Successful defibrotide treatment of a patient with veno-occlusive disease after living-donor liver transplantation: A case report

Rationale:Veno-occlusive disease (VOD) is characterized by painful hepatomegaly, ascites, weight gain, and jaundice with nonthrombotic, fibrous obliteration of the centrilobular hepatic veins. VOD after liver transplantation is a rare complication, with an incidence of approximately 2%; however, it can be life-threatening in severe cases. The precise etiology and mechanism of VOD after liver transplantation remains unclear. Acute cellular rejection, antibody-mediated rejection, and treatment with tacrolimus or azathioprine may be associated with the development of VOD after liver transplantation. Additionally, the optimal treatment of VOD after liver transplantation has not yet been established and focuses on supportive care. Defibrotide is an anti-ischemic and antithrombotic drug with no systemic anticoagulant effects. Moreover, only a few reports have investigated the use of defibrotide for VOD after liver transplantation, which has shown promising results.Patient concerns:A 39-year-old woman with primary biliary cholangitis underwent living-donor liver transplantation at our center. She experienced right upper quadrant pain with increased ascites, pleural effusion, and weight gain on postoperative day 14.Diagnoses:Imaging and pathological tests showed no evidence of rejection or vessel complications. VOD was diagnosed clinically based on the findings of weight gain, ascites, jaundice, and pathological biopsy.Interventions:Defibrotid, 25 mg/kg/day, was administered intravenously for 21 days.Outcomes:She showed complete clinical resolution of the VOD.Lessons:Herein, we report a case of successful defibrotide treatment of VOD after living-donor liver transplantation.     

Strandwise translocation of a DNA glycosylase on undamaged DNA

Base excision repair of genotoxic nucleobase lesions in the genome is critically dependent upon the ability of DNA glycosylases to locate rare sites of damage embedded in a vast excess of undamaged DNA, using only thermal energy to fuel the search process. Considerable interest surrounds the question of how DNA glycosylases translocate efficiently along DNA while maintaining their vigilance for target damaged sites. Here, we report the observation of strandwise translocation of 8-oxoguanine DNA glycosylase, MutM, along undamaged DNA. In these complexes, the protein is observed to translocate by one nucleotide on one strand while remaining untranslocated on the complementary strand. We further report that alterations of single base-pairs or a single amino acid substitution (R112A) can induce strandwise translocation. Molecular dynamics simulations confirm that MutM can translocate along DNA in a strandwise fashion. These observations reveal a previously unobserved mode of movement for a DNA-binding protein along the surface of DNA.     

A novel diaphragm-to-housing junction adhesive method: alumina ball milling

An alumina ball milling method was applied to enhance the adhesiveness and smoothness of the diaphragm-to-housing (D-H) junction. The impact produced by the three rotating alumina balls along the meshed junction made the surface of the junction uniform and smooth. The quality of the D-H junction was evaluated by various methods, such as inspection using an optical microscope and a scanning electron microscope, smoothness examination by an atomic force microscope, and measurement of the tensile strength. All the evaluations revealed marked improvements, and the platelet adhesion test revealed that the alumina ball milling method plays an important role in the blood compatibility enhancement of the D-H junction.Part of this paper was presented at the poster session of the ASAIO (2002) meeting     

Nitric oxide regulation of myocardial contractility and calcium cycling: independent impact of neuronal and endothelial nitric oxide synthases

The mechanisms by which nitric oxide (NO) influences myocardial Ca2+ cycling remain controversial. Because NO synthases (NOS) have specific spatial localization in cardiac myocytes, we hypothesized that neuronal NOS (NOS1) found in cardiac sarcoplasmic reticulum (SR) preferentially regulates SR Ca2+ release and reuptake resulting in potentiation of the cardiac force-frequency response (FFR). Transesophageal pacing (660 to 840 bpm) in intact C57Bl/6 mice (WT) stimulated both contractility (dP/dtmax normalized to end-diastolic volume; dP/dt-EDV) by 51+/-5% (P<0.001) and lusitropy (tau; tau) by 20.3+/-2.0% (P<0.05). These responses were markedly attenuated in mice lacking NOS1 (NOS1-/-) (15+/-2% increase in dP/dt-EDV; P<0.001 versus WT; and no change in tau; P<0.01 versus WT). Isolated myocytes from NOS1-/- (approximately 2 months of age) also exhibited suppressed frequency-dependent sarcomere shortening and Ca2+ transients ([Ca2+]i) compared with WT. SR Ca2+ stores, a primary determinant of the FFR, increased at higher frequencies in WT (caffeine-induced [Ca2+]i at 4 Hz increased 107+/-23% above 1 Hz response) but not in NOS1-/- (13+/-26%; P<0.01 versus WT). In contrast, mice lacking NOS3 (NOS3-/-) had preserved FFR in vivo, as well as in isolated myocytes with parallel increases in sarcomere shortening, [Ca2+]i, and SR Ca2+ stores. NOS1-/- had increased SR Ca2+ ATPase and decreased phospholamban protein abundance, suggesting compensatory increases in SR reuptake mechanisms. Together these data demonstrate that NOS1 selectively regulates the cardiac FFR via influences over SR Ca2+ cycling. Thus, there is NOS isoform-specific regulation of different facets of rate-dependent excitation-contraction coupling; inactivation of NOS1 has the potential to contribute to the pathophysiology of states characterized by diminished frequency-dependent inotropic responses.     

