Comparison of the effects of BDNF/TRKB signalling on metabolic biomarkers in the liver of sedentary and trained rats with normal and knockout BDNF genotypes.

Introduction: The effect of brain-derived neurotrophic factor (BDNF) on the modulation of metabolic processes in the liver is poorly understood. Therefore, the aim of this study was to investigate whether hepatic concentrations or activities of metabolic biomarkers depend on altered BDNF/TrkB content in the liver, resulting from different BDNF genotypes of rats. In addition, it was assessed whether 5-week moderate endurance training modifies the levels of BDNF/Trk-B signaling and studied hepatic markers. Methods: Experiments were performed on wild-type and heterozygous BDNF knockout (HET, SD-Bdnf) rats, which were divided into four groups: control with normal genotype (Bdnf+/+), control with BDNF knockout genotype (Bdnf+/-), trained with normal genotype (Bdnf+/+T) and trained with BDNF knockout genotype (Bdnf +/-T). BDNF/TrkB concentrations as well as selected metabolic biomarkers including lipids-total cholesterol (CHOL), low-density lipoprotein (LDL), triglycerides (TG); enzymes-alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP); hormones-insulin (INS) and leptin (LEPT) as well as interleukin-6 (IL-6) as regeneration indicator were measured directly in liver homogenates. Results and Discussion: The study showed that Bdnf+/- rats exhibited reduced BDNF/TrkB signaling (BDNF, p < 0.0001; Trk-B, p = 0.0005), altered lipid levels (CHOL, p < 0.0001; LDL, p < 0.0001; TG, p = 0.0006) and reduced hepatic ALAT (p = 0.0004) and GGT (p < 0.0001) activity, which may contribute to hepatic steatosis and obesity, as well as indicate impairment of specific metabolic pathways in the liver. Interestingly, endurance training did not alter hepatic BDNF and TrkB content, but improved ALAT (p = 0.0366) and ASAT (p = 0.0191) activities and increased hepatic IL-6 (p = 0.0422) levels in Bdnf +/- rats, suggesting enhanced liver regeneration in animals with BDNF allele loss.

Comparison between regular additional endobiliary radiofrequency ablation and photodynamic therapy in patients with advanced extrahepatic cholangiocarcinoma under systemic chemotherapy.

Background and aims: Extrahepatic cholangiocarcinoma (eCCA) remains a malignancy with a dismal prognosis. The first-line standard of care includes systemic chemotherapy (SC) and biliary drainage through stenting. Endobiliary ablative techniques, such as photodynamic therapy (ePDT) and radio-frequency ablation (eRFA), have demonstrated feasibility and favorable survival data. This study aimed to compare the oncologic outcome in patients treated with SC and concomitant eRFA or ePDT. Method: All patients with eCCA were evaluated for study inclusion. Sixty-three patients receiving a combination of SC and at least one endobiliary treatment were retrospectively compared. Results: Patients were stratified into three groups: SC + ePDT (n = 22), SC + eRFA (n = 28), and SC + ePDT + eRFA (n = 13). The median overall survival (OS) of the whole cohort was 14.2 months with no statistically significant difference between the three therapy groups but a trend to better survival for the group receiving ePDT as well as eRFA, during SC (ePDT + SC, 12.7 months; eRFA + SC, 13.8 months; ePDT + eRFA + SC, 20.2 months; p = 0.112). The multivariate Cox regression and subgroup analysis highlighted the beneficial effect of eRFA on OS. Overall, combined therapy was well tolerated. Only cholangitis occurred more often in the SC + eRFA group. Conclusion: Additional endobiliary ablative therapies in combination with SC were feasible. Both modalities, eRFA and ePDT, showed a similar benefit in terms of survival. Interestingly, patients receiving both regimes showed the best OS indicating a possible synergism between both ablative therapeutic techniques.

