Mitochondrial ubiquitin ligase MITOL blocks S-nitrosylated MAP1B-light chain 1-mediated mitochondrial dysfunction and neuronal cell death

Nitric oxide (NO) is implicated in neuronal cell survival. However, excessive NO production mediates neuronal cell death, in part via mitochondrial dysfunction. Here, we report that the mitochondrial ubiquitin ligase, MITOL, protects neuronal cells from mitochondrial damage caused by accumulation of S-nitrosylated microtubule-associated protein 1B-light chain 1 (LC1). S-nitrosylation of LC1 induces a conformational change that serves both to activate LC1 and to promote its ubiquination by MITOL, indicating that microtubule stabilization by LC1 is regulated through its interaction with MITOL. Excessive NO production can inhibit MITOL, and MITOL inhibition resulted in accumulation of S-nitrosylated LC1 following stimulation of NO production by calcimycin and N-methyl-D-aspartate. LC1 accumulation under these conditions resulted in mitochondrial dysfunction and neuronal cell death. Thus, the balance between LC1 activation by S-nitrosylation and down-regulation by MITOL is critical for neuronal cell survival. Our findings may contribute significantly to an understanding of the mechanisms of neurological diseases caused by nitrosative stress-mediated mitochondrial dysfunction.     

Orally Administered Liposomal Lactoferrin Inhibits Inflammation‐Related Bone Breakdown Without Interrupting Orthodontic Tooth Movement

Background: Bovine lactoferrin (bLF) modulates the production of tumor necrosis factor‐alpha (TNF‐α) and inhibits alveolar bone breakdown associated with periodontitis. This study is designed to examine the effects of orally administered liposomal bLF (LbLF) on orthodontic force (OF)‐induced alveolar bone remodeling during experimental tooth movement. Methods: Two groups of male Wistar rats were treated with either LbLF or control solution in drinking water 7 days before OF application. Lipopolysaccharide (LPS) was injected into the gingival sulcus in half the rats in each group. Thus, four groups: OF, OF+LbLF, OF+LPS, and OF+LPS+LbLF were established. Results: Orally administered LbLF significantly reduced apical migration of junctional epithelium in the OF and OF+LPS groups. In OF+LPS, osteoclast number in the alveolar crestal area was increased by LPS treatment, whereas osteoclast number was significantly reduced in OF+LPS+LbLF through suppression of TNF‐α production. Osteoclastic induction in the middle part, mainly from OF application, was not affected by LbLF administration. Inhibition of tooth movement was not induced by LbLF. Conclusions: Orally administered LbLF significantly inhibits LPS‐induced alveolar bone resorption but not OF‐induced bone remodeling. LbLF could be a potent therapeutic and preventive agent to control periodontal inflammation in patients undergoing orthodontic treatment.     

Investigation of the prognosis of patients with papillary thyroid carcinoma by tumor size

In papillary thyroid carcinoma (PTC), extrathyroid extension (Ex) and clinical lymph node metastasis (N) significantly affect the prognosis. We investigated the prognosis of patients with PTC 1 cm or less (1,220 patients), 1.1-2 cm (2,101 patients), 2.1-3 cm (1,249 patients), 3.1-4 cm (645 patients), and larger than 4 cm (563 patients). We classified N factor into three categories: N0, no clinical node metastasis: N1, clinical node metastasis smaller than 3 cm and without extranodal tumor extension requiring at least partial excision of adjacent organs for node dissection: and N2, clinical node metastasis 3 cm or larger or showing extranodal tumor extension. N2 markedly affected lymph node and distant recurrence-free survivals and cause-specific survival, regardless of the tumor size. N1 also adversely affected lymph node and distant recurrence-free survival but not cause-specific survival. Ex did not affect patients' prognosis with PTC 1 cm or less. It became a prognostic factor with PTC larger than 1 cm, and worsened lymph node and distant recurrence-free survival not only for N0 but also for N1 PTC larger than 3 cm and larger than 2 cm, respectively. However, its influence is limited for N2 PTC patients. Furthermore, Ex worsened the CSS with PTC larger than 2 cm in combination with N2. We have to note that the prognostic significance for lymph node and distant recurrence-free and cause-specific survival of Ex and N varies according to the tumor size in order to accurately predict the clinical outcomes and establish therapeutic strategies for PTC patients.     

