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Animal models are ideal to study the pathomechanism and therapy of acute pancreatitis (AP). The use of L-arginine-induced AP model is nowadays becoming increasingly popular in mice. However, carefully looking through the literature, marked differences in disease severity could be observed. In fact, while setting up the L-arginine (2×4 g/kg i.p.)-induced AP model in BALB/c mice, we found a relatively low rate (around 15%) of pancreatic necrosis, whereas others have detected much higher rates (up to 55%). We suspected that this may be due to differences between mouse strains. We administered various concentrations (5-30%, pH = 7.4) and doses (2×4, 3×3, or 4×2.5 g/kg) of L-arginine-HCl in BALB/c, FVB/n and C57BL/6 mice. The potential gender-specific effect of L-arginine was investigated in C57BL/6 mice. The fate of mice in response to the i.p. injections of L arginine followed one of three courses. Some mice (1) developed severe AP or (2) remained AP-free by 72 h, whereas others (3) had to be euthanized (to avoid their death, which was caused by the high dose of L-arginine and not AP) within 12 h., In FVB/n and C57BL/6 mice, the pancreatic necrosis rate (about 50%) was significantly higher than that observed in BALB/c mice using 2×4 g/kg 10% L-arginine, but euthanasia was necessary in a large proportion of animals, The i.p. injection of lower L-arginine concentrations (e.g. 5-8%) in case of the 2×4 g/kg dose, or other L-arginine doses (3×3 or 4×2.5 g/kg, 10%) were better for inducing AP. We could not detect any significant differences between the AP severity of male and female mice. Taken together, when setting up the L-arginine-induced AP model, there are several important factors that are worth consideration such as the dose and concentration of the administered L arginine-HCl solution and also the strain of mice.

Intraperitoneal administration of high doses of basic amino acids, such as L-lysine (L-Lys), L-arginine (L-Arg) or L-ornithine (L-Orn) induces acute pancreatitis in rodents. Although the exact mechanism of their action is not fully understood, the role of mitochondria has been implicated. We aimed to investigate the effects of basic amino acids, particularly L-Lys, on isolated pancreatic acinar cells. Isolated mouse or rat pancreatic acinar cells were treated with high concentrations (10–60 mM) of L-Lys, L-Arg or L-Orn. The morphology of acinar mitochondria was observed by electron microscopy. The function of mitochondria was assessed by mitochondrial membrane potential (∆Ψm) and cellular ATP level measurements. Changes in intracellular Ca 2+ concentration ([Ca 2+ ] i ), trypsin activity and cellular viabilities were also determined. Treatment of acinar cells with L-Lys caused mitochondrial swelling. L-Lys and L-Arg markedly decreased ∆Ψm after 6 h of treatment, whereas L-Orn had a less pronounced effect than L-Lys or L-Arg. Intracellular ATP levels were also reduced by basic amino acids. L-Lys did not alter [Ca 2+ ] i and did not induce early trypsinogen activation. Furthermore, L-Lys administration primarily caused acinar necrosis. Overall, L-Lys primarily damaged pancreatic acinar mitochondria and caused necrotic cell death without affecting the initial [Ca 2+ ] i .

It has been known for approximately 30 years that large doses of the semi-essential basic amino acid L-arginine induce severe pancreatic inflammation in rats. Recently, it has been demonstrated that L-arginine can also induce pancreatitis in mice. Moreover, other basic amino acids like L-ornithine and L-lysine can cause exocrine pancreatic damage without affecting the endocrine parenchyma and the ducts in rats. The utilization of these noninvasive severe basic amino acid-induced pancreatitis models is becoming increasingly popular and appreciated as these models nicely reproduce most laboratory and morphological features of human pancreatitis. Consequently, the investigation of basic amino acid-induced pancreatitis may offer us a better understanding of the pathogenesis and possible treatment options of the human disease.

Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that the mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene encoding a key enzyme in the M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of nonesterified cholesterol in lysosomes/autolysosomes, its depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The mechanisms mediating pancreatic cholesterol dyshomeostasis in Gnptab-/- and experimental models involve a disordered endolysosomal system, resulting in impaired cholesterol transport through lysosomes and blockage of autophagic flux. By contrast, in Gnptab-/- liver the endolysosomal system and cholesterol homeostasis were largely unaffected. Gnptab-/- mice developed spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis, particularly trypsinogen activation, the disease hallmark. The results reveal the essential role of the M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.

