The usefulness of diffusion-weighted magnetic resonance imaging performed in the acute phase as an early predictor of delayed neuropsychiatric sequelae in acute carbon monoxide poisoning.

Delayed onset of neuropsychiatric symptoms after apparent recovery from acute carbon monoxide (CO) poisoning has been described as delayed neuropsychiatric sequelae (DNS). No previous study has determined whether early use of diffusion-weighted magnetic resonance imaging (DWI) can predict which patients will develop DNS in the acute CO poisoning. This retrospective observational study was performed on adult patients with acute CO poisoning consecutively treated over a 17-month period. All included patients with acute CO poisoning underwent DWI to evaluate brain injury within 72 h after CO exposure. DWI was evaluated as follows: (1) presence of pathology, (2) number of pathologies, (3) asymmetry, and (4) location of pathology. Patients were divided into two groups. The DNS group was composed of patients with delayed sequelae, while the non-DNS group included patients with no sequelae. A total of 102 patients with acute CO poisoning were finally enrolled in this study. DNS developed in 10 patients (9.8%). Between the DNS group and the non-DNS group, presence of pathology on DWI and initial Glasgow Coma Scale (GCS) showed significant difference. There was also a statistical difference between the non-DNS group and DNS group in terms of CO exposure time, troponin I, rhabdomyolysis, acute kidney injury, and pneumonia. The presence of pathology in DWI and initial GCS (cutoff: <12) at the emergency department served as an early predictors of DNS.

The relationship between serum ammonia level and neurologic complications in patients with acute glufosinate ammonium poisoning: A prospective observational study.

Glufosinate ammonium poisoning can cause neurological complications even after a symptom-free period. We prospectively investigated the predictors of neurologic complications in acute glufosinate ammonium poisoning and the change of serum ammonia level as a predictor of patient's presence and recovery of neurologic complication. This prospective observational study collected data from consecutive patients diagnosed with acute glufosinate ammonium poisoning between September 2014 and June 2016. Serum ammonia was serially measured. The patients were divided into two groups: the neurologic complication group and the nonneurologic complication group. We also defined 25 other insecticide- or herbicide-poisoned patients as controls. The neurologic complication group included 18 patients (72.0%). The latency period for neurologic complications was within 48-h postingestion. The peak ammonia level was statistically higher in the neurologic complication group than in the control group ( p < 0.001) and the nonneurologic complication groups ( p = 0.001). There was a statistical difference between the nonneurologic complication group and the neurologic complication group ( p = 0.0085) in terms of ingested amount. The peak ammonia was the only predictor for the development of neurologic complications (the optimal cutoff: 90 µg/dL). In patients with mental changes, the mean serum ammonia levels before and after recovery of the mental changes were statistically different ( p = 0.0019). In acute glufosinate ammonium poisoning, serial serum ammonia level measurements are needed and a serum peak ammonia level greater than 90 µg/dL is a predictor of neurologic complications. Also, it is important to treat the hyperammonemia in acute glufosinate ammonium poisoning.

Serum neuron-specific enolase as an early predictor of delayed neuropsychiatric sequelae in patients with acute carbon monoxide poisoning.

Delayed onset of neuropsychiatric symptoms after apparent recovery from acute carbon monoxide (CO) poisoning has been described as delayed neuropsychiatric sequelae (DNS). To date, there have been no studies on the utility of serum neuron-specific enolase (NSE), a marker of neuronal cell damage, as a predictive marker of DNS in acute CO poisoning. This retrospective observational study was performed on adult patients with acute CO poisoning consecutively treated over a 9-month period. Serum NSE was measured after emergency department arrival, and patients were divided into two groups. The DNS group comprised patients with delayed sequelae, while the non-DNS group included patients with none of these sequelae. A total of 98 patients with acute CO poisoning were enrolled in this study. DNS developed in eight patients. The median NSE value was significantly higher in the DNS group than in the non-DNS group. There was a statistical difference between the non-DNS group and the DNS group in terms of CO exposure time, Glasgow Coma Scale (GCS), loss of consciousness, creatinine kinase, and troponin I. GCS and NSE were the early predictors of development of DNS. The area under the curve according to the receiver operating characteristic curves of GCS, serum NSE, and GCS combined with serum NSE were 0.922, 0.836, and 0.969, respectively. In conclusion, initial GCS and NSE served as early predictors of development of DNS. Also, NSE might be a useful additional parameter that could improve the prediction accuracy of initial GCS.

