Diversity of early afterdepolarizations in guinea pig myocytes: Spatial characteristics of intracellular Ca2+ concentration

Summary We classified early afterdepolarizations (EADs) into subgroups according to the spatial features of the intracellular Ca²⁺ concentration ([Ca²⁺]_i). Myocytes were enzymatically isolated from guinea pig ventricles. When fura-2 salt was applied through a whole cell patch pipette after the formation of a gigaohm seal, the membrane potential was measured using the current, clamp technique. When myocytes were loaded with fura-2 AM, the membrane potential was recorded with a conventional microelectrode technique. Spatio-temporal changes in fura-2 fluorescence and cell length were recorded simultaneously, using a digital TV system. EADs were induced after superfusion with potassium-free Tyrode solution. Irrespective of the fura-2 loading procedure, EADs could be classified into those with spatially synchronous fluorescence changes (n = 26 from eight hearts) and those with heterogeneous changes (n = 20 from three hearts). EADs with synchronous features took off from a higher membrane potential (–34mV) than EADs with heterogeneous features (–57 mV). These results suggest that EADs have at least two constituents.     

Clinical Effectiveness of Tolvaptan in Patients with Acute Decompensated Heart Failure and Renal Failure: Design and Rationale of the AQUAMARINE Study

Purpose

Over half of all admitted acute decompensated heart failure (ADHF) patients have renal failure. Although diuretics represent the mainstay of treatment strategy even in this population, there are unmet needs for safer and more effective treatment. Tolvaptan is a vasopressin-2 receptor antagonist, and we hypothesized that adding tolvaptan to standard diuretic therapy would be more effective in ADHF patients with renal function impairment.

Methods

The Answering question on tolvaptan’s efficacy for patients with acute decompensated heart failure and renal failure (AQUAMARINE) is a multicenter, randomized controlled clinical trial, which will enroll 220 patients from 17 hospitals in Japan. ADHF patients whose estimated glomerular filtration rate is above 15 and below 60 mL/min/1.72 m² will be randomly assigned within 6 h after admission to usual care with furosemide or tolvaptan add-on therapy. Primary endpoint is achieved urine output within 48 h. Secondary endpoints include dyspnea relief measured by 7-points Likert scale, incidence of worsening renal function, dose of furosemide used within 48 h, and changes of brain natriuretic peptide.

Conclusion

This study is the first multicenter study in Japan to evaluate clinical effectiveness of tolvaptan add-on therapy in ADHF patients with renal failure. The results of this study address the treatment strategy of this high-risk population (UMIN Clinical Trial Registry Number: UMIN000007109).     

Infliximab Was Found to Be Effective for Treating Immunosuppressive Drug-resistant Hepatitis due to Durvalumab

A 69-year-old man with stage III lung squamous cell carcinoma developed immune-related hepatitis following treatment with durvalumab, and was given high-dose corticosteroids and immunosuppressive drugs (mycophenolate mofetil, azathioprine, tacrolimus) but without demonstrating any improvement. Two cycles of infliximab (5 mg/kg) were then administered and thereafter the hepatitis improved. At the time of writing (9 months after the initiation of first course of durvalumab), the patient is alive without either any hepatitis symptoms nor any lung cancer progression. Infliximab may be effective for treating non-small cell lung cancer (NSCLC) patients who develop immunosuppressive drug-resistant immune-related hepatitis caused by durvalumab.     

Perfusion index as a possible predictor for postanesthetic shivering

Background

Postanesthetic shivering can be triggered by surgical stress and several aspects of anesthetic management and is frequently preceded by a decrease in peripheral blood flow due to thermoregulatory vasoconstriction. As perfusion index correlates with peripheral blood flow, we examined whether perioperative perfusion index, measured using pulse oximetry, might be correlated with postanesthetic shivering.

Methods

Twenty-eight patients presenting for elective abdominal surgery were enrolled. Core (esophagus) and peripheral (finger) temperatures and perfusion index were recorded in the perioperative periods. Correlations between perfusion index and peripheral temperature and core-to-peripheral temperature gradient were then explored. Plasma levels of epinephrine and norepinephrine were also measured. The extent of shivering was graded after emergence from anesthesia.

