An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation

The identity of the cellular mechanisms through which nitroglycerin (glyceryl trinitrate, GTN) elicits nitric oxide (NO)-based signaling to dilate blood vessels remains one of the longest standing foci of investigation and sources of controversy in cardiovascular biology. Recent evidence suggests an unexpected role for mitochondria. We show here that bioconversion by mitochondria of clinically relevant concentrations of GTN results in activation of guanylate cyclase, production of cGMP, vasodilation in vitro, and lowered blood pressure in vivo, which are eliminated by genetic deletion of the mitochondrial aldehyde dehydrogenase (mtALDH). In contrast, generation of vasoactivity from alternative nitro(so)-vasodilators is unaffected. In mtALDH(-/-) mice and their isolated vascular tissue, GTN bioactivity can still be generated, but only at substantially higher concentrations of GTN and by a mechanism that does not exhibit tolerance. Thus, mtALDH is necessary and sufficient for vasoactivity derived from therapeutic levels of GTN, and, more generally, mitochondria can serve as a source of NO-based cellular signals that may originate independently of NO synthase activity.     

Ultra-Early Induction of General Anesthesia for Reducing Rebleeding Rates in Patients with Aneurysmal Subarachnoid Hemorrhage

ObjectiveRebleeding of aneurysmal subarachnoid hemorrhage (aSAH) is one of the significant risk factors for poor clinical outcome. The rebleeding risk is the highest during the acute phase with an approximate rebleeding rate of 9-17% within the first 24 h. Theoretically, general anesthesia can stabilize a patient's vital signs; however, its effectiveness as initial management for preventing post-aSAH rebleeding remains unclear. The purpose of this study was to determine the feasibility and safety of ultra-early general anesthesia induction for reducing the rebleeding rates among patients with aSAH.Materials and methodsWe retrospectively evaluated patients with aSAH who were admitted to our department between January 2013 and December 2019. All the patients underwent ultra-early general anesthesia induction as initial management regardless of their severity. We evaluated the rebleeding rate before definitive treatment, factors influencing rebleeding, and general anesthesia complications.ResultsWe included 191 patients with two-third of them having a poor clinical grade (World Federation of Neurological Society [WFNS] grade IV or V). The median duration from admission to general anesthesia induction was 22 min. Rebleeding before definitive treatment occurred in nine patients (4.7%). There were significant differences in the Glasgow Coma Scale score (p = 0.047), WFNS grade (p = 0.02), and dissecting aneurysm (p <0.001) between the rebleeding and non-rebleeding patients. There were no cases of unsuccessful tracheal intubation or rebleeding during general anesthesia induction.ConclusionUltra-early general anesthesia induction could be performed safely in patients with aSAH, regardless of the WFNS grade; moreover, it resulted in lower rebleeding rate than that reported in previous epidemiological reports.     

Early non-convulsive seizures are associated with the development of acute encephalopathy with biphasic seizures and late reduced diffusion

IntroductionChildren with either febrile seizure or acute encephalopathy exhibit seizures and/or impaired consciousness accompanied by fever of unknown etiology (SICF). Among children with SICF, we previously reported those who have refractory status epilepticus or prolonged neurological abnormalities with normal AST levels are at a high risk for the development of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), considered to be caused by excitotoxicity. Non-convulsive seizures (NCS) are common in critically ill children and cause excitotoxic neuronal injury. The aim of this study was to elucidate the prevalence of NCS in the acute phase of children at a high risk for developing AESD and the relationship between NCS in the acute phase and neurological outcomes.MethodsWe studied 137 children with SICF at a high risk for developing AESD and who underwent continuous electroencephalogram monitoring (cEEG) upon admission to a tertiary pediatric care center at Hyogo Prefectural Kobe Children’s Hospital between October 2007 and August 2018. Patient characteristics and outcomes were compared between patients with NCS and without NCS.ResultsOf the 137 children, NCS occurred in 30 children; the first NCS were detected in cEEG at the beginning in 63.3%, during the first hour in 90%, and within 12 h in 96.7%. Neurological sequelae were more common in NCS patients (20.0%) than in non-NCS patients (1.9%; p = 0.001). Five in 30 NCS patients (16.7%) and 3 in 107 non-NCS patients (2.8%) developed AESD (p = 0.013).ConclusionThe occurrence of NCS is associated with subsequent neurological sequelae, especially the development of AESD.     

