Hepatic natural killer and natural killer T cells markedly decreased in two cases of drug-induced fulminant hepatic failure rescued by living donor liver transplantation

The human liver contains significant numbers of innate immune cells, such as natural killer (NK) cells and natural killer T (NKT) cells, which express both T-cell receptors and NK-cell receptors simultaneously. It has been suggested that the innate immune system plays a crucial role in the liver. In this report, the distribution of NK and NKT cells in the liver and peripheral blood of two patients with drug-induced fulminant hepatic failure (FHF) who had undergone living donor liver transplantation was examined. In both the liver and peripheral blood, the proportions of NK and NKT cells markedly decreased compared with those in healthy donors. It was also revealed that, unlike murine NKT cells, human CD56(+) T cells and CD57(+) T cells did not constitutively express CD28, which is one of the important costimulatory molecules on T cells. Additionally, the residual CD56(+) T cells and CD57(+) T cells in the patients expressed more CD28 than in controls. This result suggests that NKT cells might be more activated in FHF. Although the accumulation of further cases is required, it is suggested that both NK and NKT cells might be involved in hepatic injury in FHF.     

Expression of oncofetal fibronectin messenger ribonucleic acid in fibroblasts in the thyroid: a possible cause of false positive results in molecular-based diagnosis of thyroid carcinomas

Oncofetal fibronectin (onfFN) messenger ribonucleic acid (mRNA) is abundantly expressed in thyroid papillary and anaplastic carcinomas. These carcinomas can be preoperatively diagnosed by the detection of onfFN mRNA in fine needle aspiration biopsies (FNABs). However, previous reports have noted that the expression of onfFN mRNA was observed in 3.7% of the FNABs that were diagnosed as negative cytology. To clarify this discrepancy, we examined the expression of onfFN mRNA in fibroblasts in the thyroid. By RT-PCR and real-time quantitative RT-PCR analyses, we detected a high copy number of onfFN mRNA in cultured fibroblasts obtained from the normal thyroid tissues dissected surgically. Thus, we conclude that the contaminated fibroblasts in FNABs due to tumor necrosis or acute or chronic inflammation may be a cause of false positive results in molecular-based diagnosis of thyroid carcinomas.     

Unique single coronary artery with acute myocardial infarction: observation of the culprit lesion by intravascular ultrasound and coronary angioscopy

We report an acute myocardial infarction in a patient with a single coronary artery. The right coronary artery arose from the middle portion in the left anterior descending artery through the transverse branch. This type of single coronary artery has not been previously reported. Moreover, this is the first report in which the culprit lesion in a patient with a single coronary artery was observed by intravascular ultrasound and coronary angioscopy. The patient underwent successful coronary stent deployment.     

Induction of Mutant Sik3Sleepy Allele in Neurons in Late Infancy Increases Sleep Need

Sleep is regulated in a homeostatic manner. Sleep deprivation increases sleep need, which is compensated mainly by increased EEG δ power during non-rapid eye movement sleep (NREMS) and, to a lesser extent, by increased sleep amount. Although genetic factors determine the constitutive level of sleep need and sleep amount in mice and humans, the molecular entity behind sleep need remains unknown. Recently, we found that a gain-of-function Sleepy (Slp) mutation in the salt-inducible kinase 3 (Sik3) gene, which produces the mutant SIK3(SLP) protein, leads to an increase in NREMS EEG δ power and sleep amount. Since Sik3^Slp mice express SIK3(SLP) in various types of cells in the brain as well as multiple peripheral tissues from the embryonic stage, the cell type and developmental stage responsible for the sleep phenotype in Sik3^Slp mice remain to be elucidated. Here, we generated two mouse lines, synapsin1^CreERT2 and Sik3^ex13flox mice, which enable inducible Cre-mediated, conditional expression of SIK3(SLP) in neurons on tamoxifen administration. Administration of tamoxifen to synapsin1^CreERT2 mice during late infancy resulted in higher recombination efficiency than administration during adolescence. SIK3(SLP) expression after late infancy increased NREMS and NREMS δ power in male synapsin1^CreERT2; Sik3^ex13flox/+ mice. The expression of SIK3(SLP) after adolescence led to a higher NREMS δ power without a significant change in NREMS amounts. Thus, neuron-specific expression of SIK3(SLP) after late infancy is sufficient to increase sleep.SIGNIFICANCE STATEMENT The propensity to accumulate sleep need during wakefulness and to dissipate it during sleep underlies the homeostatic regulation of sleep. However, little is known about the developmental stage and cell types involved in determining the homeostatic regulation of sleep. Here, we show that Sik3^Slp allele induction in mature neurons in late infancy is sufficient to increase non-rapid eye movement sleep amount and non-rapid eye movement sleep δ power. SIK3 signaling in neurons constitutes an intracellular mechanism to increase sleep.     

