Introduction

Sarcopenia, characterized by reduced skeletal muscle mass and function, is a significant complication in patients with chronic pancreatitis (CP) and associated with a poor clinical outcome. CP is a progressive fibro-inflammatory disorder of the pancreas that affects both endocrine and exocrine pancreas.
While mechanisms underlying sarcopenia have been explored in elderly and cancer patients, understanding remains limited in chronic inflammatory disorders.

Aims & Methods

Our study aims to close this knowledge gap by comprehensively investigating the extent of sarcopenia in different experimental CP models, while elucidating the cellular mechanisms involved.
CP was induced in male C57BL/6 mice using three strategies: 1) by repetitive injections of caerulein over a period of 10 weeks, 2) ligation of the pancreatic duct, or 3) utilizing a knock-in mouse model carrying a heterozygous mutation in the cationic trypsinogen (T7D23A) which induces endogenous trypsinogen activation. PBS injected or sham operated mice served as controls.
To assess changes, we measured muscle diameter via HE-stained sections and MR-imaging, and evaluated muscle strength using grip force measurements.
In muscle lysates, we analyzed the expression levels of TGF-β superfamily members such as activin A, myostatin, and follistatin, along with E3 ubiquitin ligase RING-finger protein-1 (MuRF1), using both, qRT-PCR and immunoblotting techniques. Additionally, myogenesis factors in muscles as well as in vitro in C2C12 myotubes treated with activin A were investigated using qRT-PCR. Myotube diameters were measured after immunofluorescence staining of myosins. Moreover, activin A treated C2C12 myotubes, were assessed on proteasome expression analyzing α4, rpt6 and LMP7 subunits and chymotrypsin-like activity via native PAGE and fluorogenic substrate activity assay.

Results

Reduced skeletal muscle size and strength were observed in the caerulein injection and pancreatic duct ligation model, while no reduction was determined in T7D23A mutant mice.
A decline in muscle diameter and force coincided with elevated levels of activin A, myostatin and MuRF1, accompanied by a simultaneous reduction in follistatin expression. In contrast, the expression levels of activin A, follistatin, myostatin, and MuRF1 remained unaltered in the muscle tissue of T7D23A mutant mice.
Stimulation of C2C12 myotubes with activin A for 48 h led to a significant reduction in muscle diameter compared to untreated cells and mRNA expression of key myogenesis factors such as myocyte-specific enhancer factor 2c (MEF2C), myogenic factor 3 (MyoD), and myosin heavy chains of fast muscle fiber type (MYH 1 and MYH 2) significantly decreased in vitro and in vivo.
Additionally, activin A increases the chymotrypsin-like activity and abundance of proteasomal subunits α4 and rpt6 in a concentration dependent manner. Stimulation kinetics over 24 h revealed a dip after 4 h and significantly increased peak activity after 8 h und 12 h. Moreover, LMP7 was elevated, suggesting the formation of the immunoproteasome in vitro.

Conclusion

Signs of sarcopenia emerge in experimental CP models. Their onset appears to be associated with an activation of the activin receptor signaling pathways. These findings improve our mechanistic understanding and suggest potential biomarkers for sarcopenia. Furthermore targeting the TGF-β signaling cascade may be a promising therapeutic approach for sarcopenia in CP.

Introduction

Helicobacter pylori (H. pylori) infection remains a major public health problem. Given the high resistance to antibiotics, different treatment strategies must be validated in each specific country. The recurrence rates of H. pylori infection and its predictors remain unclear.

Aims & Methods

To determine the independent factors predicting recurrence after successful eradication with a first-line treatment for H. pylori infection.
All patients were submitted to eradication treatment with five quadruple therapies (A-Concomitant with metronidazole 500mg tid, 14 days; B-Concomitant with metronidazole 500mg bid, 14 days; C-Quadruple with bismuth, 10 days; D-Sequential, 14 days; E-Hybrid, 14 days)) in a blind, randomized trial. Esomeprazole was the proton-pump inhibitor of choice. Efficacy rate at 1-2 months and recurrence rate at 12 months using ¹³C-urea breath test were evaluated. Sociodemographic data, personal/family history, health status and biochemical parameters were assessed using univariate and multivariate analyses.

Results

A total of 126 patients (42.9% males; mean age: 57.4±16.7 years) concluded the treatment protocol (A-25; B-21; C-27; D-24; E-29). Overall efficacy rate of quadruple therapy regimens was 98.4%(n=124): Group A-100%; Group B-100.0%; Group C-100.0%; Group D-100.0%; Group E-93.1% (p=0.147). Overall recurrence rate of quadruple therapy regimens was 4.1%(n=5/123): Group A-12.0%; Group B-9.5%; Group C-0.0%; Group D-0.0%; Group E-0.0% (p=0.009). After univariate/multivariate analysis, high LDL-cholesterol level (OR 1.032, p=0.042), non-bismuth concomitant H. pylori eradication regimen (OR 8.904, p=0.064) and alcoholism (OR 8.333, p=0.035) were independent risk factors for H. pylori reinfection.

Conclusion

In this South-European country, all quadruple therapy regimens with or without bismuth are very effective for H. pylori eradication. The 12-months recurrence rate of H. pylori infection after successful eradication is <5%. High LDL-cholesterol, non-bismuth concomitant H. pylori eradication regimen and alcoholism are independent predictors for H. pylori reinfection. A close surveillance on infectious state in high-risk patients is crucial to prevent long-term H. pylori-associated complications.

References

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Disclosure

None of the authors have anything to declare with regard to personal or financial interests in carrying out this work.