A case of recurrent stent thrombosis in a drug-eluting stent following antiplateled therapy discontinuation

Stent thrombosis is one of the major complications that occur in percutaneous coronary interventions with stents. Various factors have been attributed to the development of stent thrombosis and several strategies have been recommended for its management. We report a case of 45 year-old patient with recurrent subacute and late stent thrombosis following antiplateled therapy discontinuation on the 6th day and 11th month after he discharging from hospital.     

Mannosylated lipoarabinomannan balances apoptosis and inflammatory state in mycobacteria-infected and uninfected bystander macrophages

To assess the role of mannosylated lipoarabinomannan (ManLAM) in the inflammatory and apoptotic response of mycobacteria-infected and uninfected, bystander cells we applied a mouse macrophage model of infection with avirulent strains--Mycobacterium bovis BCG, Mycobacterium tuberculosis (MTB) H37Ra and compared with a virulent MTB H37Rv strain infection. ManLAM contributed to the infection of macrophages by protection from apoptosis with stabilized Bcl-2 expression and down-regulated Bax expression for infected cells (BCG) or with stabilized Bcl-2 expression for uninfected bystander target cells (H37Ra). Additionally, ManLAM up-regulated FasL expression on the infected cells. Active extracellular signal-regulated kinase (ERK1/2) in BCG and H37Rv infection provided an anti-apoptotic effect by stabilization of anti-apoptotic Bcl-2 expression in the infected cells. Inhibitors specific for c-Jun-NH2-terminal kinase or stress-activated kinase (JNK) and p38 kinase decreased apoptosis of infected cells (BCG, H37Ra) and of uninfected bystanders (H37Ra) by down-regulating Bax. ManLAM significantly down-regulated production of pro-inflammatory IL-12 and TNF-alpha and activation of JNK by both avirulent strains. We conclude that by stabilization of Bcl-2 expression, down-regulation of JNK activity and down-regulation of pro-inflammatory cytokines production ManLAM can contribute to suppression of apoptosis and inflammatory reaction of uninfected, bystander cells.     

Stimulation of reactive oxygen species generation by disease-causing mutations of lipoamide dehydrogenase

We investigated pathogenic mutations relevant in dihydrolipoamide dehydrogenase (LADH; gene: Dld) deficiency, a severe human disease, to elucidate how they alter reactive oxygen species (ROS) generation and associated biophysical characteristics of LADH. Twelve known disease-causing mutants of human LADH have been expressed and purified to homogeneity from E. coli. Detailed biophysical and biochemical characterization of the mutants has been performed applying circular dichroism (CD) spectroscopy, nano-spray mass spectrometry (MS), calibrated gel filtration and flavin adenine dinucleotide-content analysis. Functional analyses revealed that four of the pathogenic mutations significantly stimulated the ROS-generating activity of LADH and also increased its sensitivity to an acidic shift in pH. LADH activity was reduced by variable extents in the mutants exhibiting excessive ROS generation. It is remarkable that in the P453L mutant, enzyme activity was nearly completely lost with a ROS-forming activity becoming dominant, whereas the G194C mutation, common among Ashkenazi Jews, resulted in no alteration in LADH activity but a gain in the ROS-generating activity. There have been neither major conformational alterations nor monomerization of the functional homodimer of LADH associated with the higher ROS-generating capacity as measured by CD spectroscopy and size-exclusion chromatography combined with nano-spray MS, respectively. The excessive ROS generation of selected LADH mutants could be an important factor in the pathology and clinical presentation of human LADH deficiency and raises the possibility of an antioxidant therapy in the treatment of this condition.     

Inhibition of oxidative stress in blood platelets by different phenolics from Yucca schidigera Roezl. bark

OBJECTIVE: We investigated the comparative effects of resveratrol (trans-3,4',5-trihydroxystilbene), trans-3,3',5,5'tetrahydroxy-4'-methoxystilbene, and yuccaols A and C isolated from the bark of Yucca schidigera on oxidative stress in resting blood platelets and blood platelets activated by different agonists (thrombin or thrombin receptor activating peptide). METHODS AND RESULTS: Tested phenolics (1-25 microgram/mL) reduced, to different degrees, the level of reactive oxygen species measured by the luminol-dependent chemiluminescence and changed the production of O(2)(-) measured by the reduction of cytochrome c in resting blood platelets. They also inhibited the generation of free radicals in blood platelets activated by thrombin (P < 0.05) or thrombin receptor activating peptide (P < 0.05). Treatment of platelets with resveratrol or yuccaols A and C at the concentration of 25 microgram/mL increased (statistically non-significant) the level of thiobarbituric acid reactive substances in these cells (P > 0.05), whereas trans-3,3',5,5'tetrahydroxy-4'-methoxystilbene and the alcohol yucca extract reduced lipid peroxidation in blood platelets (P < 0.05). CONCLUSIONS: Resveratrol and other phenolic compounds from the bark of Yucca schidigera inhibiting free radical generation in blood platelets may be beneficial in protecting against cardiovascular diseases when hyperactivity of platelets is observed.     