Dab1‐mediated colocalization of multi‐adaptor protein CIN85 with Reelin receptors,ApoER2 and VLDLR,in neurons

Reelin‐Dab1 signaling is indispensable for proper positioning of neurons in mammalian brain. Reelin is a glycoprotein secreted from Cajal‐Reztuis cells in marginal zone of cerebral cortex, and its receptors are Apolipoprotein E receptor 2 (ApoER2) or very low density lipoprotein receptor (VLDLR) expressed on migrating neurons. When Reelin binds to ApoER2 or VLDLR, an adaptor protein Dab1 bound to the receptors undergoes Tyr phosphorylation that is essential for Reelin signaling. We reported previously that Cdk5‐p35 phosphorylates Dab1 at Ser400 and Ser491 and the phosphorylation regulates its binding to CIN85, which is an SH3‐containing multiadaptor protein involved in endocytic downregulation of receptor‐tyrosine kinases. However, the interaction of CIN85 with Dab1 has not been addressed in neurons. We examined here a possibility that CIN85 has a role in Reelin signaling. We found nonpho‐sphorylated Dab1‐mediated colocalization of CIN85 with ApoER2. The colocalization of CIN85 with ApoER2 was increased in neurons stimulated with Reelin repeats 3‐6, an active Reelin fragment. The stimulation recruited CIN85 to domains in plasma membrane where it colocalized with ApoER2 and Dab1 and then to EEA1‐labeled early endosomes in the cytoplasm. In addition, Tyr phosphorylation of Dab1 strengthened the binding to CIN85. These results suggest that CIN85 participates in Reelin signaling through the binding to Dab1.     

Evaluation of the relationship between linezolid exposure and hyponatremia

IntroductionAims of this study were (a) to assess the development ratio of hyponatremia during treatment with linezolid and (b) to evaluate the relationship between the risk of hyponatremia and linezolid exposure and patient background.MethodClinical data including linezolid serum concentrations and serum sodium values were collected at Toyama University Hospital and Kyorin University Hospital. Data from 89 patients were used for the analysis, and a nadir serum sodium level ≤130 mmol/L during the treatment with linezolid was defined as hyponatremia. Mann-Whitney's U test was used to evaluate the effects of the area under the time-concentration curve (AUC) of linezolid at the nadir sodium level, clinical characteristics (e.g. laboratory data), and baseline serum sodium levels on the development of hyponatremia.ResultsThe hyponatremia was occurred in 21 of 89 patients (23.6%). Data are compared for baseline and nadir serum sodium levels of patients with and without hyponatremia. In both groups, nadir serum sodium levels were significantly different from those of the baseline values (P < 0.05). The values of AUC_0-12, accumulated AUC, baseline serum sodium levels and age were significantly different between patients with and without hyponatremia (P < 0.05).ConclusionsLinezolid exposure, age, and baseline sodium levels were detected as the risk factors for linezolid-related hyponatremia. Our findings suggest that regular monitoring of serum sodium levels is desirable during treatment with linezolid, especially for the elderly and patients with low serum sodium levels before the start of linezolid administration.     