In Vitro and In Vivo Studies of the Antiparasitic Activity of Sterol 14α-Demethylase (CYP51) Inhibitor VNI against Drug-Resistant Strains of Trypanosoma cruzi

Chagas disease affects more than 10 million people worldwide, and yet, as it has historically been known as a disease of the poor, it remains highly neglected. Two currently available drugs exhibit severe toxicity and low effectiveness, especially in the chronic phase, while new drug discovery has been halted for years as a result of a lack of interest from pharmaceutical companies. Although attempts to repurpose the antifungal drugs posaconazole and ravuconazole (inhibitors of fungal sterol 14α-demethylase [CYP51]) are finally in progress, development of cheaper and more efficient, preferably Trypanosoma cruzi-specific, chemotherapies would be highly advantageous. We have recently reported that the experimental T. cruzi CYP51 inhibitor VNI cures with 100% survival and 100% parasitological clearance both acute and chronic murine infections with the Tulahuen strain of T. cruzi. In this work, we further explored the potential of VNI by assaying nitro-derivative-resistant T. cruzi strains, Y and Colombiana, in highly stringent protocols of acute infection. The data show high antiparasitic efficacy of VNI and its derivative (VNI/VNF) against both forms of T. cruzi that are relevant for mammalian host infection (bloodstream and amastigotes), with the in vivo potency, at 25 mg/kg twice a day (b.i.d.), similar to that of benznidazole (100 mg/kg/day). Transmission electron microscopy and reverse mutation tests were performed to explore cellular ultrastructural and mutagenic aspects of VNI, respectively. No mutagenic potential could be seen by the Ames test at up to 3.5 μM, and the main ultrastructural damage induced by VNI in T. cruzi was related to Golgi apparatus and endoplasmic reticulum organization, with membrane blebs presenting an autophagic phenotype. Thus, these preliminary studies confirm VNI as a very promising trypanocidal drug candidate for Chagas disease therapy.     

Differentiation of pseudodyskinesis of inferior left ventricular wall from inferior myocardial infarction by assessment of regional myocardial strain using two-dimensional speckle tracking echocardiography

Purpose

To differentiate pseudodyskinesis (PD) of the inferior left ventricular (LV) wall from inferior myocardial infarction (IMI) noninvasively, we performed focal site evaluation using two-dimensional speckle tracking transthoracic echocardiography (TTE).

Materials and methods

Speckle tracking TTE was carried out in 57 patients, with 19 subjects in each of three groups (Group A, suspected PD; Group B, LV IMI; and Group C, controls). Inferior wall PD was defined as follows: compression of the inferior LV wall by the diaphragm in the LV short axis view with a normal electrocardiogram and no evidence of previous ischemic events.

Results

Respective values in Groups A-C for LV ejection fraction (EF) were 63.6 ± 4.2%, 52.3 ± 7.6%, and 61.5 ± 3.8%, for inferior wall speckle tracking focal site evaluation peak radial strain of 30.0 ± 14.3%, 7.5 ± 7.1%, and 42.1 ± 22.9%, for peak circumferential strain of 23.1 ± 6.0%, 16.8 ± 8.4%, and 22.7 ± 7.1%, and for longitudinal strain in the mid-inferior wall of 18.4 ± 3.4%, 11.4 ± 4.0% and 15.8 ± 5.9%. LVEF values were significantly lower in Group B than Groups A and C (P < 0.001), as were those of radial, circumferential, and longitudinal strains (P < 0.05). In receiver-operating characteristic analysis the optimal cut-off values with corresponding sensitivities and specificities for differentiation of PD from IMI were > 19% with 84.2% and 94.7% for radial, > 15% with 89.4% and 52.6% for circumferential, and > 15% with 73.6% and 100% for longitudinal strain, respectively.

Conclusions

Determination of regional strain from speckle tracking TTE, especially radial and longitudinal strains, can provide focal and quantitative noninvasive evaluation for distinguishing PD of the inferior wall from IMI.     

Igalan from Inula helenium (L.) suppresses the atopic dermatitis-like response in stimulated HaCaT keratinocytes via JAK/STAT3 signaling

Inflammation Research - This study aimed to evaluate the protective effect of igalan, a sesquiterpene lactone isolated from Inula helenium (L.), on inhibiting inflammation, regulating the epidermal...     

What Factors Predict Long-Term Survival and Valve Durability in Patients With Atrioventricular Valve Regurgitation in Single-Ventricle Physiology?

Although significant atrioventricular valve regurgitation (AVVR) is well known for its association with increased morbidity and mortality in patients with single-ventricle physiology, there is a lack of consensus in management of AVVR. The purpose of this study was to analyze the clinical outcomes in patients receiving AVV repair or replacement. From 2001 to 2010, a total of 33 patients (25 male and 8 female) with more than moderate-degree AVVR among 160 patients who underwent staged single-ventricle palliation were included. The median follow-up duration was 6.0 years (range 0.1–14.1). Valve repair (n = 27) or valve replacement (n = 6) was performed at the initial surgery. There were six late mortalities (18.18 %): five in the repair group and one in the replacement group and seven morbidities. Among patients with valve repair, 11 were required to undergo redo-valve operations (valve repair n = 6, valve replacement n = 5) due to deteriorated valve function. Initial shunt procedure (p = 0.04) and arrhythmia (p = 0.01) were risk factors for survival. Freedom from reoperation in the valve replacement group was higher than that in the valve repair group (67.0 ± 9.7 and 44.6 ± 11.2 % at 5 and 6 years, respectively, p = 0.03). Need for early repair (p = 0.02), presence of mitral- or tricuspid-dominant AVV (p = 0.005), and male sex (p = 0.04) were risk factors for valve durability. Early valve regurgitation affects valve durability. Thus, successful repair in the early stage may improve later outcomes. Therefore, aggressive valve surgery was required and AVV replacement might be one of the options for selected patients.