Activation of Autophagy by Everolimus Confers Hepatoprotection Against Ischemia-Reperfusion Injury.

As the criteria for liver donation have been extended to include marginal donors, liver grafts are becoming particularly vulnerable to hepatic ischemia-reperfusion injury (IRI). However, no specific measures have been validated to ameliorate hepatic IRI. In this article, we explored whether everolimus has protective effects against hepatic IRI in relation with autophagy. The effects of everolimus were investigated in both in vitro and in vivo hepatic IRI models. Mouse hepatocyte AML12 cells and BALB/c mice were utilized for the establishment of each model. In the IRI-induced AML12 cells, everolimus treatment increased the expressions of autophagic markers (microtubule-associated protein 1 light chain 3 and p62) and decreased pro-apoptotic proteins (cleaved caspase 3 and cleaved poly-ADP ribose polymerase). The blockage of autophagy, using either bafilomycin A1 or si-autophagy-related protein 5, abrogated these anti-apoptosis effects of everolimus. Subsequently, everolimus administration to the hepatic IRI-induced mice provided hepatoprotective effects in terms of (1) decreasing the expressions of pro-apoptotic proteins, (2) inhibiting the release of pro-inflammatory cytokines (IL-6 and tumor necrosis factor-α), (3) reducing elevated liver enzymes (aspartate transaminase, alanine transaminase, and ammonia), and (4) restoring liver histopathology. These findings suggest that everolimus protects the liver against hepatic IRI by way of activating autophagy, and thus could be a potential therapeutic agent for hepatic IRI.

Features of myocardial injury in severe organophosphate poisoning.

BACKGROUND: In organophosphate (OP) poisoning cardiac complications may occur. However, the current body of knowledge largely consists of limited studies, and case reports are mainly on electrocardiogram (ECG) abnormalities. As definite myocardial injury is difficult to assess through ECG, we investigated the prevalence of myocardial injury through cardiac biochemical markers such as troponin I (TnI) in severe OP poisoning. METHODS: We conducted a retrospective review of 99 consecutive OP insecticide poisoning cases that were diagnosed and treated at the emergency department of the Wonju Severance Christian Hospital between March 2008 and December 2013. RESULTS: Based on Namba classification for OP poisoning, there were no patients with mild toxicity, 9 patients (9.1%) with moderate toxicity and 90 patients (90.9%) with severe toxicity. On ECG, normal sinus rhythm was most common, and ST depression and elevation were seen in 11 patients (11.1%). Elevation of TnI within 48 h was seen in 34 patients (34.3%). The median peak level and peak time of TnI were 0.305 (IQR, 0.078-2.335) ng/mL and 15 (IQR 6.9-34.4) hours, respectively. There were differences between patients with normal TnI and elevated TnI in terms of age (yrs), number of patients who were exposed to OP via the oral route, and initial Glasgow Coma Scale (GCS; 58 ± 17 vs. 66 ± 16, p = 0.015, 56 [87.5%] vs. 33 [97.1%], p = 0.048 and 12.0 [IQR, 8.0-15.0] vs. 9.0 [IQR, 5.8-12.0], p = 0.019). CONCLUSIONS: OP can cause direct myocardial injury during the acute early phase in severe OP poisoning. Monitoring of TnI may be needed in severe OP poisoning.

[Recovery from parkinsonism with N-acetylcysteine-differentiated neurons].

The upregulation of dopaminergic neuronal differentiation is necessary for stem cell therapy in Parkinson's disease (PD). In this study, neuronal differentiation efficiency increased by more than 2 times in P19 embryonic stem cells (ESCs) induced by N-acetylcysteine (NAC) and retinoic acid (RA) as compared to RA alone, with suppressed glial differentiation. The majority of NAC-treated stem cells grafted into brains of PD mice differentiated into dopaminergic neurons and persisted well for 6 weeks. Parkinsonism was also greatly improved after grafting NAC-treated cells in comparison to cells treated with only RA. Our results strongly suggest that NAC treatment may be an effective strategy for generating stem cells fated to become dopaminergic neurons for PD clinical therapy.

N-acetylcysteine enhances neuronal differentiation of P19 embryonic stem cells via Akt and N-cadherin activation.

