Sjögren's syndrome with myalgia is associated with subnormal secretion of cytokines by peripheral blood mononuclear cells

OBJECTIVE: To measure in vitro cytokine release from peripheral blood mononuclear cells (PBMC) and serum cytokines in patients with primary Sj?gren's syndrome (SS) with and without myalgia, compared to patients with rheumatoid arthritis (RA) and healthy controls. METHODS: Sixteen women with SS (8 with myalgia, 8 without pain), 15 women with RA, and 14 healthy women were studied. PBMC were isolated and cultured. Secretion of interleukin 1 beta (IL-1 beta), IL-6, IL-10, and tumor necrosis factor-alpha (TNF-alpha) was measured in cell supernatants with or without stimulation with phytohemagglutinin, tetanus toxoid, or purified protein derivative (PPD). Enzyme-linked immunospot was used to enumerate interferon-gamma (IFN-gamma) and IL-4-secreting cells. Serum concentrations of IL-8 and IL-18 were analyzed by ELISA. RESULTS: PPD-stimulated PBMC from SS patients responded with less production of IL-10, TNF-alpha, and IFN-gamma compared to controls. Patients with SS and pain were hyporesponsive also with respect to IL-1 beta and IL-6. The generally subnormal cytokine release was statistically significant in myalgic patients with SS compared to healthy controls. Serum IL-18 was increased in both SS groups as well as in patients with RA, and the highest levels were found in myalgic patients with SS. Serum IL-8 was increased in RA but not in SS. CONCLUSION: Patients with SS, especially those with myalgia, had diminished PBMC cytokine release and increased serum IL-18. This finding suggests that impaired cytokine regulation may have pathogenetic importance for myalgia in SS.     

Postoperative blood loss in coronary surgery. No real impact of fibrinolysis detected by thromboelastography and D-dimers. A prospective, randomized study

Although in many cardiac surgery centers pharmacological strategies based on fibrinolytic inhibitors are used on a routine basis, detailed knowledge of fibrinolysis during various settings of coronary surgery is still limited. Sixty-five patients scheduled for coronary surgery were randomized into 3 groups: group A--conventional coronary artery bypass grafting, group B--off-pump surgery, and group C--coronary artery bypass grafting with modified, rheoparin coated cardiopulmonary bypass with the avoidance of reinfusion of cardiotomy blood into the circuit. The sampling time points for rotation thromboelastographic evaluations were as follows: preoperatively, 15 minutes after sternotomy, on the completion of peripheral bypass anastomoses, at the end of the procedures, and 24 hours after the end of surgery. D-dimer levels were evaluated before surgery, at the end of procedures, and 24 hours after surgery. Thromboelastographic signs of fibrinolysis (evaluated by Lysis Onset Time-intergroup differences at 60 and 150 minutes of assessment: P = 0.003 and P < 0.001, respectively) were clearly detectable during cardiopulmonary bypass in group A, but not at any time in groups B and C. At the other sampling times all thromboelastographic parameters were similar in all groups. In group A, no exceptional bleeding tendency (during 24 hours), as compared to groups B and C (geometric means and 95% confidence intervals: group A: 686.7 [570.8; 826.1] mL, group B: 555.3 [441.3; 698.9] mL, group C: 775.6 [645.1; 932.3] mL, P = 0.157), and no significant correlations between Lysis Onset Time, postoperative blood loss, and D-dimer levels were found. No significant differences in postoperative blood loss related to cardiac surgeons and assistant surgeons were detected. Thromboelastographic signs of increased fibrinolysis were detectable in the important proportion of coronary surgery patients operated on with the use of conventional cardio-pulmonary bypass, but not in off-pump patients and those operated on with the biocompatible surface-modified circuit without reinfusion of cardiotomy suction blood. These signs resolved spontaneously at the end of surgery and were not associated with increased postoperative bleeding. No significant correlation with D-dimer levels was found.     