Results

Perfusion index declined before emergence from anesthesia in patients who then developed postanesthetic shivering. This coincided with the time at which the difference between core and peripheral temperature became dissociated and peripheral temperature declined. Perioperative perfusion index was correlated with peripheral temperature and peripheral-core temperature gradient. Perfusion index at closure of the peritoneum predicted postanesthetic shivering and was significantly correlated with the extent of shivering. Plasma levels of both epinephrine and norepinephrine were significantly elevated after shivering events.

Conclusions

Perfusion index was significantly lower in patients with postanesthetic shivering before emergence from anesthesia, indicating that measurement of perfusion index during and before the end of anesthesia might be a useful means of predicting postanesthetic shivering.     

Stratification of atopic dermatitis patients by patterns of response to proactive therapy with topical tacrolimus: low serum IgE levels and inadequately controlled disease activity at the start of treatment predict its failure

PurposeTopical calcineurin inhibitors (TCIs) are an important anti-inflammatory drug for treating atopic dermatitis (AD). However, those treatment responses are variable. In this study, we stratified AD patients by patterns of response to remission maintenance therapy (proactive therapy) with topical tacrolimus, a typical TCI. Thereafter, we explored patient features that predict the success or failure of proactive therapy using TCI (TCI proactive therapy).MethodsA single-arm open-label clinical study aimed to evaluate the efficacy of TCI proactive therapy was conducted in 31 patients with AD. Patients were treated with TCS to induce remission (remission-induction period) followed by daily TCI ointment (0.1% tacrolimus) application for 4 weeks (maintenance therapy period), and twice-weekly application for 12 weeks (proactive therapy period). Based on its results, treatment outcomes were correlated with the patients’ clinical and laboratory findings.ResultsOf the 31 patients enrolled in the study, 21 successfully completed maintenance therapy (TCI responders). Among them, 13 completed (proactive-completed group) and 8 failed proactive therapy (proactive-dropout group). At the beginning of maintenance therapy, the serum IgE level was significantly higher in the TCI responders than in those who failed maintenance therapy (p = 0.049). At the beginning of proactive therapy, the mean-SCORing Atopic Dermatitis (SCORAD) score was significantly different between the proactive-completed (11.7 ± 4.6) and proactive-dropout (16.6 ± 4.2) groups (p = 0.025). In proactive-dropout group patients, worsened disease activity correlated well with the elevation of serum lactate dehydrogenase (LDH) and Thymus and activation-regulated chemokine (TARC) levels and peripheral eosinophil count.ConclusionAD patients were stratified into three different response patterns to TCI proactive therapy. Patients with less involvement of IgE in the pathogenesis and inadequate remission induction by TCS may not be expected to respond well to TCI proactive therapy.

Key messages

• AD patients can be stratified into three types according to their pattern of responsiveness to TCI proactive therapy.
• The efficacy of TCI proactive therapy is lower in AD patients with lower serum IgE levels.
• TCI proactive therapy should be done after the achievement of adequate remission induction by TCS.

     

Pancreas-hanging maneuver in laparoscopic pancreaticoduodenectomy: a new technique for the safe resection of the pancreas head

Background  

Laparoscopic pancreaticoduodenectomy (PD) is challenging, and the performance of successful laparoscopic PD has been limited. The dissection of the pancreatic head from the right aspect of the portal vein and the superior mesenteric artery is one of the most difficult procedures in laparoscopic PD.     

Immune checkpoint inhibitor-induced diarrhea: Clinicopathological study of 11 patients

We reviewed the records of patients with immune checkpoint inhibitor (ICI)-induced diarrhea during 2015 to 2019. ICI included nivolumab and ipilimumab. There were 11 patients with ICI-induced diarrhea aged 46–81 years (median, 63 years). On colonoscopy, four patients appeared normal, whereas loss of vascularity, erythema, granularity, erosions or ulcerations apparently mimicking ulcerative colitis were found in seven patients. Those seven patients had acute inflammation, cryptitis, crypt abscess and apoptosis, suggestive of ICI-induced colitis. Five of the seven patients were treated with prednisolone, two of whom were resistant to prednisolone and required infliximab. In contrast, none of the four patients without ICI-induced colitis required further treatment. Our observations suggest that diversity exists in the clinical, endoscopic and histological severity of patients with ICI-induced diarrhea. Colonoscopy together with biopsy is inevitable for the diagnosis of ICI-induced colitis, which requires intensive treatment.     