We examined whether N-acetylcysteine (NAC) enhanced embryonic body (EB) formation and neuronal differentiation in terms of EB formation, neuronal marker (microtubule-associated protein 2; MAP-2) expression, and neuron maturation using P19 embryonic stem cells. The size and numbers of EBs were greatly increased, together with the up-regulated N-cadherin expression. Also, MAP-2 expression and neurite outgrowth were much increased with activation of serine/threonine protein kinase (Akt) and blocked by addition of an Akt inhibitor (LY294002). Our results suggested that NAC increased EB formation by up-regulating the N-cadherin expression. Furthermore, NAC-enhanced neuronal differentiation was mediated by activation of Akt.

Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.

BACKGROUND: Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. OBJECTIVES AND METHODS: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. RESULTS: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. CONCLUSION: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

Atypical teratoid/rhabdoid tumors of the central nervous system: imaging and clinical findings in 16 children.

AIM: To investigate the imaging and clinical findings of central nervous system (CNS) atypical teratoid/rhabdoid tumours (AT/RTs) in children. MATERIALS AND METHODS: The computed tomography (CT) and magnetic resonance imaging (MRI) findings and clinical records of 16 children with CNS AT/RTs were retrospectively reviewed. Tumour location, size, composition, enhancement pattern, peritumoural oedema, signal intensity (SI) on MRI and CT attenuation were evaluated. RESULTS: A total of 17 lesions from 16 patients (median age 2.3 years, age range 0.7-15 years) were included in the evaluation. Tumour location was infratentorial for 11 lesions and supratentorial for six lesions. The mean diameter of the largest dimension for a tumour was 4 cm. The tumour was mainly solid in 65% of cases, and solid and cystic or cystic and solid in 35% of cases. The solid component of the tumours had a homogeneous iso SI (n=15) on T2-weighted MRI images and iso SI (n=14) on T1-weighted images. Moderate to strong enhancement of the solid component was noted in most cases. In spite of a large tumour size, peritumoural oedema was minimal or mild except in four cases. Rapid growth of the tumour was demonstrated in three cases. Seven patients died from tumour progression, with a mean survival time of 8.4 months (range 2-12 months). CONCLUSION: Although the AT/RTs had non-specific imaging findings, the tumours tended to be large in size, have iso SI on T1 and T2-weighted MR images with prominent enhancement, and relatively mild peritumoural oedema. Rapid growth of the tumour was seen during the follow-up period.

Inhibition of c-erbB-2 expression an activity in human ovarian carcinoma cells by hypericin.

The c-erbB-2 oncogene encodes a tyrosine kinase that constitutes the internal and transmembrane part of the epidermal growth factor receptor (EGFR). ErbB-2 overexpression has been reported in 20% to 30% of human adenocarcinomas of the breast and ovary, and has been linked to an unfavorable prognosis in patients. Hypericin is a protein tyrosine kinase inhibitor that has been exploited in models for anti-tumor and anti-viral activity. In this study, we investigated the effects of hypericin on the activity of the c-erbB-2 oncoprotein and its downstream kinases. We also investigated the effect of hypericin on metastasis. We used ovarian SK-OV-3 cells as a model to determine whether hypericin-induced cell death was associated with inhibition of c-erbB-2 expression and activation. The IC50 of hypericin after 72 hrs exposure was 7.5 microM as determined by the MTT assay. Apoptosis, which was assessed by morphological changes and a flow cytometric assay, was observed at 24 h after continuous exposure to 5 microM hypericin. Inhibition of expression of the c-erbB-2 protein was detected, using a monoclonal anti-erbB-2 antibody after 12-48 hrs of exposure to hypericin. Hypericin was found to inhibit autophosphorylation of the erbB-2 protein and downstream kinases such as MEK and ERK1/2. We also found up-regulation of p21WAF1 expression and down-regulation of Bcl-2 in hypericin treated cells. An invasion assay showed that hypericin inhibited the movement of SK-OV-3 cells into the Matrigel. However, gelatin zymography showed that hypericin had no effect on the secretion of matrix metalloproteinases (MMPs) in SK-OV-3 cells. From these results, we conclude that hypericin inhibits the growth of SK-OV-3 ovarian cancer cells, inhibits the autophosphorylation of c-erbB-2, induces apoptosis, and may inhibit invasion.

US in the diagnosis of pediatric chest diseases.