Epithelial proliferation,cell death,and gene expression in experimental colitis: alterations in carbonic anhydrase I,mucin MUC2, and trefoil factor 3 expression

BACKGROUND AND AIMS: To gain insight in intestinal epithelial proliferation, cell death, and gene expression during experimental colitis rats were treated with dextran sulfate sodium (DSS) for 7 days. MATERIALS AND METHODS: Proximal and distal colonic segments were excised on days 2, 5, 7, and 28. Epithelial proliferation, cell death, enterocyte gene expression (carbonic anhydrase I (CA I) and goblet cell gene expression (mucin, MUC2; trefoil factor 3, TFF3) were studied immunohistochemically and biochemically. RESULTS: Proliferative activity was decreased in the proximal and distal colon at the onset of disease (day 2). However, during active disease (days 5-7) epithelial proliferation was increased in the entire proximal colon and in the proximity of ulcerations in the distal colon. During DSS treatment the number of apoptotic cells in the epithelium of both colonic segments was increased. In the entire colon surface enterocytes became flattened and CA I negative during active disease (day 5-7). Additionally, CA I levels in the distal colon significantly decreased during this phase. In contrast, during the regenerative phase (day 28) CA I levels were restored in the distal colon and up-regulated in the proximal colon. During all disease phases increased numbers of goblet cells were observed in the surface epithelium of the entire colon. In the distal colon TFF3 expression extended to the bottom of the crypts during active disease. Finally, MUC2 and TFF3 expression was increased in the proximal colon during disease. CONCLUSION: DSS affected the epithelium by inhibiting proliferation and inducing apoptosis. DSS-induced inhibition of CA I expression indicates down-regulation of specific enterocyte functions. Accumulation of goblet cells in the surface epithelium and up-regulation of MUC2 and TFF3 expression in the proximal colon underline the importance of goblet cells in epithelial protection and repair, respectively.     

Physical activity, dipping and haemodynamics

OBJECTIVE: To determine the effect of physical activity on diurnal blood pressure (BP) and haemodynamic variation. METHODS: Ambulatory measurements were performed during 24 h in 36 subjects (18 hypertensive, 13 male), aged 49.7 +/- 13.5 years. BP was recorded in the brachial artery. Physical activity and posture were measured with five acceleration sensors. RESULTS: Of the subjects 50% were dippers (nocturnal decrease in systolic or diastolic BP >/= 10%). Dippers and non-dippers had similar daytime BP, daytime, night-time, and day-night difference in physical activity, subjective sleep quality, and nocturnal cardiac output decrease (14.9 +/- 9.6 and 16.0 +/- 5.9%). In non-dippers vascular resistance increased from day to night by 9.7 +/- 8.3%, while it remained unchanged (-1.0 +/- 13.9%) in dippers. Day-night changes in heart rate and cardiac output were correlated with day-night changes in physical activity (r = 0.39 and 0.43), whereas day-night changes in systolic BP were correlated with night-time activity (r = -0.34). By selection of the active (i.e. walking) and inactive (i.e. not walking) periods during the day, we showed that physical activity has a large potential effect on dipping status and diurnal haemodynamic variation underlying BP variation. Depending on the BP taken (systolic or diastolic, respectively) the proportion of dippers increased to 81% or decreased to 25% if only the walking period was considered, whereas it decreased to 36% or increased to 53% if only the non-walking period was considered. CONCLUSIONS: Non-dippers differ from dippers by an increase of vascular resistance during the night. The degree of physical activity normally encountered during ambulatory monitoring has little influence on the diurnal BP profile or dipping status, but significantly influences underlying haemodynamics. Related to the different effects of posture and activity on systolic and diastolic BP, dipping classification may vary with the BP index taken.     

Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma

Objectives:  Mantle cell lymphoma (MCL) is an incurable B cell lymphoma, and novel treatment strategies are urgently needed. We evaluated the effects of combined treatment with the proteasome inhibitor bortezomib and the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) on MCL. Bortezomib acts by targeting the proteasome, and – among other mechanisms – results in a reduced nuclear factor-kappa B (NF-κB) activity. HDACi promote histone acetylation, and also interfere with NF-κB signaling.
Methods:  Human MCL cell lines (JeKo-1, Granta-519 and Hbl-2) were exposed to bortezomib and/or SAHA. Cell viability and apoptosis were quantified by the MTT and annexin-V assay, respectively. Reactive oxygen species (ROS) were analyzed using the fluorophore H₂DCFDA. In addition, activated caspases, proteasome- and NF-κB activity were quantified.
Results:  Combined incubation with bortezomib and SAHA resulted in synergistic cytotoxic effects, as indicated by combination index values <1 using the median effect method of Chou and Talalay. The combination of both inhibitors led to a strong increase in apoptosis as compared to single agents and was accompanied by enhanced ROS generation, while each agent alone only modestly induced ROS. The free radical scavenger N -acetyl- l -cysteine blocked the ROS generation and reduced the apoptosis significantly. In addition, coexposure of bortezomib and SAHA led to increased caspase-3, -8 and -9 activity, marked reduction of proteasome activity and decrease of NF-κB activity.
Conclusions:  This is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in MCL cells. These data build the framework for clinical trials using combined proteasome and histone deacetylase inhibition in the treatment of MCL.     

