Impaired clearance of apoptotic cells leads to HMGB1 release in the bone marrow of patients with myelodysplastic syndromes and induces TLR4-mediated cytokine production

Excessive pro-inflammatory cytokine production in the bone marrow has been associated with the pathogenesis of myelodysplastic syndromes. We herein investigated the involvement of toll-like receptors and their endogenous ligands in the induction/maintenance of the inflammatory process in the marrow of patients with myelodysplastic syndromes. We evaluated the expression of toll-like receptors in marrow monocytes of patients (n=27) and healthy controls (n=25) by flow-cytometry and also assessed the activation of the respective signaling using a real-time polymerase chain reaction-based array. We measured the high mobility group box-1 protein, a toll-like receptor-4 ligand, in marrow plasma and long-term bone marrow culture supernatants by an enzyme-linked immunosorbent assay and we performed cross-over experiments using marrow plasma from patients and controls in the presence/absence of a toll-like receptor-4 inhibitor to evaluate the pro-inflammatory cytokine production by chemiluminescence. We assessed the apoptotic cell clearance capacity of patients’ macrophages using a fluorescence microscopy-based assay. We found over-expression of toll-like receptor-4 in patients’ marrow monocytes compared to that in controls; this over-expression was associated with up-modulation of 53 genes related to the respective signaling. Incubation of patients’ monocytes with autologous, but not with normal, marrow plasma resulted in over-production of pro-inflammatory cytokines, an effect that was abrogated by the toll-like receptor-4 inhibitor suggesting that the pro-inflammatory cytokine production in myelodysplastic syndromes is largely mediated through toll-like receptor-4. The levels of high mobility group box-1 protein were increased in patients’ marrow plasma and culture supernatants compared to the levels in controls. Patients’ macrophages displayed an impaired capacity to engulf apoptotic cells and this defect was associated with excessive release of high mobility group box-1 protein by dying cells. A primary apoptotic cell clearance defect of marrow macrophages in myelodysplastic syndromes may contribute to the induction/maintenance of the inflammatory process through aberrant release of molecules inducing toll-like receptor-4 such as high mobility group box-1 protein.     

Fibrin glue for sealing the needle track after percutaneous lung biopsy: Part I—experimental study

Purpose Evaluate the effectiveness of fibrin glue for the embolic occlusion of needle tracks following percutaneous lung biopsy (PLB).Methods Twenty-six rabbits underwent computed tomography (CT)-guided PLB using a coaxial system consisting of 19-and 22-gauge needles. Thirteen rabbits were used as controls (group A). In 13 other rabbits (group B), fibrin glue labelled with I¹³¹ fibrinogen and contrast medium was injected into the track. Both groups were examined by CT for the presence and severity of pneumothorax (mild: less than 20%; severe: more than 20%). Group B was also examined scintigraphically and their lungs were studied histologically. Results: In group A, pneumothorax developed in eight animals (61.6%) and was severe in six (46.1%) whereas in group B, pneumothorax developed in five animals (38.5%) and was severe in one (7.7%). Though the difference between the two groups in overall incidence of pneumothorax was not significant (p > 0.1), it was significantly higher (p < 0.025) for severe pneumothorax in group A. No signs of systemic embolism were observed.Conclusions Based on this animal model, fibrin glue is a safe and useful sealant following PLB and reduces the incidence of severe pneumothorax.     

Acute, reversible myocardial ischemia in a patient with an asthmatic attack

A 61-year-old woman with chronic asthma sustained an episode of dyspnea and chest heaviness and was brought to the emergency department. Her examination revealed tachypnea, tachycardia, hypotension, and diffuse prolonged respiratory wheezing. Arterial blood gas analysis showed severe hypoxemia and hypercapnia. A 12-lead electrocardiogram showed marked, downsloping ST-segment depression, with deep, negative T waves in leads I, II, III, and aVF and precordial leads V₃-V₆. After 15 minutes of therapy with oxygen, beta-agonists, and corticosteroids, the electrocardiographic abnormalities subsided and 2 hours later they had disappeared. Subsequent coronary angiography and ventriculography revealed normal coronary arteries and good left ventricular ejection fraction. It is concluded that an acute asthmatic paroxysm may produce transient myocardial ischemia even with angiographically documented normal coronary arteries.     

