Augmentation of lipopolysaccharide-induced nitric oxide production by alpha-galactosylceramide in mouse peritoneal cells

The effect of alpha-galactosylceramide (alpha-GalCer) on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse peritoneal cells was studied. alpha-GalCer augmented LPS-induced NO production in mouse peritoneal cells, but not in RAW 264.7 macrophage cells. alpha-GalCer augmented NO production, but not tumor necrosis factor (TNF)-alpha production in LPS-stimulated peritoneal cells. Peritoneal cells produced a significant level of interferon (IFN)-gamma in response to alpha-GalCer and anti-IFN-gamma antibody abolished the augmentation of LPS-induced NO production by alpha-GalCer. Moreover, anti-IFN-gamma antibody prevented the enhanced expression of an inducible type of NO synthase mRNA by alpha-GalCer. alpha-GalCer did not augment LPS-induced NO production in peritoneal cells from natural killer T (NKT)-deficient mice. Therefore, it was suggested that alpha-GalCer might augment LPS-induced NO production in peritoneal cells through release of IFN-gamma from NKT cells.     

Imipenem Treatment Induces Expression of Important Genes and Phenotypes in a Resistant Acinetobacter baumannii Isolate

Acinetobacter baumannii has emerged as a notorious multidrug-resistant pathogen, and development of novel control measures is of the utmost importance. Understanding the factors that play a role in drug resistance may contribute to the identification of novel therapeutic targets. Pili are essential for A. baumannii adherence to and biofilm formation on abiotic surfaces as well as virulence. In the present study, we found that biofilm formation was significantly induced in an imipenem-resistant (Imp^r) strain treated with a subinhibitory concentration of antibiotic compared to that in an untreated control and an imipenem-susceptible (Imp^s) isolate. Using microarray and quantitative PCR analyses, we observed that several genes responsible for the synthesis of type IV pili were significantly upregulated in the Imp^r but not in the Imp^s isolate. Notably, this finding is corroborated by an increase in the motility of the Imp^r strain. Our results suggest that the ability to overproduce colonization factors in response to imipenem treatment confers biological advantage to A. baumannii and may contribute to clinical success.     

Serum vitamin D levels correlate to coronary artery disease severity: a retrospective chart analysis

Background: The pro-atherosclerotic nature of vitamin D deficiency has been shown to increase cardiovascular events. We further emphasized and evaluated the severity of coronary artery disease (CAD) with varying levels of vitamin D in relation to age, gender, ethnicity and baseline confounders.

Methods: A retrospective, single-center study of 9,399 patients admitted between 2005 and 2014 for chest pain who underwent coronary angiography. Patients without a vitamin D level, measured as 25-dihydroxyvitamin D (25[OH]D) were excluded from our study. 25(OH)D deficiency and insufficiency were defined by having serum concentration levels of less than 20 ng/ml and 20 to 29.9 ng/ml, respectively, while normal levels were defined as greater than or equal to 30 ng/ml. We assessed levels of 25(OH)D and extent of coronary disease with coronary angiography as obstructive CAD (left main stenosis of ≥50% or any stenosis of ≥70%), non-obstructive CAD (≥1 stenosis ≥20% but no stenosis ≥70%) and normal coronaries (no stenosis >20%).

Results: Among 9,399 patients, 1,311 qualified, of which 308 patients (23%) had normal 25(OH)D levels, 552 patients (42%) had 25(OH)D deficiency and 451 patients (35%) had 25(OH)D insufficiency. In an analysis of the extent of coronary disease, we identified 20% of patients having normal coronaries, 55% having obstructive CAD and 25% having non-obstructive CAD. Baseline clinical risk factors and co-morbidities did not differ between the groups.

Patients with normal 25(OH)D levels were found to have normal coronaries compared to patients with 25(OH)D deficiency or insufficiency (OR: 7, 95% CI: 5.2 – 9.5, p < 0.0001). Comparing patients with normal 25(OH)D levels, patients with 25(OH)D deficiency or insufficiency (<29 ng/ml), 62% were found to have obstructive CAD (n = 624, OR: 2.9, 95% CI: 2.3-3.7, p < 0.0001) and 25% had non-obstructive CAD (n = 249, OR: 1.5, 95% CI: 1.1-2, p = 0.02).

Conclusion: Normal coronaries and CAD were shown to correlate with normal and low levels of 25(OH)D, respectively. There is an inverse relationship between the percentage of coronary artery occlusion and serum 25(OH)D concentrations. Vitamin D may provide benefits in risk stratification of patients with CAD and serve as a possible risk factor.     

