Surgical Endoscopic Vacuum Therapy for Defects of the Upper Gastrointestinal Tract

Introduction

Intraluminal therapy used in the gastrointestinal (GI) tract was first shown for anastomotic leaks after rectal resection. Since a few years vacuum sponge therapy is increasingly being recognized as a new promising method for repairing upper GI defects of different etiology. The principles of vacuum-assisted closure (VAC) therapy remain the same no matter of localization: Continuous or intermittent suction and drainage decrease bacterial contamination, secretion, and local edema. At the same time, perfusion and granulation is promoted. However, data for endoscopic vacuum therapy (EVT) of the upper intestinal tract are still scarce and consist of only a few case reports and small series with low number of patients.

Objectives

Here, we present a single center experience of EVT for substantial wall defects in the upper GI tract.

Methods

Retrospective single-center analysis of EVT for various defects of the upper GI tract over a time period of 4 years (2011–2015) with a mean follow-up of 17 (2–45) months was used. If necessary, initial endoscopic sponge placement was performed in combination with open surgical revision.

Results

In total, 126 polyurethane sponges were placed in upper gastrointestinal defects of 21 patients with a median age of 72 years (range, 49–80). Most frequent indication for EVT was anastomotic leakage after esophageal or gastric resection (n?=?11) and iatrogenic esophageal perforation (n?=?8). The median number of sponge insertions was five (range, 1–14) with a mean changing interval of 3 days (range, 2–4). Median time of therapy was 15 days (range, 3–46). EVT in combination with surgery took place in nine of 21 patients (43 %). A successful vacuum therapy for upper intestinal defects with local control of the septic focus was achieved in 19 of 21 patients (90.5 %).

Conclusion

EVT is a promising approach for postoperative, iatrogenic, or spontaneous lesions of the upper GI tract. In this series, EVT was combined with operative revision in a relevant proportion of patients.

     

Adenosine A2A receptors and basal ganglia physiology

Adenosine A2A receptors are highly enriched in the basal ganglia system. They are predominantly expressed in enkephalin-expressing GABAergic striatopallidal neurons and therefore are highly relevant to the function of the indirect efferent pathway of the basal ganglia system. In these GABAergic enkephalinergic neurons, the A2A receptor tightly interacts structurally and functionally with the dopamine D2 receptor. Both by forming receptor heteromers and by targeting common intracellular signaling cascades, A2A and D2 receptors exhibit reciprocal antagonistic interactions that are central to the function of the indirect pathway and hence to basal ganglia control of movement, motor learning, motivation and reward. Consequently, this A2A/D2 receptors antagonistic interaction is also central to basal ganglia dysfunction in Parkinson's disease. However, recent evidence demonstrates that, in addition to this post-synaptic site of action, striatal A2A receptors are also expressed and have physiological relevance on pre-synaptic glutamatergic terminals of the cortico-limbic-striatal and thalamo-striatal pathways, where they form heteromeric receptor complexes with adenosine A1 receptors. Therefore, A2A receptors play an important fine-tuning role, boosting the efficiency of glutamatergic information flow in the indirect pathway by exerting control, either pre- and/or post-synaptically, over other key modulators of glutamatergic synapses, including D2 receptors, group I metabotropic mGlu5 glutamate receptors and cannabinoid CB1 receptors, and by triggering the cAMP-protein kinase A signaling cascade.     

Rocaglates as Antivirals: Comparing the Effects on Viral Resistance,Anti-Coronaviral Activity,RNA-Clamping on eIF4A and Immune Cell Toxicity

Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5′-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here, we compared the effects of rocaglates on viral 5′-UTR-mediated reporter gene expression and binding to an eIF4A-polypurine complex. Furthermore, we analyzed the cytotoxicity of rocaglates on several human immune cells and compared their antiviral activities in coronavirus-infected cells. Finally, the potential for developing viral resistance was evaluated by passaging human coronavirus 229E (HCoV-229E) in the presence of increasing concentrations of rocaglates in MRC-5 cells. Importantly, no decrease in rocaglate-sensitivity was observed, suggesting that virus escape mutants are unlikely to emerge if the host factor eIF4A is targeted. In summary, all three rocaglates are promising antivirals with differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E.     

