reaction prevented endothelin-1-induced vasodilation. CONCLUSIONS: Endothelin-1 in the human skin microcirculation stimulates polimodal nociceptor fibres leading to the release of nitric oxide. This response may play a pathophysiological role in inflammatory processes in the human skin.

[The Tube-Stat: a useful aid in difficult intubation]. / Tube-Stat: ein nützliches Hilfsmittel bei schwieriger Intubation.

A patient (ASA class I) scheduled for an elective gynecological operation, could not be intubated by conventional means, as no part of the glottis could be seen on direct laryngoscopy. Endotracheal intubation was successful on the first attempt using a lighted intubation stylet (Tube-Stat, Concept Corporation, Clearwater, Florida, USA). Transillumination of the neck tissues acted as a guide for correct placement of the endotracheal tube. Postoperatively, the patient complained of hoarseness and sore throat that cleared up completely within 5 days. Cases of difficult-intubation are often impossible to recognize preoperatively [3]. When problems arise, a difficult-intubation drill should be instituted without delay. The view obtained at laryngoscopy in our patient corresponded to a Grade III case according to the classification of Cormack and Lehane [3]. Our usual routine in such cases calls for blind intubation using a flexible introducer passed posteriorly to the epiglottis or blind nasal intubation. Recent reports testify to the potential dangers of blind procedures [4, 19, 23]. Light-wand-guided intubation has been reported to be an easily learned, atraumatic alternative to laryngoscopic or blind nasal intubation [6, 9]. We employed the Tube-Stat light-wand in a series of routine surgical cases with encouraging results. Our case report documents our first patient intubated with the light-wand after failure of conventional larnygoscopy. The first lighted stylet was described some 30 years ago, and the method of transillumination as an aid in difficult intubation developed over the following years.(ABSTRACT TRUNCATED AT 250 WORDS)