Background and aims The measurement of electrical capacitance in root–soil system (CR) is a useful method for estimating the root system size (RSS) in situ; however, CR–RSS regressions are often poor. It was hypothesized that this weak relationships could be partly due to the variable energy-loss rate, indicated by the dissipation factor (DF). Methods The values of CR and the associated DF were measured in six plant species grown in quasihydroponic pumice medium, arenosol and chernozem soil. The dielectric properties of the plant growth media were also recorded. A modified root–soil capacitance, CDF, was calculated from each CR/DF pair according to the formula CDF = CR·(DF/DFmean)α by estimating α with a standard nonlinear minimization of the sum of squared residuals for CDF–RSS regressions. Results The capacitive behavior of the medium improved (mean DF decreased) but fluctuated increasingly as the substrate became more complex. The mean DF values in plant–substrate systems were chiefly determined by the plant and were the most variable in chernozem soil. This strengthening substrate effect on CR measurements appeared as a decreasing trend in the R2 values obtained for the CR–RSS regressions. The regression slope was influenced by plant species and medium, while the y-intercept differed only between substrate types. The proposed use of CDF in place of CR could significantly improve the R2 of CDF–RSS regressions, particularly in chernozem soil (R2 increased by 0.07–0.31). Conclusions The application of CDF will provide more reliable and accurate RSS estimations and more efficient statistical comparisons. The findings are worth considering in future investigations using the root capacitance method.

Background The outcome of rheumatoid arthritis (RA) should be determined early. Rapid radiological progression (RRP) is > or = 5 units increase according to the van der Heijde-Sharp score within a year. The risk of RRP can be estimated by a matrix model using non-radiographic indicators, such as C-reactive protein (CRP), rheumatoid factor (RF) and swollen joint count (SJC). Patients and methods A non-interventional, cross-sectional, retrospective study was conducted in eleven Hungarian arthritis centres. We assessed RRP risk in biologic-naïve RA patients with the prevalence of high RRP risk as primary endpoint. RRP was calculated according to this matrix model. As a secondary endpoint, we compared RRP in methotrexate (MTX) responders vs non-responders. Results We analyzed data from 1356 patients. Mean CRP was 17.7 mg/l, RF was 139.3 IU/ml, mean 28-joint disease activity score (DAS28) was 5.00 and mean SJC was 6.56. Altogether 18.2% of patients had high risk (≥40%) of RRP. RA patients with high RRP risk of RRP ( n  = 247) had significantly lower age compared to those with RRP < 40% ( n  = 1109). MTX non-response (OR: 16.84), male gender (OR: 1.67), erosions at baseline (OR: 1.50) and ACPA seropositivity (OR: 2.18) were independent predictors of high-risk RRP. Male gender (OR: 5.20), ACPA seropositivity (OR: 4.67) and erosions (OR: 7.98) were independent predictors of high RRP risk in MTX responders. Conclusions In this Hungarian study, high RRP risk occurred in 18% of RA patients. These patients differ from others in various parameters. RRP was associated with non-response to MTX.

Implanted devices can provide objective assessment of physical activity over prolonged periods. The purpose of this study was to investigate the prognostic value of device-measured physical activity data compared with a six-minute walk test (6MWT) in predicting clinical response to cardiac resynchronization therapy (CRT). This was a single-center study in which patients who underwent CRT for standard indications were evaluated. Daily physical activity and 6MWT were evaluated postimplant at 1, 3, and 6 months. The primary end point was a composite of heart failure hospitalization, transplant, left ventricular (LV) assist device, and all-cause death at 3 years. Echocardiographic response, defined as a ≥10% improvement in LV ejection fraction (LVEF), at 6 months was the secondary end point. About 164 patients were included: average age was 67.3 ± 12.9 years, 77% were men, baseline LVEF was 25% ± 7%. Kaplan-Meier curves showed superior freedom from the composite end point in the highest tertile of both 6MWT and physical activity compared with the lowest tertile (41 vs 23 cases, respectively, p <0.001) for 6MWT and for activity (22 vs 7 cases, respectively, p = 0.001). In an adjusted multivariate model, independent predictors of improved clinical outcome included 1-month physical activity (hazard ratio 0.546, 95% confidence interval [CI] 0.361 to 0.824, p = 0.004) and 6MWT (hazard ratio 0.581, 95% CI 0.425 to 0.795, p = 0.001). An additional hour of higher activity at 1 month translated to a 1.38 times (95% CI 1.075 to 1.753, p = 0.011) higher likelihood of improved echocardiographic response. In conclusion, device-based measures of physical activity may be useful in predicting echocardiographic reverse remodeling and long-term clinical outcome in patients receiving CRT.