IL-6-Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with periductal inflammation and fibrosis. Genetic studies suggest inflammatory cytokines and IL-6-dependent activation of transcription factor STAT3 as pivotal steps in PSC pathogenesis. However, details of inflammatory regulation remain unclear. METHODS: We recruited 50 patients with PSC (36 with inflammatory bowel disease, 14 without inflammatory bowel disease), 12 patients with autoimmune hepatitis, and 36 healthy controls to measure cytokines in the serum, bile, and immune cell supernatant using bead-based immunoassays and flow cytometry and immunohistochemistry to analyze phosphorylation of STATs in immune cells. Finally, we analyzed cytokines and STAT3 phosphorylation of T cells in the presence of JAK1/2 inhibitors. RESULTS: In PSC, IL-6 specifically triggered phosphorylation of STAT3 in CD4 + T cells and lead to enhanced production of interferon (IFN) gamma and interleukin (IL)-17A. Phospho-STAT3-positive CD4 + T cells correlated with systemic inflammation (C-reactive protein serum levels). Combination of immunohistology and flow cytometry indicated that phospho-STAT3-positive cells were enriched in the peribiliary liver stroma and represented CD4 + T cells with prominent production of IFN gamma and IL-17A. JAK1/2 inhibitors blocked STAT3 phosphorylation and production of IFN gamma and IL-6, whereas IL-17A was apparently resistant to this inhibition. DISCUSSION: Our results demonstrate systemic and local activation of the IL-6/STAT3 pathway in PSC. Resistance of IL-17A to STAT3-targeted inhibition points to a more complex immune dysregulation beyond STAT3 activation.

Identification and characterization of a hepatic IL-13-producing ILC3-like population potentially involved in liver fibrosis.

BACKGROUND AND AIMS: Human innate lymphoid cells (ILCs) are critically involved in the modulation of homeostatic and inflammatory processes in various tissues. However, only little is known about the composition of the intrahepatic ILC pool and its potential role in chronic liver disease. Here, we performed a detailed characterization of intrahepatic ILCs in both healthy and fibrotic livers. APPROACH AND RESULTS: A total of 50 livers (nonfibrotic = 22, and fibrotic = 29) were analyzed and compared with colon and tonsil tissue (each N = 14) and peripheral blood (N = 32). Human intrahepatic ILCs were characterized ex vivo and on stimulation using flow cytometry and single-cell RNA sequencing. ILC differentiation and plasticity were analyzed by both bulk and clonal expansion experiments. Finally, the effects of ILC-derived cytokines on primary human HSteCs were studied. Unexpectedly, we found that an "unconventional" ILC3-like cell represented the major IL-13-producing liver ILC subset. IL-13 + ILC3-like cells were specifically enriched in the human liver, and increased frequencies of this cell type were found in fibrotic livers. ILC3-derived IL-13 production induced upregulation of proinflammatory genes in HSteCs, indicating a potential role in the regulation of hepatic fibrogenesis. Finally, we identified KLRG1-expressing ILC precursors as the potential progenitor of hepatic IL-13 + ILC3-like cells. CONCLUSIONS: We identified a formerly undescribed subset of IL-13-producing ILC3-like cells that is enriched in the human liver and may be involved in the modulation of chronic liver disease.

Do long-lasting effects of epidural polarization of afferent fibres depend on persistent sodium current?

Few attempts have so far been made to define the mechanisms underlying the hour-long effects of trans-spinal stimulation combined with epidural polarization. In the present study, we investigated the potential involvement of non-inactivating sodium channels in afferent fibres. To this end, riluzole, a blocker of these channels, was administered locally to the dorsal columns close to the site of the excitation of afferent nerve fibres by epidural stimulation in deeply anaesthetized rats in vivo. Riluzole did not prevent the induction of the polarization-evoked sustained increase in the excitability of dorsal column fibres but tended to weaken it. It likewise weakened but did not abolish the sustained polarization-evoked shortening of the refractory period of these fibres. These results lead to the conclusion that the persistent sodium current may contribute to the sustained post-polarization-evoked effects but is only partly involved in both the induction and the expression of these effects.

Influence of altered serum and muscle concentrations of BDNF on electrophysiological properties of spinal motoneurons in wild-type and BDNF-knockout rats.