Most pediatric chest diseases are adequately evaluated with chest radiography. However, when chest radiography does not allow identification of the location and nature of an area of increased opacity, ultrasonography (US) can help establish the diagnosis. US may be helpful in evaluation of persistent or unusual areas of increased opacity in the peripheral lung, pleural abnormalities, and mediastinal widening; US is particularly useful in patients with complete opacification of a hemithorax at radiography. In cases of pulmonary parenchymal lesions, identification of air or fluid bronchograms at US and of pulmonary vessels at color flow imaging is useful for differentiating pulmonary consolidation or atelectasis from lung masses and pleural lesions. US allows characterization of pleural fluid collections as simple, complicated, or fibroadhesive, which is important information for planning thoracentesis or thoracotomy. Computed tomography and magnetic resonance imaging are superior to US in evaluation of the mediastinum, but US is a reasonable alternative in certain situations (eg, to avoid unnecessary investigation of a normal thymus simulating a mediastinal mass). In cases of chest wall lesions, US may enable localization of the site of origin to soft tissues or an extrapleural intrathoracic location. Osseous involvement, particularly rib involvement, is easily evaluated with US.

A qualitative analysis of brain SPECT for prognostication of gross motor development in children with cerebral palsy.

PURPOSE: In this report, the authors assessed the clinical significance of decreased regional cerebral blood flow (rCBF) in the thalamus or cerebellar hemispheres in relation to gross motor performance in the children with cerebral palsy. MATERIALS AND METHODS: Thirty-six children with bilateral spastic cerebral palsy (BSCP) underwent brain SPECT. Visual analysis was used for the brain SPECT interpretation. The rCBF in the thalamus or cerebellum was graded as normal, mildly decreased, or severely decreased. A marked decrease or near absence of rCBF in the thalamus or cerebellum was considered as severely decreased. RESULTS: All 36 children with BSCP had hypoperfusion in the thalamus or cerebellar hemispheres. Eight of 20 children (40%) with mildly decreased rCBF on brain SPECT had mild developmental delays. On the other hand, only 1 of 16 children (6.3%) with severe hypoperfusion in the thalamus or cerebellum had a mild developmental delay, and the remaining 15 of 16 children (93.8%) had severe developmental delays. There was good correlation between the degree of developmental delay and the severity of hypoperfusion in the thalamus or cerebellum (P = 0.023). CONCLUSION: The measurement of rCBF by Tc-99m ethyl cysteinate dimer brain SPECT appears to be valuable in prognostication of gross motor development in children with BSCP.

Glucocorticoid receptor-induced down-regulation of MMP-9 by ginseng components, PD and PT contributes to inhibition of the invasive capacity of HT1080 human fibrosarcoma cells.

We examined the effects of the purified ginseng components, panaxadiol (PD) and panaxatriol (PT), on the expression of matrix metalloproteinase-9 (MMP-9) in highly metastatic HT1080 human fibrosarcoma cell line. A significant down-regulation of MMP-9 by PD and PT was detected by Northern blot analysis. However, the expression of MMP-2 was not changed by treatment with PD and PT. Quantitative gelatin based zymography confirmed a markedly reduced expression of MMP-9, but not MMP-2 in the treatment of PD and PT. To investigate whether the reduced level of MMP-9 by PD and PT affects the invasive capacity of HT1080 cells, we conducted an in vitro invasion assay with PD and PT treated cells. The results of the in vitro invasion assay revealed that PD and PT reduced tumor cell invasion through a reconstituted basement membrane in the transwell chamber. Because of the similarity of chemical structure between PD, PT and dexamethasone (Dexa), a synthetic glucocorticoid, we investigated whether the down-regulation of MMP-9 by PD and PT were mediated by the nuclear translocation of glucocorticoid receptor (GR). Increased GR in the nucleus of HT1080 human fibrosarcoma cells treated by PD and PT was detected by immunocytochemistry. Western blot and gel retardation assays confirmed the increase of GR in the nucleus after treatment with PD and PT. These results suggest that GR-induced down-regulation of MMP-9 by PD and PT contributes to reduce the invasive capacity of HT1080 cells.

Anti-tumor promoting potential of naturally occurring diarylheptanoids structurally related to curcumin.