Spontaneous atrial fibrillation initiated by tyramine in canine atria with increased sympathetic nerve sprouting

Sympathetic Activation and Atrial Fibrillation. Background: Chronic left ventricular myocardial infarction (LVMI) promotes atrial and pulmonary veins (PV) sympathetic nerve sprouting. Objectives: To test the hypothesis that sympathetic stimulation with tyramine initiates atrial fibrillation (AF) by early afterdepolarization (EAD)‐mediated triggered activity at the left atrial PV (LAPV) junction. Methods: LVMI was created in 6 dogs and 6 dogs served as controls. Six to 8 weeks later the activation pattern of the isolated LAPV was optically mapped using dual voltage and intracellular Ca⁺² (Ca_i²⁺)‐sensitive epifluorescent dyes before and after tyramine (5 μM) perfusion. Results: Tyramine initiated spontaneous AF in 5 of 6 atria but none in the control group (P < 0.01). The AF was initiated by late phase 3 EAD‐mediated triggered activity that arose from the LAPV junction causing functional conduction block in LA, reentry, and AF. The AF was subsequently maintained by mixed reentrant and focal mechanisms. The EADs arose during the late phase 3, when the Ca_i²⁺ level was 64 ± 12% of the peak systolic Ca_i²⁺ transient amplitude, a property caused by tyramine's simultaneous shortening of the action potential duration and lengthening of the Ca_i²⁺ transient duration in the LVMI group but not in the control. Tyrosine hydroxylase and growth associated protein 43 positive nerve sprouts were significantly increased in the sinus node, LAA, and the LSPV in the LVMI group compared to control (P < 0.01). Conclusions: Increased atrial sympathetic nerve sprouts after LVMI makes the LAPV junction susceptible to late phase 3 EAD‐mediated triggered and AF during sympathetic stimulation with tyramine.     

A neonate with an anomalous bone attached to the cervical spine

Background contextA digit/rib-like ectopic bone is a rare congenital anomaly that is most commonly seen in the thorax or pelvis. There is a single report of an adult possessing a phalanx-like bone in the cervical region; however, whether the abnormal bone was congenital or acquired remains elusive.PurposeTo elucidate that a phalanx-like bone in the cervical region represents a congenital anomaly.Study designCase report.MethodsReport of the imaging findings in a neonate with a palpable bone projection in the posterior neck.ResultsPlain radiographs demonstrated an ectopic bone posterior to the spinous process of the C5 vertebra. Three-dimensional computed tomography demonstrated that the anomalous bone was attached to the left lamina of the C5 vertebra and that there was abnormal segmentation of the left side of the cervical spine.ConclusionsThe anomalous bone in the neck is a congenital malformation that is accompanied by the maldevelopment of the cervical spine.     

Safety and efficacy of azilsartan in paediatric patients with hypertension: a phase 3, single-arm,open-label,prospective study

Clinical and Experimental Nephrology - Azilsartan is an angiotensin II receptor blocker indicated for the treatment of adult hypertension. A previous single-dose study suggested that azilsartan may...     

Revisiting Low-Risk Thyroid Papillary Microcarcinomas Resected Without Observation: Was Immediate Surgery Necessary?

Introduction

Low-risk thyroid papillary microcarcinomas (PMCs) without evidence of metastasis grow slowly if at all. However, we recommended surgery for tumors touching the trachea (TR) or located in the course of the recurrent laryngeal nerve (RN). Here we compared the cases of low-risk PMC patients who underwent immediate surgery to cases of TR- and RN-involved PMCs.

Materials and methods

We enrolled 1143 low-risk PMC patients who underwent immediate surgery in the years 2006–2014. The PMCs of 437 patients touched the TR on imaging studies: 270, 104, and 63 were graded as low, intermediate, and high risk, respectively, for TR invasion based on the angles between the tumor and the TR surface. The tumor was in the course of the RN in 144 patients, with 35 graded low risk and 109 high risk for RN invasion based on the normal rim of the thyroid in the direction of the RN.

Results

Invasion of the TR cartilage was observed only in high-risk patients. Peritracheal connective tissue was resected in 21, 15, and 6 of the high-, intermediate- and low-risk patients, respectively. Significant invasion of the RN requiring complete resection was observed in only nine patients at high risk for RN invasion. The incidence of TR invasion in high- and intermediate patients and the incidence of RN invasion in the high-risk patients were significantly higher than those of the low-risk patients. Tumors <7 mm did not show TR or RN invasion.

Conclusion

Among PMCs that touched the TR or were located in the course of the RN, observation could be the first choice for tumors <?7 mm and those ≥?7 mm judged as low risk for TR or RN invasion. However, for PMCs with high-risk features, immediate surgery after cytological diagnosis by a needle aspiration biopsy is recommended.