The purpose of this study was to determine whether altered serum and/or muscle concentrations of brain-derived neurotrophic factor (BDNF) can modify the electrophysiological properties of spinal motoneurons (MNs). This study was conducted in wild-type and Bdnf heterozygous knockout rats (HET, SD-BDNF). Rats were divided into four groups: control, knockout, control trained, and knockout trained. The latter two groups underwent moderate-intensity endurance training to increase BDNF levels in serum and/or hindlimb muscles. BDNF and other neurotrophic factors (NFs), including glial cell-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF), and neurotrophin-4 (NT-4) were assessed in serum and three hindlimb muscles: the tibialis anterior (TA), medial gastrocnemius (MG), and soleus (Sol). The concentrations of tropomyosin kinase receptor B (Trk-B), interleukin-15 (IL-15), and myoglobin (MYO/MB) were also evaluated in these muscles. The electrophysiological properties of lumbar MNs were studied in vivo using whole-cell current-clamp recordings. Bdnf knockout rats had reduced levels of all studied NFs in serum but not in hindlimb muscles. Interestingly, decreased serum NF levels did not influence the electrophysiological properties of spinal MNs. Additionally, endurance training did not change the serum concentrations of any of the NFs tested but significantly increased BDNF and GDNF levels in the TA and MG muscles in both trained groups. Furthermore, the excitability of fast MNs was reduced in both groups of trained rats. Thus, changes in muscle (but not serum) concentrations of BDNF and GDNF may be critical factors that modify the excitability of spinal MNs after intense physical activity.

Single-cell RNA sequencing identifies a population of human liver-type ILC1s.

Group 1 innate lymphoid cells (ILCs) comprise a heterogeneous family of cytotoxic natural killer (NK) cells and ILC1s. We identify a population of "liver-type" ILC1s with transcriptional, phenotypic, and functional features distinct from those of conventional and liver-resident NK cells as well as from other previously described human ILC1 subsets. LT-ILC1s are CD49a+CD94+CD200R1+, express the transcription factor T-BET, and do not express the activating receptor NKp80 or the transcription factor EOMES. Similar to NK cells, liver-type ILC1s produce IFN-γ, TNF-α, and GM-CSF; however, liver-type ILC1s also produce IL-2 and lack perforin and granzyme-B. Liver-type ILC1s are expanded in cirrhotic liver tissues, and they can be produced from blood-derived ILC precursors in vitro in the presence of TGF-ß1 and liver sinusoidal endothelial cells. Cells with similar signature and function can also be found in tonsil and intestinal tissues. Collectively, our study identifies and classifies a population of human cross-tissue ILC1s.

Real-time use of artificial intelligence (CADEYE) in colorectal cancer surveillance of patients with Lynch syndrome-A randomized controlled pilot trial (CADLY).

BACKGROUND: Lynch syndrome (LS), an autosomal dominant disorder caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, represents the most common hereditary colorectal cancer (CRC) syndrome. Lynch syndrome patients are at high risk of CRC despite regular endoscopic surveillance. OBJECTIVE: Our aim was to investigate the diagnostic performance of artificial intelligence (AI)-assisted colonoscopy in comparison to High-Definition white-light endoscopy (HD-WLE) for the first time. METHODS: Patients ≥18 years with LS, with a pathogenic germline variant (MLH1, MHS2, MSH6), and at least one previous colonoscopy (interval 10-36 months) were eligible. Patients were stratified by previous CRC and affected MMR gene with a 1:1 allocation ratio (AI-assisted vs. HD white-light endoscopy) in this exploratory pilot trial. RESULTS: Between Dec-2021 and Dec-2022, 101 LS patients were randomised and 96 patients were finally analyzed after exclusion of 5 patients due to insufficient bowel preparation. In the HD-WLE arm, adenomas were detected in 12/46 patients compared to 18/50 in the AI arm (26.1% [95% CI 14.3-41.1] vs. 36.0% [22.9-50.8]; p = 0.379). The use of AI-assisted colonoscopy especially increased detection of flat adenomas (Paris classification 0-IIb) (examinations with detected flat adenomas: 3/46 [6.5%] vs. 10/50 [20%]; p = 0.07; numbers of detected flat adenomas: 4/20 vs. 17/30, p = 0.018). The median withdrawal time did not differ significantly between HD-WLE and AI (14 vs. 15 min; p = 0.170). CONCLUSION: We here present first data suggesting that real-time AI-assisted colonoscopy is a promising approach to optimize endoscopic surveillance in LS patients, in particular to improve the detection of flat adenomas.