Robotic Assistance System for Cone-Beam Computed Tomography-Guided Percutaneous Needle Placement

CardioVascular and Interventional Radiology - The study aimed to evaluate a new robotic assistance system (RAS) for needle placement in combination with a multi-axis C-arm angiography system for...     

Lower anticoagulation for mechanical heart valves: experience with the ATS bileaflet valve

Background: The design of the bileaflet ATS (ATS Medical Inc., Minneapolis, USA) mechanical valve incorporates an open pivot at the hinge mechanism. Total washout of the blood at the pivot area was observed using 3-D computational fluid dynamics modelling. This phenomenon could make the valve less vulnerable to clot formation in patients without major thromboembolic risk factors.

Methods: From January 1993 to June 1999, 286 consecutive patients had the ATS valve inserted in the aortic position. Patients were divided into two groups. Group 1 comprised all patients in regular sinus rhythm with good left ventricular function (144 patients). Group 2 included patients in non-sinus rhythm and/or with large hypocontractile left ventricles (142 patients). The anticoagulation regime in group 1 was used to obtain an international normalised ratio (INR) between 1.5 and 2.5. This contrasts with our regular aim to maintain the INR strictly between 2.5 and 3.5 for all mechanical valves, as achieved in group 2.

Results: The follow-up period (99% completeness) ranged from 18 to 84 months. Survival (Kaplan-Meier) was 97 and 98% and 92 and 81% at 1 and 5 years in group 1 and group 2, respectively (P = 0.12). Log rank analysis failed to detect a statistical difference in thromboembolism or bleeding between both groups (P > 0.05). However, trends were in favour of group 1. Univariate analysis selected poor ventricular function and an ‘erratic’ INR value (P = 0.002) as risk factors for death. The sole independent risk factor for bleeding was the use of aspirin (P = 0.025).

Conclusions: The excellent group 1 data and outcome encouraged us to continue our low intensive anticoagulation regime and perhaps should be regarded as a new concept for treatment of selected mechanical valve patients.     

Effect of laparoscopic partial fundoplication on reflux mechanisms

OBJECTIVES: Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism causing gastroesophageal reflux. Since 1994 we have performed laparoscopic partial instead of complete fundoplication as standard surgical treatment for therapy resistant reflux disease to minimize postoperative dysphagia. To better understand the management of gastroesophageal reflux, we conducted a prospective study of the effects of laparoscopic partial fundoplication on TLESRs and other reflux mechanisms. METHODS: From 1994 to 1999, 65 patients underwent laparoscopic partial fundoplication (180-200 degrees) and 28 of these patients (16 female, 12 male, mean age 43 +/- 2 yr [range, 26-66 yr]) agreed to participate in this prospective study on reflux mechanisms. Before and 6 months after surgery, all patients were evaluated by simultaneous recording of pH and lower esophageal sphincter characteristics, using sleeve manometry. RESULTS: After partial fundoplication basal LES pressure increased significantly (p < 0.05), from 14.3 +/- 1.2 mm Hg to 17.8 +/- 1 mm Hg. Partial fundoplication significantly (p < 0.05) decreased the number of TLESRs, from 3.4 +/- 0.8 to 1.6 +/- 0.3 per hour in the fasting period, and from 4.7 +/- 0.5 to 1.9 +/- 0.3 per hour postprandially. The percentage of TLESRs associated with reflux also decreased significantly (p < 0.05), from 45 +/- 7% to 27 +/- 6% after operation. The number of reflux episodes decreased significantly (p < 0.05), from 4.1 +/- 0.7 to 1.3 +/- 0.3 per hour postoperatively. The majority of these episodes were associated with TLESRs: 57% and 46%, pre- and postoperatively, respectively. CONCLUSIONS: Laparoscopic partial fundoplication significantly increased fasting and postprandial LES pressure and significantly decreased TLESR frequency. This resulted in a significant reduction in esophageal acid exposure, with preservation of postprandial LES characteristics.     

N-acetylcysteine in acute cardiology: 10 years later: what do we know and what would we like to know?!

N-acetylcysteine (NAC) is known in a variety of branches of medicine. This paper addresses in detail the action of NAC as it is emerging from research and clinical trials over the past decade in cardiology, giving rise to new concepts. The result is a process resembling creation of a mosaic from individual pieces. Also, the role of NAC in acute cardiology, during acute reperfusion in particular, is defined.