Mitomycin C and High‐Dose 5‐Fluorouracil With Folinic Acid as a Therapeutic Option for Heavily Pretreated Patients With Metastatic Colorectal Cancer: Prospective Phase II Trial

Background.

Standard treatment for patients with unresectable colorectal cancer metastases includes chemotherapy regimens based on irinotecan, oxaliplatin, fluoropyrimidines, anti-vascular endothelial growth factor therapy, and anti-EGFR. Additional therapeutic options are needed for patients with good performance status who have disease progression during or after standard therapies.

Methods.

A nonrandomized phase II study was modeled as a two-stage Chen design. Eligible patients had a diagnosis of metastatic colorectal cancer (mCRC) with progression after prior cytotoxic regimens based on oxaliplatin and irinotecan. Treatment consisted of mitomycin C in combination with high-dose 5-fluorouracil (5-FU) and folinic acid (the MLF regimen; mitomycin C as an intravenous bolus of 6 mg/m² i.v. on days 1 and 22 every 7 weeks; folinic acid at 250 mg/m² in combination with 5-FU at 2,600 mg/m² as a continuous intravenous infusion (24 hours) weekly for 6 of every 7 weeks.

Results.

The median age of the 74 eligible patients was 62 years (range: 47–79 years). In these heavily pretreated patients with mCRC, the MLF regimen was the fourth or fifth line in more than 60% of the patients. Two patients (3.2%) achieved a partial response, and 33 (53.2%) achieved a best response of stable disease, defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Median progression-free survival was 4.9 months. The median overall survival was 9.7 months. The most common nonhematologic side effects included mucositis (24.4% for all grades, and 9.5% with grade 3/4), diarrhea (15.0% for all grades, 13.6% with grade 3/4), fatigue (44.7% for all grades, 13.6% with grade 3/4), nausea (12.3% for all grades, 6.8% with grade 3/4), and peripheral neuropathy (17.6% for all grades, 2.7% with grade 3/4). Among the most frequent hematological toxicities were neutropenia (27.1% for all grades, 14.9% with grade 3/4), thrombocytopenia (18.9% for all grades, 8.1% with grade 3/4), and anemia (13.6% for all grades, 4.1% with grade 3/4). Dose reductions due to adverse events were necessary in 29 of 74 patients (37.6%), and discontinuation of therapy due to toxicity was necessary for 14 of 74 patients (18.2%).

Conclusion.

Our study shows the MLF regimen can be administered safely to patients with heavily pretreated mCRC. Median progression-free and overall survival compares favorably with other options used or approved in this setting. A randomized trial in this setting should be considered.     

Anti-CD11d monoclonal antibody treatment for rat spinal cord compression injury

This paper by Hurtado et al. examined responses of spinal cord-injured rats to treatment with a monoclonal antibody to the CD11d integrin, as a replication study of the paper by Gris et al. published in J. Neuroscience, 2004. The Hurtado et al. study addressed a portion of our investigation and obtained similar findings in the experiments that closely replicated ours in methodology and design, specifically the open field locomotor study. The high variability in their study of mechanical allodynia probably precluded detection of effects of the anti-CD11d treatment on this form of neuropathic pain. The lesion assessments were greatly different from those done in the Gris et al. study, and may not have been ideal for the extent of injury produced in this model, but did reveal a trend toward myelin preservation. The positive aspects of the study by Hurtado et al. encourage us to investigate this novel treatment further, in different animals and in different models of spinal cord injury.     