The B-Mode Image-Guided Ultrasound Attenuation Parameter Accurately Detects Hepatic Steatosis in Chronic Liver Disease

The purpose of our study was to evaluate the diagnostic accuracy of the ultrasound-guided attenuation parameter (UGAP) for the detection of hepatic steatosis in comparison with the controlled attenuation parameter (CAP), using histopathology as the reference standard. We prospectively analyzed 163 consecutive chronic liver disease patients who underwent UGAP, CAP, computed tomography and a liver biopsy on the same day between April 2016 and July 2017. Radiofrequency signals corresponding to the images were compensated by the reference signal previously measured from the uniform phantom with known attenuation (0.44 dB/cm/MHz). The attenuation coefficient was calculated from the signals’ decay slope. The median attenuation coefficient values in patients with S0 (n?=?62), S1 (n?=?63), S2 (n?=?23) and S3 grade (n?=?15) were 0.485, 0.560, 0.660 and 0.720, respectively. Significant correlations were found between attenuation coefficient and percentage steatosis, CAP values and liver-to-spleen computed tomography attenuation ratio (p < 0.001). The areas under the receiver operating characteristic curve of UGAP for identifying ≥S1, ≥S2 and ≥S3 were 0.900, 0.953 and 0.959, respectively, which were significantly better than the results obtained with CAP for identifying ≥S2 and ≥S3. In conclusion, UGAP had high diagnostic accuracy for detecting hepatic steatosis in patients with chronic liver disease     

Calpain 10 gene polymorphisms are related, not to type 2 diabetes, but to increased serum cholesterol in Japanese

A G-to-A (UCSNP-43) polymorphism of the calpain-10 gene was significantly associated with type 2 diabetes (DM) in Mexican-American, and was postulated, together with a T-to-C (UCSNP-44) polymorphism, as a risk factor for DM. We examined the association of these genotypes with DM in Japanese. Eighty-one subjects with DM and 81 non-diabetic subjects (NGT) were recruited. The number of subjects with genotypes UCSNP-43 G/G, G/A and A/A were 76, 5 and 0, respectively, for the DM and NGT groups. The number of subjects with genotypes UCSNP-44 T/T, T/C and C/C were 66, 14 and 1 for the DM group and 64, 17 and 0 for the NGT group. There was no difference between the groups in terms of frequency of any genotype combinations. No association between the genotypes and DM was observed. We next examined the differences between the genotypes or genotype combinations in terms of the traits related to DM, obesity, hypertension and dyslipidemia. No differences were observed between the genotypes UCSNP43 G/G and G/A, between UCSNP-44 T/T and the others, or between the genotype combination UCSNP-43 G/G and UCSNP-44 T/T and the others, except that the individuals with the genotype combination had significantly increased serum cholesterol levels (212.6 +/- 34.3 vs. 198.5 +/- 29.9, P=0.020). The genotype combination might be a risk factor, not for DM, obesity and hypertension, but for increased serum cholesterol.     

New catalysts for the oxidative polymerization of 2,6-dimethylphenol, 2. Copper complexes containing the dicyanoethenedithiolatocuprate structure as the ligand

It was found that the reaction of 1,2-dicyano-1,2-ethenedithiolate, resp. of bis(1,2-dicyano-1,2-ethenedithiolato)cuprate(2-), with Cu²⁺ does not lead to copper bis(1,2-dicyano-1,2-ethenedithiolato)cuprate(2-) dihydrate ( 1a ) as described in the literature but to a reaction product which has a complex structure containing mainly Cu⁺. This compound as well as complexes with the same ligand, but with Cu⁺, Cu²⁺ or Cu³⁺ as the central atom, were synthesized and tested with and without added cuprous chloride as catalysts for the oxidative polymerization of 2,6-dimethylphenol. Included in this investigation were some copper complexes with the isomeric ligand 2,2-dicyano-1,1-ethenedithiolate.