Covered self-expandable metal stents for pancreatic duct stricture: a systematic review and meta-analysis

Background and study aims Placement of a covered (C)-self-expandable metal stent (SEMS) has been recently investigated as an alternative endoscopic treatment for main pancreatic duct stricture (MPDS) in chronic pancreatitis. Our aim was to carry out a systematic review and meta-analysis of studies quantifying efficacy and safety of C-SEMSs in the management of MPDS.Methods A multiple database search was performed, including MEDLINE, Embase and Cochrane Library, from January 2000 to September 2020, to identify studies reporting the efficacy and safety of C-SEMSs in patients with MPDS. Stricture and pain resolution were investigated. Other outcomes included technical success, stent migration, stricture recurrence and need for repeated stent placement. Pancreatitis, severe abdominal pain requiring stent removal and de-novo stricture were recorded as complications.Results Nineteen studies were identified, which included a total of 300 patients. C-SEMSs showed a pooled stricture resolution rate of 91 % [95 % confidence interval (CI), 85 %-96 %] and a pooled pain resolution rate of 92 % (95 % CI, 85 %-98 %). The pooled proportion for stricture recurrence was equal to 6 % (95 % CI, 1 %-14 %), while stent migration occurred in 33 of 300 patients, the pooled proportion being 7 % (95 % CI 1 %-15 %). The pooled mean stent duration was 133 days (95 % CI, 100-166 days). The most common complication was pancreatitis (3 %, 95 % CI 0 %-8 %), while de-novo stricture pooled proportion was 2 % (95 % CI, 0 %-5 %).Conclusions C-SEMSs are effective and safe in the treatment of MPDS. However, there is a significant need for further high-quality, well-designed studies to produce evidence-based data on short and long-term efficacy, safety, costs of C-SEMSs, and also optimal stent duration

Transforming growth factor-β-induced upregulation of transforming growth factor-β receptor expression in pancreatic regeneration

AbstractThe transforming growth factor-β (TGFβ) signaling pathway is one important player in the regulation of extracellular matrix turnover and cell proliferation in epithelial regeneration. We used cerulein-induced pancreatitis in rats as a model to investigate the regulation of TGFβ receptor type I and type II expression on protein and messenger RNA level during regeneration. In the regenerating pancreas, mRNA levels of TGFβ receptor I and II were significantly increased with a maximum after 2 days. On protein level, expression of TGFβ receptor II was significantly increased after 3–5 days. This elevated expression could be inhibited by neutralizing the endogenous biological activity of TGFβ1 with a specific antibody. In cultured pancreatic epithelial cells, TGFβ1 reduced cell proliferation as measured by [3H]thymidine incorporation. Furthermore the transcript levels of TGFβ1 as well as mRNA and protein concentrations of type I and type II receptor increased during TGFβ stimulation in vitro. These results indicate that epithelial pancreatic cells contribute to the enhanced TGFβ1 synthesis during pancreatic regeneration by an autocrine mechanism. TGFβ1, furthermore, upregulates the expression of its own receptors during the regenerative process, thereby contributing to the increase of the TGFβ-induced cellular responses

Tumor biology and cancer therapy – an evolving relationship

The aim of palliative chemotherapy is to increase survival whilst maintaining maximum quality of life for the individual concerned. Although we are still continuing to explore the optimum use of traditional chemotherapy agents, the introduction of targeted therapies has significantly broadened the therapeutic options. Interestingly, the results from current trials put the underlying biological concept often into a new, less favorable perspective. Recent data suggested that altered pathways underlie cancer, and not just altered genes. Thus, an effective therapeutic agent will sometimes have to target downstream parts of a signaling pathway or physiological effects rather than individual genes. In addition, over the past few years increasing evidence has suggested that solid tumors represent a very heterogeneous group of cells with different susceptibility to cancer therapy. Thus, since therapeutic concepts and pathophysiological understanding are continuously evolving a combination of current concepts in tumor therapy and tumor biology is needed. This review aims to present current problems of cancer therapy by highlighting exemplary results from recent clinical trials with colorectal and pancreatic cancer patients and to discuss the current understanding of the underlying reasons

Small intestinal bacterial overgrowth mimicking acute flare as a pitfall in patients with Crohn's Disease