Adjuvant dose-dense sequential chemotherapy with epirubicin, CMF, and weekly docetaxel is feasible and safe in patients with operable breast cancer

Currently, randomized phase III trials have demonstrated that docetaxel is an effective strategy in the adjuvant treatment of breast cancer. However, previous attempts to incorporate docetaxel with an anthracycline in a dose-dense regimen have been unsuccessful. Therefore, new schedules containing both drugs should be explored. Forty-four patients with high-risk operable breast cancer entered this feasibility study. They were treated with three cycles of epirubicin 110 mg/m2 every 2 wk with G-CSF followed by three cycles of "intensified" CMF (840 mg/m2 cyclophosphamide; 57 mg/m2 methotrexate; 840 mg/m2 fluorouracil) every 2 wk with G-CSF followed 3 wk later by nine weekly cycles of 35 mg/m2 docetaxel (E-CMF-doc). Totally, 39 patients (89%) received all cycles of chemotherapy. The vast majority (92%) of cycles were administered at full dose. Therefore, dose intensity was sufficiently maintained for all drugs. Toxicity was generally mild to moderate. Most frequently recorded side effects apart from alopecia were neutropenia (54%) and nausea/vomiting (89%). Infection developed in nine patients. Two cases of febrile neutropenia were reported. The E-CMF-doc regimen, as used in this study, is feasible and well tolerated. Its impact on survival should be evaluated in phase III trials.     

Single trocar laparoscopically assisted placement of central nervous system-peritoneal shunts

BACKGROUND: Lumbar peritoneal and ventriculoperitoneal shunts are widely used for the treatment of hydrocephalus. In the past, the abdominal portion of these procedures required laparotomy. With the advent of minimally invasive techniques, laparoscopically assisted placement of the distal catheter has been tried. MATERIALS AND METHODS: We performed 10 shunt procedures (3 lumbar peritoneal, 6 ventriculoperitoneal, and 1 meningomyelocele-peritoneal) in 10 patients (mean age 56; age range, 30-78 years). Four patients had undergone previous open shunt placement that failed. The abdominal portion of the procedure was performed using a 5-mm trocar and a 10Fr introducer for camera and catheter insertion. In 3 cases, an additional 5-mm port was necessary for lysis of adhesions. These access punctures did not require fascial closure and caused minimal pain and limitation. RESULTS: No intra- or postoperative complications were encountered in this small patient group. At a median follow-up of 50 months (range, 3-56 months) all patients had functioning shunts. CONCLUSION: Single trocar laparoscopically assisted placement of central nervous system-peritoneal shunts is safe and simple, and should be considered the procedure of choice. This technique is also suitable for repositioning migrated catheters and other catheter-tip manipulations.     

The role of ascorbic acid in the prevention of atrial fibrillation after elective on-pump myocardial revascularization surgery: a single-center experience--a pilot study

Atrial fibrillation (AF) is a common arrhythmia that occurs postoperatively in cardiac surgery. There is evidence for the role of oxidative stress in the etiology of AF. In our study, we examined whether antioxidant ascorbic acid (vitamin C), could help in the reduction of the incidence of postoperative AF. Patients who were scheduled to undergo elective isolated on-pump coronary artery bypass grafting (CABG) were included in our study. One hundred and seventy patients were randomly divided in two groups: Group A (n=85) received vitamin C preoperatively and postoperatively whereas Group B (n=85) did not receive any (control group). The incidence of AF was 44.7% in the vitamin C group and 61.2% in the control group (P=0.041). The hospitalization time, the intensive care unit stay and the time interval for the conversion of AF into sinus rhythm was significantly shorter in the vitamin C group. Patients that developed AF also had longer hospital length of stay (9.5±2.8?days vs. 6.7±1.9, P=0.034). Supplementation of vitamin C reduces the incidence of postCABG AF, and decreases the time needed for rhythm restoration and length of hospital stay.     