Ablation of striatal somatostatin interneurons affects MSN morphology and electrophysiological properties,and increases cocaine‐induced hyperlocomotion in mice

The striatum is mainly composed by medium spiny neurons (95 %) (MSNs). Although outnumbered, in other brain regions such as the hippocampus and the cortex, somatostatin interneurons (SSTi) are known to control and fine‐tune the activity of principal cells. This information is still fragmented for the striatum. Here, we questioned the striatal functional consequences of the selective ablation of SSTi in the striatum at the behavioural and cellular levels. We identified increased excitability coupled with decreased distal spine density in MSNs from SSTi‐ablated mice. Although the ethological behavioural analysis did not reveal differences between the groups, SSTi‐ablated mice were significantly more sensitive to the locomotor effects of cocaine without changes in motivation. This was accompanied by increased expression of the dopamine transporter (DAT) in the ventral striatum. Altogether, we show that SSTi are important players in the maintenance of MSN excitability and spine density impacting on mechanisms towards hyperdopaminergic states.     

Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement

We describe the postmortem findings of a 47-year-old man with Fabry disease, an X-linked glycolipid storage disorder, who was on enzyme replacement therapy with recombinant α-galactosidase A for more than 2 years. The patient had widespread atherosclerotic coronary artery disease that culminated in a massive acute myocardial infarction. Atherosclerotic lesions were seen in the right and left coronary systems, aorta, and the basilar artery. Typical Fabry cardiomyopathy and glomerular nephropathy were found. With the exception of vascular endothelial cells, extensive glycolipid storage deposits were seen in all vascular and nonvascular cells and organ systems. We conclude that, at least in this patient, repeated infusions with α-galactosidase A over a prolonged period did not appreciably clear storage material in cells other than vascular endothelial cells. These findings also illustrate accelerated atherosclerosis in susceptible patients with Fabry disease.     

Adherence to pelvic lymph node dissection recommendations according to the National Comprehensive Cancer Network pelvic lymph node dissection guideline and the D'Amico lymph node invasion risk stratification

Purpose

To assess adherence rates to pelvic lymph node dissection (PLND) according to National Comprehensive Cancer Network (NCCN) PLND guideline (2% or higher risk) and D’Amico lymph node invasion (LNI) risk stratification (intermediate/high risk) in contemporary North American patients with prostate cancer treated with radical prostatectomy (RP).

Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus

Cree leukoencephalopathy is a rapidly fatal infantile autosomal recessive leukodystrophy of unknown cause observed in the native North American Cree and Chippewayan indigenous population. We found in the brain of affected individuals the typical foamy cells with the oligodendroglial phenotype described in central hypomyelination syndrome/vanishing white matter, a syndrome related to mutations in the genes encoding the five subunits of the eucaryotic translation initiation factor eIF2B. In three patients of two Cree families, we found a homozygous missense mutation resulting in a histidine substitution at arginine 195 of epsilon-eIF2B.     

Dimethylcelecoxib inhibits prostaglandin E2 production

Dimethylcelecoxib (DMC), a derivative of celecoxib, has been developed to distinguish between the COX-dependent and COX-independent anti-carcinogenic effects of celecoxib. Although DMC has been shown to have no COX-inhibitory activity, it is important to ensure that DMC has no other influence on prostaglandin production. Interestingly, in this study we show that DMC inhibits PGE(2) production in vitro in the low micromolar range in different cancer cell lines. This effect can be at least partly explained by our findings that DMC inhibits microsomal prostaglandin E synthase-1 (mPGES-1) activity in a cell-free assay. Moreover, it prevents mPGES-1 up-regulation after stimulation of HeLa cells with IL-1beta and TNFalpha. Conversely, DMC has no effect on the expression levels of COX-1, COX-2, cytosolic PGES (cPGES) or mPGES-2 in these cells. However, in the cell-free assay DMC inhibits mPGES-1 to a maximum of 65% only and concentrations needed for inhibition of mPGES-1 activity are about 10-fold higher than needed for inhibition of PGE(2) production in cell culture. This suggests that DMC also has an impact on other proteins involved in PGE(2) production. In cell culture experiments the anti-proliferative effect of DMC, measured by the WST-1 assay, seems not to be dependent on PGE(2) inhibition, as DMC was equally effective in unstimulated HeLa cells as well as in stimulated HeLa cells, and the addition of external PGE(2) did not reverse the anti-proliferative effect of DMC in HCA-7 cells. We conclude that DMC is not a suitable non-prostaglandin-inhibiting control substance for research purposes.