Background: In rheumatoid arthritis (RA), anti-citrullinated protein/peptide antibodies (ACPAs) are responsible for disease onset and progression, however, our knowledge is limited on ligand binding affinities of autoantibodies with different citrulline-peptide specificity. Methods: Citrulline-peptide-specific ACPA IgGs were affinity purified and tested by ELISA. Binding affinities of ACPA IgGs and serum antibodies were compared by surface plasmon resonance (SPR) analysis. Bifunctional nanoparticles harboring a multi-epitope citrulline-peptide and a complement-activating peptide were used to induce selective depletion of ACPA-producing B cells. Results: KD values of affinity-purified ACPA IgGs varied between 10−6 and 10−8 M and inversely correlated with disease activity. Based on their cross-reaction with citrulline-peptides, we designed a novel multi-epitope peptide, containing Cit-Gly and Ala-Cit motifs in two–two copies, separated with a short, neutral spacer. This peptide detected antibodies in RA sera with 66% sensitivity and 98% specificity in ELISA and was recognized by 90% of RA sera, while none of the healthy samples in SPR. When coupled to nanoparticles, the multi-epitope peptide specifically targeted and depleted ACPA-producing B cells ex vivo. Conclusions: The unique multi-epitope peptide designed based on ACPA cross-reactivity might be suitable to develop better diagnostics and novel therapies for RA.

C-reactive protein (CRP) is a traditional nonspecific marker of inflammation, with Crohn's disease (CD) being associated with a strong CRP response. Thus far, no clear cutoff values have been determined. The authors' aim was to investigate whether high-sensitivity (hs)-CRP is useful for the identification disease phenotype, active disease, and relapse during follow-up, using a classification based on the hs-CRP value at diagnosis.MethodsIn all, 260 well-characterized, unrelated, consecutive CD patients (male/female: 120/140; duration: 7.0 ± 6.1 years), with a complete clinical follow-up, were included. Hs-CRP, clinical activity according to the Harvey–Bradshaw Index, and clinical data (disease phenotype according to the Montreal Classification, extraintestinal manifestations, smoking habits, medical therapy, and surgical events) were prospectively collected between January 1, 2008 and June 1, 2010. Medical records prior to the prospective follow-up period were analyzed retrospectively.ResultsIn all, 32.3% of CD patients had normal hs-CRP at diagnosis. Elevated hs-CRP at diagnosis was associated with disease location (P = 0.002), noninflammatory disease behavior (P = 0.058), and a subsequent need for later azathioprine/biological therapy (P < 0.001 and P = 0.024), respectively. The accuracy of hs-CRP for identifying patients with active disease during prospective follow-up was good (area under the curve [AUC]: 0.82, cutoff: 10.7 mg/L). AUC was better in patients with an elevated hs-CRP at diagnosis (AUC: 0.92, cutoff: 10.3 mg/L). In Kaplan–Meier and Cox-regression analyses, hs-CRP was an independent predictor of 3- (P = 0.007) or 12-month (P = 0.001) clinical relapses for patients in remission who had elevated hs-CRP at diagnosis. In addition, perianal involvement (P = 0.01) was associated with the 12-month relapse frequency.ConclusionsOur data suggest that hs-CRP positivity at diagnosis is associated with disease location and behavior, and in patients who are hs-CRP positive at diagnosis, is an accurate marker of disease activity and a predictor of short- and medium-term clinical flare-ups during follow-up.

Hyponatremia portends a poor prognosis in patients with heart failure (HF). The aim of this study was to evaluate prognostic implication of hyponatremia on adverse events in patients with HF receiving cardiac resynchronization therapy (CRT). Additionally, the impact of improvement of hyponatremia after CRT device implantation was also evaluated. In this retrospective analysis, we included patients in whom a CRT device was implanted between April 2004 and April 2010 at our institution and had a baseline sodium level obtained within 72 hours of implantation. The patients were followed up for 3 years after implantation for subsequent primary composite end points, that is, hospitalization for HF, left ventricular assist device or heart transplant, and all-cause death. Sodium levels were followed up at 3 to 6 months after device implantation. Hyponatremia was defined as a serum sodium level of <135 mmol/L. A total of 402 patients were included (age 68.7 ± 12.3 years, women 20.9%). One hundred seventy-nine adverse events were noted in this period. In a Cox proportional hazards univariate model, hyponatremia (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.113 to 2.131, p = 0.009), creatinine (HR 1.267, 95% CI 1.156 to 1.389, p <0.001), and diuretics (HR 2.652, 95% CI 1.401 to 5.019, p = 0.003) were associated with occurrence of the composite end point. A total of 57.9% of patients with hyponatremia at baseline had the composite end point compared with 40.7% of those with normal sodium concentration (p = 0.004). Kaplan-Meier curve showed that hyponatremic patients fared worse. Also, patients in whom hyponatremia resolved after CRT device implantation had lower incidence of the composite end point compared with patients who had normal pre-CRT sodium levels but developed hyponatremia later. In conclusion, baseline hyponatremia is associated with poor prognosis in patients with HF. CRT can resolve hyponatremia in some patients after device implantation. Patients with postimplantation hyponatremia (either newly developed or persistent from baseline) have a poor clinical outcome. Post-CRT improvement of hyponatremia is associated with improved clinical outcomes.