The combination of oral-recombinant methioninase and azacitidine arrests a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft mouse model

Cancer Chemotherapy and Pharmacology - Cancers are methionine (MET) and methylation addicted, causing them to be highly sensitive to MET restriction. The present study determined the efficacy of...     

Confirmation of Age-dependence in the Leakage of Contrast Medium around the Cortical Veins into Cerebrospinal Fluid after Intravenous Administration of Gadolinium-based Contrast Agent

Purpose:It has been reported previously that intravenously administered gadolinium-based contrast agent (GBCA) leaks into the subarachnoid space around the cortical veins at 4 h after injection in all old people over 37 years, but not in younger people up to 37 years of age in 3D-real IR images. The purpose of this study was to investigate whether there was a strict threshold of 37 years of age for the leakage of the GBCA into the subarachnoid space.Methods:The subjects included 190 patients, that were scanned for 3D-real IR images at 4 hours after intravenous injection of GBCA as a diagnostic test for endolymphatic hydrops. The patient’s age ranged from 14 to 81 years. Two experienced neuroradiologists evaluated the images to determine whether the GBCA leakage around the cortical veins was positive or negative. Any discrepancies between the two observers were discussed and a consensus was obtained.A Mann–Whitney U test and receiver operating characteristic (ROC) curve analysis were used to compare the positive and the negative group and to set the age cut-off value for the prediction of GBCA leakage.Results:The GBCA leakage around the cortical veins was negative in 35 patients and positive in 155 patients. The average age was 33 ± 11 years in the negative group, and 55 ± 12 years in the positive group (P < 0.01). In the ROC analysis for the age and leakage of the GBCA, an area under the curve was 0.905 and the cut-off age was 37.317 years (sensitivity of 0.942 and specificity of 0.771).Conclusion:Intravenously administered GBCA leaks into the subarachnoid space around the cortical veins in most patients over 37 years of age. However, it should be noted that it can be found occasionally in patients under 37 years of age.     

Feasibility and mid- to long-term results of endovascular treatment for portal vein thrombosis after living-donor liver transplantation

PURPOSEWe aimed to evaluate mid- to long-term results of endovascular treatment for portal vein thrombosis (PVT) after living-donor liver transplantation (LDLT).METHODSThirty cases (14 males, 16 females; age range, 0.67–65 years) who underwent endovascular treatment including thrombolysis, angioplasty, stent placement, and/or collateral embolization for PVT after LDLT from 2001 to 2017 were retrospectively reviewed. Clinical and procedural data were collected and analyzed regarding the patency of the PVT site at the last follow-up date (PVT-free persistency) using Log-rank test. Results were considered statistically significant at p < 0.05.RESULTSMedian follow-up was 120 months. The technical success rate was 80% (n=24). Patency rates at 1 week and 1, 3, 6, 12, 36, and 60 months were 73%, 59%, 55%, 51%, 51%, 51%, and 51% for primary patency and 80%, 70%, 66%, 66%, 66%, 61%, and 61% for assisted patency after secondary endovascular treatment. PVT-free persistency rates regarding the subgroups were as follows: children under 12 years vs. adults, 50% vs. 68% (p = 0.42); acute vs. nonacute, 76% vs. 46% (p = 0.10); localized vs. extensive, 90% vs. 50% (p = 0.035); transileocolic approach vs. percutaneous-transhepatic approach, 71% vs. 54% (p = 0.39); and thrombolysis-based treatment vs. non-thrombolysis-based treatment, 71% vs. 44% (p = 0.12), respectively. Among technically successful cases, PVT-free persistency rate was 94% for those with hepatopetal flow in the peripheral portal vein vs. 17% for those without hepatopetal flow (p < 0.001). The only major complication occurring was pleural hemorrhage (n=1). Minor complications (i.e., fever) occurred in 18 patients (60%).CONCLUSIONIn conclusion, mid- to long-term portal patency following endovascular treatment was approximately 50%–60% in PVT patients after LDLT. PVT site patency over three months after the first endovascular treatment, localized PVT, and hepatopetal flow in the peripheral portal vein were identified as key prognostic factors for mid- to long-term portal patency.

Portal vein thrombosis (PVT) is a vascular complication of living-donor liver transplantation (LDLT), with an estimated incidence of up to 4% (1, 2). The risk of vascular complications, including PVT, is higher in LDLT compared with conventional deceased-donor liver transplantation, because of the smaller vessels, insufficient vessel length for reconstruction, neointimal proliferation, and higher risk of twisting and kinking of the vascular pedicle (3) due to smaller graft size than in deceased-donor liver transplantation. PVT after LDLT can lead to graft failure and the need for retransplantation or death (2), making immediate treatment crucial.Endovascular-based treatment is one option for treating PVT. The utility of target-focused thrombolysis, balloon angioplasty, and stent placement to restore portal flow has been reported previously (4–10). However, the efficacy of endovascular treatment after LDLT has only been presented in some case reports (11, 12) and the mid- to long-term outcomes remain unclear.The purpose of this study was to evaluate the technical success, feasibility, and mid- to long-term results of endovascular treatment for PVT after LDLT in our institution.     

Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension.

Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension. This study evaluated the antihypertensive efficacy, safety and tolerability of aliskiren in Japanese patients with hypertension. Forty hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95-110 mmHg were randomized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75, 150 or 300 mg or placebo. Aliskiren produced significant, dose-dependent reductions in mean sitting diastolic blood pressure (p<0.0005 vs. placebo for each dose) and mean sitting systolic blood pressure (p<0.001 vs. placebo for each dose). The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure were 5.7/4.0, 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75, 150 and 300 mg groups, respectively. After 8 weeks' treatment, 27.8%, 47.8%, 48.2% and 63.7% of patients in the placebo and aliskiren 75, 150 and 300 mg groups, respectively, achieved a successful treatment response (diastolic blood pressure <90 mmHg and/or reduced by > or =10 mmHg from baseline; p<0.005 vs. placebo for each dose). Aliskiren treatment was well tolerated, with the incidence of adverse events reported in the active treatment groups (53-55%) being similar to that in the placebo group (50%). This study, which is the first to assess the antihypertensive efficacy and safety of aliskiren in Japanese patients with hypertension, demonstrates that the once-daily oral renin inhibitor aliskiren provides significant, dose-dependent reductions in blood pressure with placebo-like tolerability.     

Severe Graves' ophthalmopathy accompanied by myasthenia gravis]

We report a 53-year-old woman with severe Graves' ophthalmopathy accompanied by uncontrolled myasthenia gravis. She presented remarkable exophthalmos, chemosis, and restriction of eye movement. Despite plasma exchange, steroid pulse therapy, local injection of steroid, and irradiation, ocular symptoms did not ameliorate. Since optic neuropathy was seen, orbital decompression surgery was performed in the left eye. Bilateral chemosis was improved after the surgery. Five years after surgery, there was no ocular palsy in the operated left eye, but in the contralateral eye. For the good prognosis of the eye movement, orbital decompression might be recommended in the severe Graves' ophthalmopathy accompanied by the optic neuropathy and/or ophthalmoplegia with proptosis.     

Cibenzoline-induced respiratory muscular paralysis in a hemodialysis patient

A 69-year-old man was admitted to our kidney center with endstage renal failure. We started intermittent peritoneal dialysis immediately because of severe azotemia, hyperkalemia, and metabolic acidosis. Two weeks after admission, he developed uremic pericarditis with frequent ventricular premature contractions and supraventricular premature contractions. The intermittent peritoneal dialysis was then replaced by intensive hemodialysis, and oral administration of 300 mg/d of cibenzoline was started. Four days later, he developed thirst, weakness, and dyspnea due to respiratory muscular paralysis. We initiated respiratory support with a respirator because analysis of his blood gases revealed marked hypercapnia and hypoxia. He also developed hypoglycemia and prolonged PQ and QRS intervals on the electrocardiogram, which we believed were due to cibenzoline intoxication; we discontinued the cibenzoline immediately. All symptoms improved, and he was extubated 5 days later. After 2 months, his pericardial effusion disappeared. He now continues maintenance hemodialysis as an outpatient. We suspect that the cibenzoline induced the respiratory muscular paralysis for 2 reasons: 1) the patient experienced the respiratory muscular paralysis, at the same time he also experienced thirst, weakness, hypoglycemia, and prolonged PQ and QRS intervals on electrocardiogram, and all of these symptoms improved after the discontinuation of cibenzoline, and 2) his plasma concentration of cibenzoline became remarkably elevated, to 20 times above the standard therapeutic level. This patient's clinical course indicates that hemodialysis might be superior to intermittent peritoneal dialysis for treatment of cibenzoline intoxication.     

l-DOPA induces concentration-dependent facilitation and inhibition of presynaptic acetylcholine release in the guinea-pig submucous plexus

Neurotransmitter- or neuromodulator-like actions ofl-DOPA were investigated with intracellular recordings from submucous plexus neurons of the guinea-pig caecum.l-DOPA at 30 nM augmented the amplitude of fast EPSPs, but did not affect depolarizations elicited by puff application of acetylcholine (ACh). The augmenting effect ofl-DOPA on the fast EPSPs was counteracted byl-DOPA methyl ester. The fast EPSPs were depressed by 10 μMl-DOPA, but transiently augmented after rinsing the drug.l-DOPA methyl ester did not affect the inhibitory action ofl-DOPA on the fast EPSPs, but antagonized the potentiation following the inhibition. The depolarization elicited by exogenously applied. ACh was inhibited by 10 μMl-DOPA. Intracellular Ca²⁺ concentrations ([Ca²⁺]_i) of the neuronal soma were measured with fura-2 microfluorophotometry. The transient increase in the [Ca²⁺]_i evoked by the somatic action potential (Δ[Ca²⁺]_AP) was facilitated by 30 nMl-DOPA, but decreased by the drug at 10 μM. It is concluded thatl-DOPA at low concentrations enhances the Δ[Ca²⁺]_AP, increasing the neurotransmitter release, but at high dose diminishes the Δ[Ca²⁺]_AP, inhibiting the neurotransmission.