<p>Abstract</p> <p>Background</p> <p>Small intestinal bacterial overgrowth (SIBO) is characterized by excessive proliferation of colonic bacterial species in the small bowel. Potential causes of SIBO include fistulae, strictures or motility disturbances. Hence, patients with Crohn's Disease (CD) are especially predisposed to develop SIBO. As result, CD patients may experience malabsorption and report symptoms such as weight loss, watery diarrhea, meteorism, flatulence and abdominal pain, mimicking acute flare in these patients.</p> <p>Methods</p> <p>One-hundred-fifty patients with CD reporting increased stool frequency, meteorism and/or abdominal pain were prospectively evaluated for SIBO with the Hydrogen Glucose Breath Test (HGBT).</p> <p>Results</p> <p>Thirty-eight patients (25.3%) were diagnosed with SIBO based on positive findings at HGBT. SIBO patients reported a higher rate of abdominal complaints and exhibited increased stool frequency (5.9 vs. 3.7 bowel movements/day, p = 0.003) and lower body weight (63.6 vs 70.4 kg, p = 0.014). There was no correlation with the Crohn's Disease Activity Index. SIBO was significantly more frequent in patients with partial resection of the colon or multiple intestinal surgeries; there was also a clear trend in patients with ileocecal resection that did not reach statistical significance. SIBO rate was also higher in patients with affection of both the colon and small bowel, while inflammation of the (neo)terminal ileum again showed only tendential association with the development of SIBO.</p> <p>Conclusion</p> <p>SIBO represents a frequently ignored yet clinically relevant complication in CD, often mimicking acute flare. Because symptoms of SIBO are often difficult to differentiate from those caused by the underlying disease, targeted work-up is recommended in patients with corresponding clinical signs and predisposing factors.</p

Hepcidin Is an Antibacterial, Stress-Inducible Peptide of the Biliary System

BACKGROUND/AIMS: Hepcidin (gene name HAMP), an IL-6-inducible acute phase peptide with antimicrobial properties, is the key negative regulator of iron metabolism. Liver is the primary source of HAMP synthesis, but it is also produced by other tissues such as kidney or heart and is found in body fluids such as urine or cerebrospinal fluid. While the role of hepcidin in biliary system is unknown, a recent study demonstrated that conditional gp130-knockout mice display diminished hepcidin levels and increased rate of biliary infections. METHODS: Expression and localization of HAMP in biliary system was analyzed by real time RT-PCR, in-situ hybridization, immunostaining and -blotting, while prohepcidin levels in human bile were determined by ELISA. RESULTS: Hepcidin was detected in mouse/human gallbladder and bile duct epithelia. Biliary HAMP is stress-inducible, in that it is increased in biliary cell lines upon IL-6 stimulation and in gallbladder mucosa of patients with acute cholecystitis. Hepcidin is also present in the bile and elevated prohepcidin levels were observed in bile of primary sclerosing cholangitis (PSC) patients with concurrent bacterial cholangitis compared to PSC subjects without bacterial infection (median values 22.3 vs. 8.9; p = 0.03). In PSC-cholangitis subjects, bile prohepcidin levels positively correlated with C-reactive protein and bilirubin levels (r = 0.48 and r = 0.71, respectively). In vitro, hepcidin enhanced the antimicrobial capacity of human bile (p<0.05). CONCLUSION: Hepcidin is a stress-inducible peptide of the biliary epithelia and a potential marker of biliary stress. In the bile, hepcidin may serve local functions such as protection from bacterial infections

Translating self-efficacy in job performance over time: The role of job crafting

This investigation intends to uncover the mechanisms linking self-efficacy to job performance by analyzing the mediating role of job crafting. A two-wave study on 465 white-collar workers was conducted, matching participants’ self-report data (i.e., self-efficacy and job crafting) with supervisory performance ratings. The structural equation model showed a positive reciprocal relationship between self-efficacy and crafting behaviors. In turn, job crafting predicted performance positively over time. More importantly, results confirmed the mediating role of crafting actions, which may represent the behavioral process underlying the positive effect of self-efficacy on individual outcomes. Practical implications for organizations, such as encouraging bottom-up job design or designing job-crafting interventions, and future research directions are also offered

Monitoring mountains in a changing world: new horizons for the Global Network for Observations and Information on Mountain Environments (GEO-GNOME)

Mountains are globally distributed environments that provide significant societal benefits, a function that is increasingly compromised by climatic change, environmental stress, political and socioeconomic transformations, and unsustainable use of natural resources. Gaps in our understanding of these processes and their interactions limit our capacity to inform decisions, where both generalities of mountain regions (eg climate processes) and specificities (eg context-specific manifestations of climate risks) matter. The Global Network for Observations and Information on Mountain Environments (GEO-GNOME), a Group on Earth Observations initiative, aims to fill these gaps through accessible Earth Observation (EO) as well as in-situ data and information on global change drivers, conditions, and trends. A workshop convened by the Mountain Research Initiative (MRI) revised GEO-GNOME's work plan, galvanizing a network that promotes relevant monitoring of global change in mountains and is responsive to the integrated knowledge needs of policy, research, and management