A reassessment of P2X7 receptor inhibition as a neuroprotective strategy in rat models of contusion injury

These experiments were completed as part of an NIH "Facilities of Research Excellence in Spinal Cord Injury" contract to support independent replication of published studies that could be considered for eventual clinical testing. Recent studies have reported that selective inhibition of the P2X7 receptor improves both the functional and histopathological consequences of a contusive spinal cord injury (SCI) in rats. We repeated two published studies reporting the beneficial effects of pyridoxal-5'-phosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS) or Brilliant blue G (BBG) treatment after SCI (Wang et al., 2004 and Peng et al., 2009). Mild thoracic SCI was first produced in Experiment 1 by means of the MASCIS impactor at T10 (height 6.25 mm, weight 10 g) followed by intraspinal administration of a P2X7 antagonist (2 μl/10 mM) after injury. Treatment with PPADS or another highly selective P2X7R antagonist Brilliant Blue G (BBG) (2 μl/02 mM) did not improve locomotive (BBB rating scale) over a 7 week period compared to vehicle treated rats. Also, secondary histopathological changes in terms of overall lesion and cavity volume were not significantly different between the PPADS, BBG, and vehicle treated animals. In the second experiment, the systemic administration of BBG (10 or 50 mg/kg, iv) 15 min, 24 and 72 h after moderate (12.5 mm) SCI failed to significantly improve motor recovery or histopathological outcome over the 6 week observational period. Although we cannot conclude that there will be no long-term beneficial effects in other spinal cord injury models using selective P2X7 receptor antagonists at different doses or treatment durations, we caution researchers that this potentially exciting therapy requires further preclinical investigations before the implementation of clinical trials targeting severe SCI patients.     

Sibutramine-induced mania as the first manifestation of bipolar disorder

Background

Sibutramine, used in obesity treatment, has been associated with many neuropsychiatric side effects including hypomanic and manic episodes. Hypomanic/manic episodes related to sibutramine treatment were earlier reported in patients who had previous history of bipolar disorder, after sibutramine overdose, after over-the-counter product illegally containing very high dose of sibutramine, together with psychotic symptoms, in organic patient, or after interaction of sibutramine with other drugs.

Case presentation

We report the first case of a patient with clear manic episode, after treatment with recommended dose of sibutramine, without previous history of mood disorders, organic changes or drug interactions, that was followed by episode of depression.

Conclusion

Minimal recommended dose of sibutramine induced manic episode that was the first manifestation of bipolar disorder. The manic episode, associated with sibutramine treatment, was induced in a person without previous history of mood disorders. Potential risks associated with the treatment of obesity using sibutramine warn physicians to be alert not only to common and cardiovascular but also to psychiatric adverse effects. A careful assessment of patient’s mental state and detailed psychiatric family history should be done before sibutramine treatment. In patients with a family history for bipolar disorder the use of even minimal dose of sibutramine should be contraindicated.     

Ultrastructure of meningiomas: autophagy is involved in the pathogenesis of "intranuclear vacuoles"

We report here common ultrastructural findings in a short list of meningiomas. At the lower power magnification, a tumour consisted of elongated or round cells and innumerable cellular processes connected with diverse intercellular junctions. Nuclei presented no specific features, nucleoli were infrequently seen and heterochromatin was clumped beneath the nuclear membranes. In a case of clear cell meningioma, cells were of watery cytoplasm. Occasionally, immobile cilia, completely ensheathed by the cytoplasm and anchored by blepharoplasts were seen; as we did not encounter those rare cilia in cross-sections, no further insight into their inner microtubular-doublet structure was possible. The cytoplasm of the cells and the processes were filled with the intermediate filaments. In the intercellular space, collagen fibrils and electron-dense material was occasionally observed. The majority of the tumour samples were filled with processes. Several types of junctional complexes were observed. The most frequent were desmosomes and in the proper plane of section their whole pentalaminar structure was readily discernible. However, robust tonofilaments, as seen in epithelial neoplasms, were not observed. Those desmosomal junctions were either completely symmetric or asymmetric, but the exact symmetry could not be judged without the assistance of a goniometer. Some junctional complexes were more elaborate, with desmosomal junctions separated by a tight apposition of membranes, which suggests tight junctions. "Intranuclear vacuoles" well-visible even at low power were defined as indentation of the cytoplasm into the nucleus. Within these vacuoles, autophagic vacuoles and lysosomal bodies were seen, suggesting an active macroautophagy process. In 2 cases, severe lipidization of meningioma cell cytoplasm was observed. In a case of anaplastic meningioma, a mitotic figure was found. In another case, empty rectangular spaces in the cytoplasm, suggestive of pre-existing crystalloid structures, were seen.