Prognostic significance of the MDM2/HMGA2 ratio and histological tumor grade in dedifferentiated liposarcoma

Dedifferentiated liposarcoma (DDLPS) is a relatively common soft tissue sarcoma that results from the progression of well‐differentiated liposarcoma (WDLPS). This study aimed to investigate the progression process and to clarify the pathological and genetic factors related to poor prognosis in DDLPS. In 32 DDLPS cases and five WDLPS cases, genetic factors were analyzed by custom comparative genomic hybridization (CGH) array, which was designed to densely cover gene regions known to be frequently amplified in WD/DDLPS. The analyses comparing primary and metastatic lesions and those comparing histologically different areas in the same tumor revealed intra‐tumoral genetic heterogeneity and progression. According to a prognostic analysis comparing the good‐prognosis and the poor‐prognosis groups, we selected MDM2 and HMGA2 as candidate genes associated with poor and good prognosis, respectively. The ratios of the amplification or gain levels of MDM2 and HMGA2 expressed in log ratios (log[MDM2/HMGA2] = log[MDM2]‐log[HMGA2]) were significantly associated with prognosis. An amplification or gain level of MDM2 that was more than twice that of HMGA2 (MDM2/HMGA2 > 2, log[MDM2/HMGA2] > 1) was strongly related to poor OS (P < .001) and poor distant metastasis‐free survival (DMFS) (P < .001). In the pathological analysis of 44 cases of DDLPS, histological tumor grade, cellular atypia, and MDM2 immunoreactivity were related to overall survival (OS), while HMGA2 immunoreactivity tended to be associated with OS. Cellular atypia was also associated with DMFS. In conclusion, histological grade and MDM2 expression were determined to be prognostically important, and the MDM2/HMGA2 amplification or gain ratio was found to have significant prognostic value by the custom CGH array analysis.     

Mantle cell lymphoma with EBV-positive Hodgkin and Reed–Sternberg-like cells in a patient after autologous PBSCT: Phenotypically distinct but genetically related tumors

The case of 70-year-old man with mantle cell lymphoma (MCL) carrying t(11;14) translocation that relapsed as nodal lymphoma combining MCL and classic Hodgkin lymphoma (cHL) 9 years after autologous peripheral blood stem cell transplant (auto-PBSCT) is reported. Lymph nodes contained two separate areas of MCL and cHL-like components. Hodgkin and Reed–Sternberg (HRS)-like cells were accompanied by a prominent histiocyte background. HRS-like cells were CD5⁻, CD15⁺, CD20⁻, CD30⁺, PAX5⁺, Bob.1⁻, Oct2⁻ and EBER⁺. The MCL component expressed cyclin D1 and SOX11, whereas cyclin D1 and SOX11 expressions were reduced and lost, respectively, in HRS-like cells. Polymerase chain reaction results showed a single clonal rearrangement of the IGH gene in MCL and cHL-like components. CCND1 break apart fluorescence in situ hybridization showed split signals in both MCL and HRS-like cells, suggesting that MCL and cHL-like components were clonally related. Acquisition of p53 expression and Epstein–Barr virus (EBV)-positivity was seen in HRS-like cells. The patient died of disease progression with elevated hepatobiliary enzymes. The autopsy showed both MCL and cHL-like components around the bile ducts, splenic white pulp and bone marrow. The two components were phenotypically distinct, but genetically related, suggesting that transformation of MCL to HRS-like cells during the course of MCL in association with EBV infection.     