Long-term modulation of the axonal refractory period.

The main question addressed in this study was whether the refractoriness of nerve fibres can be modulated by their depolarisation and, if so, whether depolarisation of nerve fibres evokes a long-term decrease in the duration of the refractory period as well as the previously demonstrated increase in their excitability. This was investigated on nerve fibres within the dorsal columns, dorsal roots and peripheral nerves in deeply anaesthetised rats in vivo. The results revealed major differences depending on the sites of fibre stimulation and polarisation. Firstly, the relative refractory period was found to be shorter in epidurally stimulated dorsal column fibres than in fibres stimulated at other sites. Secondly, the minimal effective interstimulus intervals reflecting the absolute refractory period were likewise shorter for nerve fibres within the dorsal columns even though action potentials evoked by the second of a pair of stimuli were similarly delayed with respect to the preceding action potentials at all the stimulation sites. Thirdly, the minimal interstimulus intervals were reduced by epidurally applied cathodal direct current polarisation but not at other stimulation sites. Consequently, higher proportions of dorsal column fibres could be excited at higher frequencies, especially following their depolarisation, at interstimulus intervals as short as 0.5-0.7 ms. The results demonstrate that epidural depolarisation results in long-lasting effects not only on the excitability but also on the refractoriness of dorsal column fibres. They also provide further evidence for specific features of afferent fibres traversing the dorsal columns previously linked to properties of their branching regions.

Management of esophageal perforations in infants by endoscopic vacuum therapy: a single center case series.

BACKGROUND: Endoscopic vacuum therapy (EVT) has become a standard treatment method for esophageal perforations in adults. However, experience with EVT in infants is scarce. In this retrospective case series, we report on four very young infants who were successfully treated with EVT for esophageal perforations of different etiology. METHODS: Four infants were diagnosed with esophageal perforations on day 7, 32, 35 and 159 of life, respectively. The youngest one was prematurely born in the 31st week of pregnancy weighing 980 g only. Three infants had perforations due to foreign body insertion (nasogastric tube or pulling through of percutaneous endoscopic gastrostomy (PEG) tube through the esophagus). One child had an anastomotic dehiscence after Foker's surgery for atresia. In three children EVT was applied as first-line therapy for perforation, in one child EVT was a rescue therapy due to persisting leakage after surgical closure involving thoracotomy. Depending on the esophageal diameter, either an open-pore drainage film or polyurethane sponge was attached to a single-lumen 8 Fr suction catheter, endoscopically (or fluoroscopically by wire-guidance) placed into the esophagus (intraluminal EVT) and supplied with continuous negative pressure (ranging between 75 and 150 mmHg). The EVT system was exchanged twice per week. RESULTS: Complete closure of the perforation/leakage could be achieved in all four infants (100%) after 22 days of continuous EVT (median value; range 7-39) and 4.5 EVT exchanges (median value; range 1-12). No serious adverse events occurred. CONCLUSIONS: EVT is an effective and safe addition to our therapeutic armamentarium in the management of esophageal perforations irrespective of its etiology. Here we prove the feasibility of EVT even in very young infants. The use of an extra thin vacuum open-pore drainage film is helpful to cope with the small esophageal diameter. EVT settings and exchange rates similar to those known from adult treatment were used.

Motor Unit Fatigability following Chronic Carnosine Supplementation in Aged Rats.