Nonarteritic anterior ischemic optic neuropathy associated with coexisting factor V Leiden and methylenetetrahydrofolate reductase mutations

We present a case of bilateral, not simultaneous, nonarteritic anterior ischemic optic neuropathy in a 53-year-old man with thrombophilic tendency. The investigation included determination of protein C, free protein S, antithrombin III, activated protein C resistance, and antiphospholipid syndrome study. Polymerase chain reaction and hybridization to allele-specific oligonucleotide probes were performed to determine the presence of thrombophilic polymorphisms. The patient was found to be heterozygous for factor V G1691A (Leiden) mutation and homozygous for methylenetetrahydrofolate reductase (MTHFR) C677T mutation.This case serves to demonstrate that the additive effect of two mild thrombophilic mutations may contribute to the occurrence of nonarteritic anterior ischemic optic neuropathy.     

Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study

BACKGROUND: It is not clear if long-term antithrombotic treatment has a beneficial effect on the incidence of thromboembolism in chronic heart failure (CHF). The HELAS study (Heart failure Long-term Antithrombotic Study) is a multicentre, randomised, double-blind, placebo-controlled trial to evaluate antithrombotic treatment in patients with CHF. METHODS: 197HF patients (EF <35%) were enrolled. Patients with Ischaemic Heart Disease were randomised to receive either aspirin 325mg or warfarin. Patients with Dilated Cardiomyopathy (DCM) were randomised to receive either warfarin or placebo. RESULTS: Analysis of the data from 312 patient years showed an incidence of 2.2 embolic events per 100 patient years, with no significant difference between groups. The incidence of myocardial infarction, hospitalisation, exacerbation of heart failure, death and haemorrhage were not different between the groups. No peripheral or pulmonary emboli were reported. Echocardiographic follow-up for 2years showed an overall increase in left ventricular ejection fraction from 28.2+/-6 to 30.3+/-7 p<0.05, which was most obvious in patients with DCM taking warfarin (EF 26.8+/-5.3 at baseline, 30.7+/-10 at 2 years, p<0.05). CONCLUSIONS: (1) Overall embolic events are rare in heart failure regardless of treatment. (2) Treatment does not seem to affect outcome.     

The interplay between haemodynamic load, brain natriuretic peptide and left atrial size in the early stages of essential hypertension

OBJECTIVE: Left atrial (LA) enlargement is an index of adverse cardiovascular events. We sought to investigate any possible correlation between haemodynamic load, neurohumoral factors and LA size in the early stages of essential hypertension. METHODS: We studied 94 consecutive middle-aged subjects, with newly diagnosed stage I-II essential hypertension without left ventricular (LV) hypertrophy and 34 age and sex-matched normotensive individuals. Ambulatory blood pressure (BP) monitoring, plasma levels of brain natriuretic peptide (BNP), metabolic profile and left atrial volume index (LAVI), an echocardiographic measurement of LA volume indexed for the body surface area, constituted the work-up of all subjects. RESULTS: Hypertensive compared with normotensive subjects had significantly increased office and ambulatory systolic and diastolic BP (P < 0.0001 for all cases) as well as body mass index and waist-to-hip ratio (P < 0.05 for both cases). BNP levels were greater in hypertensive compared with normotensive subjects but were not statistically significant (20.4 versus 17.1 pg/ml, P = NS). Hypertensive compared with normotensive subjects also had significantly increased LV mass index (105 versus 84 g/m, P < 0.0001), LA diameter (39 versus 36 mm, P < 0.0001), and LAVI (22 versus 19 ml/m, P < 0.05). In the hypertensive population, LAVI exhibited significant positive relationships with office systolic BP, ambulatory pulse pressure, LV mass index and BNP. In multiple linear regression analysis only LV mass index and BNP were significantly associated with LAVI (beta = 0.298, P = 0.030 and beta = 0.322, P = 0.009, respectively). CONCLUSIONS: Increased LAVI, closely associated with LV mass index and BNP, was still found in the early stages of essential hypertension. However, the clinical significance of these findings remains to be elucidated in future studies.