Autophagy is activated by proteasomal inhibition and involved in aggresome clearance in cultured astrocytes

A common pathway underlying a variety of neurodegenerative disorders is the aggregation and deposition of misfolded proteins. Proteasomal inhibition has been demonstrated to promote the formation of intracellular inclusions. We have shown before that astrocytes respond to the treatment with the proteasome inhibitor MG‐132 by aggresome formation and cytoskeletal disturbances, but unlike oligodendrocytes do not die by apoptotic cell death and have the capability to recover. This study was undertaken to elucidate if the autophagy‐lysosomal pathway participates in the efficient recovery process in astrocytes and is modulated under conditions of proteasomal inhibition. The data show that the autophagic pathway was stimulated during a 24‐h treatment with the proteasome inhibitor MG‐132 in a time and concentration‐dependent manner. It remained at an elevated level throughout a 24‐h recovery period in the absence of MG‐132 and participates in the aggregate clearing process. In the presence of the specific inhibitor of macroautophagy, 3‐methyladenine, cell viability was impaired, aggregates were not as efficiently removed and HSP25, αB‐crystallin and ubiquitinated proteins remained in the insoluble protein fraction. LC3‐II positive puncta, indicative of autophagosomes, were formed abundantly in the cells after proteasome inhibition and were seen in close association with the aggregates. Hence, the ability of astrocytes to upregulate autophagic degradation might contribute to their resistance against proteasomal stress situations and act as a compensatory mechanism when the proteasome is impaired. © 2010 Wiley‐Liss, Inc.     

Chemotherapy in gallbladder carcinoma

Gallbladder cancer is an aggressive tumor. Its incidence varies according to geography. Surgery is the standard treatment for localized stage but there is no standard treatment in metastatic or locally advanced disease. Because of the rarity of bile tract cancer (BTC) and gallblader carcinoma (GBC), most studies have grouped all BTC and GBC together, and there are very few GBC-specific studies. In addition, there is a paucity of randomized controlled studies in this disease with small numbers of patients and inclusion bias. One randomized trial ABC-02?was well conducted and showed a survival benefit in favor of gemcitabine (GEM)+cisplatin (CDDP), which can be regarded as the standard in locally advanced BTC. Adjuvant therapy after surgical resection is not validated. Understanding the molecular mechanisms of carcinogenesis of GBC has opened the way for the use of targeted therapies. This new treatment would improve survival and quality of life of our patients.     

Left main coronary artery fistula to the right atrium and superior vena cava: case report and review of the literature

A unique arteriovenous fistula, originating from the left main coronary artery and branching to drain into the right atrium and superior vena cava is presented with review of the literature.     

Prospective randomized controlled trial of an injectable esophageal prosthesis versus a sham procedure for endoscopic treatment of gastroesophageal reflux disease

Background

This study aimed to assess whether endoscopic implantation of an injectable esophageal prosthesis, the Gatekeeper Reflux Repair System (GK), is a safe and effective therapy for controlling gastroesophageal reflux disease (GERD).

Methods

A prospective, randomized, sham-controlled, single-blinded, international multicenter study planned final enrollment of 204 patients in three groups: up to 60 lead-in, 96 GK, and 48 sham patients. The sham patients were allowed to cross over to the GK treatment arm or exit the study at 6 months. The primary end points were (1) reduction in serious device- and procedure-related adverse device effects compared with a surgical composite complication rate and (2) reduction in heartburn symptoms 6 months after the GK procedure compared with the sham procedure. The secondary end point was improved esophageal pH (total time pH was <4) 6 months after the GK procedure compared with baseline.

Results

A planned interim analysis was performed after 143 patients were enrolled (25 lead-in, 75 GK, and 43 sham patients), and the GK study was terminated early due to lack of compelling efficacy data. Four reported serious adverse events had occurred (2 perforations, 1 pulmonary infiltrate related to a perforation, and 1 severe chest pain) at termination of the study with no mortality or long-term sequelae. Heartburn symptoms had improved significantly at 6 months compared with baseline in the GK group (p < 0.0001) and the sham group (p < 0.0001), but no significant between-group difference in improvement was observed (p = 0.146). Esophageal acid exposure had improved significantly at 6 months compared with baseline in the GK group (p = 0.021) and the sham group (p = 0.003), but no significant between-group difference in improvement was observed (p = 0.27).

Conclusions

The GK procedure was associated with some serious but infrequent complications. No statistically significant difference in outcomes was observed between the treatment and control groups at 6 months compared with baseline.