Assessing Blood Flow in an Intracranial Stent: A Feasibility Study of MR Angiography Using a Silent Scan after Stent-Assisted Coil Embolization for Anterior Circulation Aneurysms

BACKGROUND AND PURPOSE:Blood flow in an intracranial stent cannot be visualized with 3D time-of-flight MR angiography owing to magnetic susceptibility and radiofrequency shielding. As a novel follow-up tool after stent-assisted coil embolization, we applied MRA by using a Silent Scan algorithm that contains an ultrashort TE combined with an arterial spin-labeling technique (Silent MRA). The purpose of this study was to determine whether Silent MRA could visualize flow in an intracranial stent placed in the anterior circulation.MATERIALS AND METHODS:Nine patients treated with stent-assisted coil embolization for anterior circulation aneurysms underwent MRAs (Silent MRA and TOF MRA) and x-ray digital subtraction angiography. MRAs were performed in the same session on a 3T unit. Two neuroradiologists independently reviewed the MRA images and subjectively scored flow in a stent as 1 (not visible) to 4 (excellent) by referring to the latest x-ray digital subtraction angiography image as a criterion standard.RESULTS:Both observers gave MRA higher scores than TOF MRA for flow in a stent in all cases. The mean score for Silent MRA was 3.44 ± 0.53, and for TOF MRA, it was 1.44 ± 0.46 (P < .001).CONCLUSIONS:Silent MRA was able to visualize flow in an intracranial stent more effectively than TOF MRA. Silent MRA might be useful for follow-up imaging after stent-assisted coil embolization, though these study results may be only preliminary due to some limitations.

Endovascular therapy for intracranial aneurysms has been widely used since the International Subarachnoid Aneurysm Trial.¹ The number of cases of coil embolization for aneurysms is increasing, and the stent-protection technique has widened the applicability to cases that had been otherwise difficult to treat with conventional coil embolization.² Nevertheless, there is a risk of coil compaction or in-stent restenosis after stent-assisted coil embolization. X-ray digital subtraction angiography is the optimal technique used to examine these adverse events, and it is commonly used as a follow-up tool after using an intracranial stent. However, DSA presents some unavoidable risks related to the catheter procedure, radiation, and contrast media.^3–53D time-of-flight MR angiography is widely used for the assessment of cerebral vascular diseases and has also been examined as a noninvasive substitute for DSA.^6–9 These studies generally reported difficulty in visualizing flow in a stent with TOF MRA because of magnetic susceptibility and radiofrequency shielding, though some beneficial aspects were observed in assessing the residual lumen of aneurysms. As a novel follow-up tool after stent-assisted coil embolization, we applied MRA by using a Silent Scan algorithm (GE Healthcare, Milwaukee, Wisconsin) that contains an ultrashort TE combined with an arterial spin-labeling technique (Silent MRA). In this situation, visualizing flow means visualizing arterial geometry and patency. It does not mean directly visualizing blood flow rate. The purpose of this study was to determine whether Silent MRA can visualize flow in an intracranial stent placed at the anterior circulation.     

Analysis of acute and chronic heart failure in view of hepatic oxygen supply-demand relationship using hepatic venous oxygen saturation

The adequacy of hepatic circulation in terms of oxygen supply-demand relation was assessed by measuring hepatic venous oxygen saturation (Shvo2) in patients. Among those with congenital cardiac lesions (n = 11), Shvo2 during the early postoperative period was markedly low as less than 20% in Fontan operation group (n = 5) with subsequent clinical findings of acute hepatic dysfunction. Significant correlations were found between Shvo2 values early after surgery and subsequent peak values in serum hepatic enzymes. Serum total bilirubin and prothrombin time started to deteriorate when Shvo2 became below 30%. Cardiac index, hepatic perfusion pressure and mixed venous oxygen saturation showed positive linear correlations with Shvo2, and central venous pressure (CVP) with an inverse relation. In chronic valvular disease (n = 28), those with NYHA class IV patients showed lower Shvo2 (average; 47.4%) at cardiac catheterization than the others (class-I; 66.4%, class-II; 63.9%, p less than 0.05). These results indicate that Shvo2 monitoring appears to be useful to assess the hepatic perfusion in terms of oxygen supply-demand relation in acute and chronic heart failure, and Shvo2 of 30% seems to be a critical level.