In recent years, there have been considerable efforts to search for naturally occurring substances for intervention of carcinogenesis. Many components from medicinal or dietary plants have been identified to possess potential chemopreventive properties. For instance, curcumin, a yellow colouring agent from turmeric (Curcuma longa Linn., Zingiberaceae) has been shown to inhibit tumor formation in diverse animal models. Alpinia oxyphylla Miquel that also belongs to ginger family has been used in oriental herbal medicine. In the present work, we have evaluated the anti-tumor promoting potential of yakuchinone A (1-[4'-hydroxy-3'-methoxyphenyl]-7-phenyl-3-heptanone) and yakuchinone B (1-[4'-hydroxy-3'-methoxyphenyl]-7-phenylhept-1-en-3-one), major pungent ingredients of A. oxyphylla. Thus, topical application of yakuchinone A or B significantly suppressed TPA-induced epidermal ornithine decarboxylase activity. They also reduced TPA-stimulated production of tumor necrosis factor-alpha in cultured human promyelocytic leukemia (HL-60) cells. Both compounds blunted the TPA-induced superoxide generation in differentiated HL-60 cells in a concentration-related manner and also inhibited lipid peroxidation in rat brain homogenates. Furthermore, yakuchinone A and yakuchinone B nullified the activation of the activator protein-1 (AP-1) in immortalized mouse fibroblast cells in culture. These findings indicate that pungent diarylheptanoids from A. oxyphylla have anti-tumor promotional properties that can contribute to their chemopreventive potential.

Atypical skeletal changes in otopalatodigital syndrome type II: phenotypic overlap among otopalatodigital syndrome type II, boomerang dysplasia, atelosteogenesis type I and type III, and lethal male phenotype of Melnick-Needles syndrome.

We report on 2 cases of otopalatodigital syndrome type II (OPD II) with atypical skeletal changes, overlapping those of boomerang dysplasia, atelosteogenesis type I (AO I) and type III (AO III), and the lethal male phenotype of Melnick-Needles syndrome. One patient exhibited strikingly broad, bowed femora, which resembled those of boomerang dysplasia. The other patient possessed conspicuous undertubulation of the long bones, defective ossification of the spine, and severe undermineralization of the calvaria, which may have caused diagnostic confusion with AO I, AO III, and the lethal male phenotype of Melnick-Needles syndrome. OPD II is transmitted as an X-linked recessive trait, whereas AO I, AO III, and boomerang dysplasia are considered to result from a new dominant mutation, and Melnick-Needles syndrome is inherited as an X-linked dominant trait. Accordingly, differential diagnosis is mandatory to provide the affected families with adequate genetic counseling. Awareness of these skeletal changes in OPD II will prevent the misdiagnosis of this entity as other disorders. Furthermore, the phenotypic overlap among these disorders may expand the entities that constitute the OPD-Larsen dysplasia family proposed by Spranger [1985].

Intracranial and extracranial MR angiography in Menkes disease.

We report a case of Menkes disease in which brain MR imaging and MR angiography (MRA) were performed. In addition to minimal brain atrophy, severe intracranial and extracranial vascular tortuosity was demonstrated on head and neck MRA. Additional neck MRA was useful in evaluating the extent of the extracranial vascular abnormality in Menkes disease.

Conformational properties of the A-state of cytochrome c studied by hydrogen/deuterium exchange and electrospray mass spectrometry.

Hydrogen/deuterium (H/D) exchange studies that were monitored by liquid chromatography-electrospray ionization mass spectrometry (LC-ESIMS) were used to obtain a structural description of the compact acid-denatured state of ferricytochrome c (A-state). Due to the very different solvent conditions necessary to generate the nonnative states, it was essential that after deuterium labeling the nonnative states were refolded to the native state to insure high reproducibility during sample preparation and LC-ESIMS analysis. Approximately 30% lower deuterium was found incorporated in the A-state compared to the acid-denatured (UA) state. The analysis of the width of the mass peak suggests that the distribution of conformers sampled in the A-state was relatively narrow and that the compactness of the A-state was much closer to that of the native state than to the acid-denatured state. The LC-ESIMS study of partially deuterium-labeled peptic fragments derived from the A-state conformer generated under H/D quenching conditions were interpreted in terms of a significant loss of structural integrity within amino acid region 22-46.

Axial spondylometaphyseal dysplasia.

UNLABELLED: We present a previously undescribed skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings. Two of the three cases were siblings. Retinitis pigmentosa and optic atrophy are associated findings. CONCLUSION: We describe a new type of spondylometaphyseal dysplasia (SMD) and propose the name axial SMD.