Studies suggest that carnosine (beta-alanyl-L-histidine) is effective in treating neuromuscular diseases associated with aging, but there is still a need to clarify its role in motor units (MUs) function during aging. In this study, 40 male Wistar rats aged 15 months were randomly assigned to a control or to two experimental groups in which 0.1% carnosine supplementation was performed for 10 or 34 weeks. After 34 weeks, we examined fast fatigable (FF), fast fatigue-resistant (FR) and slow (S) MUs' force properties and fatigability, as well as antioxidant potential, advanced glycation end products, activity of enzymes, and histidyl dipeptides content in the medial gastrocnemius muscle. Short- and long-term carnosine supplementation maintained the force of FF MUs at a higher level during its rapid decline seen from the initial 10 to 70 s of the fatigue test. In FF, especially long-term, and in FR MUs, especially short-term, carnosine supplementation resulted in less rapid force decline during the initial 70 s of the second fatigue protocol. Carnosine supplementation did not change muscle antioxidant potential and mortality rate (~35% in all groups), nor muscle mass with aging. Moreover, instead of the expected increase, a decrease in histidyl dipeptides by ~30% in the red portion of medial gastrocnemius muscle after long-term supplementation was found. After chronic carnosine supplementation, the specific changes in fatigue resistance were observed in FF and FR units, but not in S MU types that were not accompanied by an improvement of antioxidant potential and activity of glycolytic or oxidative enzymes in aged rats. These observations indicate that carnosine supplementation during aging may generate different physiological adaptations which should be considered as an important factor when planning treatment strategies.

Preoperative TIPS prevents the development of postoperative acute-on-chronic liver failure in patients with high CLIF-C AD score.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a syndrome associated with organ failure and high short-term mortality. Recently, the role of surgery as a precipitating event for ACLF has been characterised. However, the impact of preoperative transjugular intrahepatic portosystemic shunt (TIPS) placement on ACLF development in patients with cirrhosis undergoing surgery has not been investigated yet. METHODS: A total of 926 patients (363 with cirrhosis undergoing surgery and 563 patients with TIPS) were screened. Forty-five patients with preoperative TIPS (TIPS group) were 1:1 propensity matched to patients without preoperative TIPS (no-TIPS group). The primary endpoint was the development of ACLF within 28 and 90 days after surgery. The secondary endpoint was 1-year mortality. Results were confirmed by a differently 1:2 matched cohort (n = 176). RESULTS: Patients in the no-TIPS group had significantly higher rates of ACLF within 28 days (29 vs. 9%; p = 0.016) and 90 days (33 vs. 13%; p = 0.020) after surgery as well as significantly higher 1-year mortality (38 vs. 18%; p = 0.023) compared with those in the TIPS group. Surgery without preoperative TIPS and Chronic Liver Failure Consortium-Acute Decompensation (CLIF-C AD) score were independent predictors for 28- and 90-day ACLF development and 1-year mortality after surgery, especially in patients undergoing visceral surgery. In the no-TIPS group, a CLIF-C AD score of >45 could be identified as cut-off for patients at risk for postoperative ACLF development benefiting from TIPS. CONCLUSIONS: This study suggests that preoperative TIPS may result in lower rates of postoperative ACLF development especially in patients undergoing visceral surgery and with a CLIF-C AD score above 45. LAY SUMMARY: Acute-on-chronic liver failure (ACLF) is a syndrome that is associated with high short-term mortality. Surgical procedures are a known precipitating event for ACLF. This study investigates the role of preoperative insertion of a transjugular intrahepatic portosystemic shunt (TIPS) on postoperative mortality and ACLF development. Patients with TIPS insertion before a surgical procedure exhibit improved postoperative survival and lower rates of postoperative ACLF, especially in patients undergoing visceral surgery and with a high CLIF-C AD prognostic score. Thus, this study suggests preoperative TIPS insertion in those high-risk patients.

Impact of regular additional endobiliary radiofrequency ablation on survival of patients with advanced extrahepatic cholangiocarcinoma under systemic chemotherapy.