Evaluation of an artificial intelligence system for detecting vertical root fracture on panoramic radiography

Objectives

The aim of this study was to evaluate the use of a convolutional neural network (CNN) system for detecting vertical root fracture (VRF) on panoramic radiography.

Methods

Three hundred panoramic images containing a total of 330 VRF teeth with clearly visible fracture lines were selected from our hospital imaging database. Confirmation of VRF lines was performed by two radiologists and one endodontist. Eighty percent (240 images) of the 300 images were assigned to a training set and 20% (60 images) to a test set. A CNN-based deep learning model for the detection of VRFs was built using DetectNet with DIGITS version 5.0. To defend test data selection bias and increase reliability, fivefold cross-validation was performed. Diagnostic performance was evaluated using recall, precision, and F measure.

Results

Of the 330 VRFs, 267 were detected. Twenty teeth without fractures were falsely detected. Recall was 0.75, precision 0.93, and F measure 0.83.

Conclusions

The CNN learning model has shown promise as a tool to detect VRFs on panoramic images and to function as a CAD tool.

     

Diagnostic value of measurement of serum type I procollagen carboxy terminal peptides in patients with scirrhous carcinoma of the stomach.

We have evaluated the radioimmunoassay for type I procollagen carboxy terminal peptide (type I C-peptide), which is liberated from type I procollagen during its conversion to collagen, in the serodiagnosis of scirrhous carcinoma of the stomach. The mean (SD) serum concentration of type I C-peptide in 39 normal subjects was 41.7 (19.7) ng/ml. The mean serum values and the positive ratio of type I C-peptide in 11 patients with stages II and III scirrhous carcinoma of the stomach were 91.2 (41.9) ng/ml and 54.5%, respectively. In 10 patients with other types of gastric carcinoma, the mean type I C-peptide values were not significantly different from the normal value. Serum type I C-peptide values reflected the clinical course of scirrhous gastric carcinoma in five patients who underwent either operation or chemotherapy. The measurement of serum type I C-peptide concentrations could provide a useful way of diagnosing and monitoring scirrhous carcinoma of the stomach.     

Effects of cardioplegia on myocardial metabolism during hypothermic ischemia--components and mode of administration

Isolated rat heart preparations were used to determine the effect of cardioplegia on myocardial metabolism during profound hypothermic (15 degrees C) ischemia. The hearts were grouped according to the components of cardioplegia and the mode of administration. The six groups were normokalemic (GI), calcium-containing hyperkalemic (GII), calcium-free hyperkalemic (GIII) and single dose (A), multidose (B). Following 120 min of ischemia, tissue ATP decreased from 25.4 +/- 2.2 to 10.3 +/- 2.7, 3.9 +/- 2.4, 4.1 +/- 1.2, 15.5 +/- 3.2, 14.5 +/- 2.4 and 20.0 +/- 2.7 (I-A vs II-A p less than 0.005, I-A vs III-A p less than 0.005, I-B vs III-B p less than 0.05, II-B vs III-B p less than 0.005), and tissue lactate increased from 9.6 +/- 1.5 to 163.4 +/- 12.0, 174.1 +/- 13.5, 166.8 +/- 21.3, 99.1 +/- 8.3, 102.6 +/- 12.2 and 83.5 +/- 9.3 (I-B vs III-B p less than 0.02, II-B vs III-B p less than 0.02) mumol/dry wt g, in GI-A, GII-A, GIII-A, GI-B and GII-B, respectively. The results of this study suggests that (1) potassium cardioplegia in a single dose does not prevent degradation of high energy phosphate (HEP) in the hypothermic arrested heart, (2) though multidose cardioplegia is effective in preserving HEP during ischemia, the extent of its effects varies with the composition, and (3) the omission of calcium is beneficial in GIK cardioplegia in terms of preserving HEP at the end of ischemia.