Extension of the Chiral Perturbation Theory Meson Lagrangian to Order P6P^6

We have derived the most general chirally invariant Lagrangian ${\cal L}_6$ for the meson sector at order $p^6$. The result provides an extension of the standard Gasser-Leutwyler Lagrangian ${\cal L}_4$ to one higher order, including as well all the odd intrinsic parity terms in the Lagrangian. The most difficult part of the derivation was developing a systematic strategy so as to get all of the independent terms and eliminate the redundant ones in an efficient way. The 'equation of motion' terms, which are redundant in the sense that they can be transformed away via field transformations, are separated out explicitly. The resulting Lagrangian has been separated into groupings of terms contributing to increasingly more complicated processes, so that one does not have to deal with the full result when calculating $p^6$ contributions to simple processes.Comment: 59 pages in LaTex, using RevTex macro, TRIUMF preprint TRI-PP-94-6

Probing For New Physics and Detecting non linear vacuum QED effects using gravitational wave interferometer antennas

Low energy non linear QED effects in vacuum have been predicted since 1936 and have been subject of research for many decades. Two main schemes have been proposed for such a 'first' detection: measurements of ellipticity acquired by a linearly polarized beam of light passing through a magnetic field and direct light-light scattering. The study of the propagation of light through an external field can also be used to probe for new physics such as the existence of axion-like particles and millicharged particles. Their existence in nature would cause the index of refraction of vacuum to be different from unity in the presence of an external field and dependent of the polarization direction of the light propagating. The major achievement of reaching the project sensitivities in gravitational wave interferometers such as LIGO an VIRGO has opened the possibility of using such instruments for the detection of QED corrections in electrodynamics and for probing new physics at very low energies. In this paper we discuss the difference between direct birefringence measurements and index of refraction measurements. We propose an almost parasitic implementation of an external magnetic field along the arms of the VIRGO interferometer and discuss the advantage of this choice in comparison to a previously proposed configuration based on shorter prototype interferometers which we believe is inadequate. Considering the design sensitivity in the strain, for the near future VIRGO+ interferometer, of $h<2\cdot10^{-23} \frac{1}{\sqrt{\rm Hz}}$ in the range 40 Hz $- 400$ Hz leads to a variable dipole magnet configuration at a frequency above 20 Hz such that $B^{2}D \ge 13000$ T$^{2}$m/$\sqrt{\rm Hz}$ for a `first' vacuum non linear QED detection

Protein Kinase D2 Is an Essential Regulator of Murine Myoblast Differentiation

Muscle differentiation is a highly conserved process that occurs through the activation of quiescent satellite cells whose progeny proliferate, differentiate, and fuse to generate new myofibers. A defined pattern of myogenic transcription factors is orchestrated during this process and is regulated via distinct signaling cascades involving various intracellular signaling pathways, including members of the protein kinase C (PKC) family. The protein kinase D (PKD) isoenzymes PKD1, -2, and -3, are prominent downstream targets of PKCs and phospholipase D in various biological systems including mouse and could hence play a role in muscle differentiation. In the present study, we used a mouse myoblast cell line (C2C12) as an in vitro model to investigate the role of PKDs, in particular PKD2, in muscle stem cell differentiation. We show that C2C12 cells express all PKD isoforms with PKD2 being highly expressed. Furthermore, we demonstrate that PKD2 is specifically phosphorylated/activated during the initiation of mouse myoblast differentiation. Selective inhibition of PKCs or PKDs by pharmacological inhibitors blocked myotube formation. Depletion of PKD2 by shRNAs resulted in a marked inhibition of myoblast cell fusion. PKD2-depleted cells exhibit impaired regulation of muscle development-associated genes while the proliferative capacity remains unaltered. Vice versa forced expression of PKD2 increases myoblast differentiation. These findings were confirmed in primary mouse satellite cells where myotube fusion was also decreased upon inhibition of PKDs. Active PKD2 induced transcriptional activation of myocyte enhancer factor 2D and repression of Pax3 transcriptional activity. In conclusion, we identify PKDs, in particular PKD2, as a major mediator of muscle cell differentiation in vitro and thereby as a potential novel target for the modulation of muscle regeneration