Prognosis of patients with advanced extrahepatic cholangiocarcinoma (eCCA) is poor. The current standard first-line treatment is systemic chemotherapy (CT) with gemcitabine and a platinum derivate. Additionally, endobiliary radiofrequency ablation (eRFA) can be applied to treat biliary obstructions. This study aimed to evaluate the additional benefit of scheduled regular eRFA in a real-life patient cohort with advanced extrahepatic cholangiocarcinoma under standard systemic CT. All patients with irresectable eCCA treated at University Hospital Bonn between 2010 and 2020 were eligible for inclusion. Patients were stratified according to treatment: standard CT (n = 26) vs. combination of eRFA with standard CT (n = 40). Overall survival (OS), progression free survival (PFS), feasibility and toxicity were retrospectively analyzed using univariate and multivariate approaches. Combined eRFA and CT resulted in significantly longer median OS (17.3 vs. 8.6 months, p = 0.004) and PFS (12.9 vs. 5.7 months, p = 0.045) compared to the CT only group. While groups did not differ regarding age, sex, tumor stage and chemotherapy treatment regimen, mean MELD was even higher (10.1 vs. 6.7, p = 0.015) in the eRFA + CT group. The survival benefit of concomitant eRFA was more evident in the subgroup with locally advanced tumors. Severe hematological toxicities (CTCAE grades 3 - 5) did not differ significantly between the groups. However, therapy-related cholangitis occurred more often in the combined treatment group (p = 0.031). Combination of eRFA and systemic CT was feasible, well-tolerated and could significantly prolong survival compared to standard CT alone. Thus, eRFA should be considered during therapeutic decision making in advanced eCCA.

TIPS for the management of stomal variceal bleeding due to cirrhotic and non-cirrhotic portal hypertension.

BACKGROUND: Portal hypertension (PH) is associated with the development of esophageal or gastric varices, which can cause bleedings with high mortality. Varices can also manifest at sites of stomata. These parastomal varices can cause recurrent variceal bleedings (VB) despite local therapies. We present a case series of parastomal VB due to PH that were managed with implantation of transjugular intrahepatic portosystemic shunt (TIPS). METHODS: We retrospectively included all patients (pt) from 2 tertiary medical centers with parastomal VB between January 2014 and February 2020 who underwent the TIPS procedure. RESULTS: Nine pt were included. Seven pt had liver cirrhosis, mostly alcohol-related. Two pt had non-cirrhotic PH due to porto-sinusoidal vascular disease (PSD). Four pt had a colostomy, 1 an ileostomy, and 4 an ileal conduit. Malignancy was the leading cause of stoma surgery. All 9 pt suffered from recurrent parastomal VB despite non-selective beta-blocker and/or local therapy (e.g., compression, coagulation, suture ligation, or surgical stoma revision). All pt received TIPS implantation. In 7 pt, TIPS implantation led to sustainable hemostasis. Two pt suffered a bleeding relapse that was attributable to TIPS dysfunction. TIPS revision with coil embolization of the varices terminated the VB sustainably in both pt. CONCLUSIONS: In pt presenting with recurrent stomal bleedings, parastomal varices as a rare complication of PH must be taken into consideration as an underlying cause. In our case series, we managed to sustainably cease parastomal VB by TIPS implantation with or without coil embolization of the ectopic varices.

Management of post-operative pancreatic fistulas following Longmire-Traverso pylorus-preserving pancreatoduodenectomy by endoscopic vacuum-assisted closure therapy.

BACKGROUND: Pylorus-preserving pancreatoduodenectomy (PPPD) with pancreatogastrostomy is a standard surgical procedure for pancreatic head tumors, duodenal tumors and distal cholangiocarcinomas. Post-operative pancreatic fistulas (POPF) are a major complication causing relevant morbidity and mortality. Endoscopic vacuum therapy (EVT) has become a widely used method for the treatment of intestinal perforations and leakages. Here we report on a pilot single center series of 8 POPF cases specifically caused by dehiscences of the pancreatogastric anastomosis (PGD), successfully managed by EVT. METHODS: We included all patients with PGD after PPPD, who were treated with EVT between 07/2017 and 08/2020. For EVT a vacuum drainage film (EVT film) or open-pore polyurethane foam sponge (EVT sponge) was fixed to a 14Fr or 16Fr suction catheter and placed endoscopically within the PGD for intracavitary EVT with continuous suction between - 100 and - 150 mmHg. The EVT film/sponge was exchanged twice per week. EVT was discontinued when the PGD was sufficiently healed. RESULTS: PGD closure was achieved in 7 of 8 patients after a mean EVT time of 16 days (range 8-38) and 3 EVT film/sponge exchanges (range 1-9). One patient died on day 18 after PPPD from acute hemorrhagic shock, unlikely related to EVT, before effectiveness of EVT could be fully achieved. There were no adverse events directly attributable to EVT. CONCLUSIONS: EVT could be an effective and safe addition to our therapeutic armamentarium in the management of POPF with PGD. Unless prospective comparative studies are available, EVT as minimally invasive therapeutic alternative should be considered individually by an interdisciplinary team involving endoscopists, surgeons and radiologists.

Motor Unit Force Potentiation and Calcium Handling Protein Concentration in Rat Fast Muscle After Resistance Training.

Post-tetanic potentiation (PTP) of force depends on intramuscular Ca2+ levels and sensitivity and may be affected by fatigue. The aim of this study was to determine the ability of isolated fast fatigue-resistant (FR) and fast-fatigable (FF) motor units (MUs) to potentiate force evoked with single and 40-Hz electrical stimulation after 5 weeks of voluntary weight-lifting training. Tetanic contractions evoked by gradually increasing (10-150 Hz) stimulation frequency served as conditioning stimulation. Additionally, the concentration of myosin light chain kinase and proteins engaged in calcium handling was measured in rat fast medial gastrocnemius muscle. After the training, the potentiation of twitch force and peak rate of force development was increased in FF but not FR MUs. Force potentiation of 40-Hz tetanic contractions was increased in both fast MU types. After the training, the twitch duration of FR MUs was decreased, and FF MUs were less prone to high-frequency fatigue during conditioning stimulation. Muscle concentration of triadin was increased, whereas concentrations of ryanodine receptor 1, junctin, FKBP12, sarcoplasmic reticulum calcium ATPase 1, parvalbumin, myosin light chain kinase, and actomyosin adenosine triphosphatase content were not modified. After short-term resistance training, the twitch contraction time and twitch:tetanus force ratio of FR MUs are decreased, and PTP ability is not changed. However, PTP capacity is increased in response to submaximal activation. In FF MUs increase in PTP ability coexists with lesser fatigability. Further work is required to find out if the increase in triadin concentration has any impact on the observed contractile response.

Transpapillary tissue sampling of biliary strictures: balloon dilatation prior to forceps biopsy improves sensitivity and accuracy.

The early and definitive diagnosis of malignant bile duct stenoses is essential for a timely and adequate therapy. However, tissue sampling with transpapillary brush cytology (BC) or forceps biopsy (FB) remains challenging. With this study, we aimed to compare the effectiveness and safety of different tissue sampling modalities (BC, FB without/after previous balloon dilatation). Standardized database research identified all patients, who underwent endoscopic retrograde cholangiography with BC and/or FB for indeterminate bile duct stenosis between January 2010 and April 2018 and with a definitive diagnosis. 218 patients were enrolled (149 cases with malignant and 69 with benign disease). FB had a significant higher sensitivity than BC (43% vs. 16%, p < 0.01). Prior balloon dilatation of the stenosis improved the sensitivity of FB from 41 to 71% (p = 0.03), the NPV from 36 to 81% (p < 0.01) and the accuracy from 55 to 87% (p < 0.01). The complication rates did not differ significantly between the modalities. In our center FB turned out to be the diagnostically more effective procedure. Balloon dilatation of the stenosis before FB had a significant diagnostic benefit and was not associated with a higher complication rate.