Clinical and electroencephalogram characteristics of methylmalonic acidemia with MMACHC and MUT gene mutations.

OBJECTIVE: This study investigated the clinical, imaging, and electroencephalogram (EEG) characteristics of methylmalonic acidemia (MMA) with nervous system damage as the primary manifestation. METHODS: From January 2017 to November 2022, patients with nervous system injury as the main clinical manifestation, diagnosed with methylmalonic acidemia by metabolic and genetic testing, were enrolled and analyzed. Their clinical, imaging, and electroencephalogram data were analyzed. RESULTS: A total of 18 patients were enrolled, including 15 males and 3 females. The clinical symptoms were convulsions, poor feeding, growth retardation, disorder of consciousness, developmental delay, hypotonia, and blood system changes. There were 6 cases (33%) of hydrocephalus, 9 (50%) of extracerebral space widened, 5 (27%) of corpus callosum thinning, 3 (17%) of ventricular dilation, 3 (17%) of abnormal signals in the brain parenchyma (frontal lobe, basal ganglia region, and brain stem), and 3 (17%) of abnormal signals in the lateral paraventricular. In addition, there were 3 cases (17%) of cerebral white matter atrophy and 1 (5%) of cytotoxic edema in the basal ganglia and cerebral peduncle. EEG data displayed 2 cases (11%) of hypsarrhythmia, 3 (17%) of voltage reduction, 12(67%) of abnormal discharge, 13 (72%) of abnormal sleep physiological waves or abnormal sleep structure, 1 (5%) of immature (delayed) EEG development, and 8 (44%) of slow background. There were 2 cases (11%) of spasms, 1 (5%) of atonic seizures, and 1 (5%) of myoclonic seizures. There were 16 patients (89%) with hyperhomocysteinemia. During follow-up, 1 patient was lost to follow-up, and 1 died. In total, 87.5% (14/16) of the children had varying developmental delays. EEG was re-examined in 11 cases, of which 8 were normal, and 3 were abnormal. Treatments included intramuscular injections of vitamin B12, L-carnitine, betaine, folic acid, and oral antiepileptic therapy. Acute treatment included anti-infective, blood transfusion, fluid replacement, and correcting acidosis. The other treatments included low-protein diets and special formula milk powder. CONCLUSION: Methylmalonic acidemia can affect the central nervous system, leading to structural changes or abnormal signals on brain MRI. Metabolic screening and genetic testing help clarify the diagnosis. EEG can reflect changes in brain waves during the acute phase.

Pharmacological inhibition of ferroptosis as a therapeutic target for sepsis-associated organ damage.

Sepsis is a complex clinical syndrome caused by dysfunctional host response to infection, which contributes to excess mortality and morbidity worldwide. The development of life-threatening sepsis-associated organ injury to the brain, heart, kidneys, lungs, and liver is a major concern for sepsis patients. However, the molecular mechanisms underlying sepsis-associated organ injury remain incompletely understood. Ferroptosis, an iron-dependent non-apoptotic form of cell death characterized by lipid peroxidation, is involved in sepsis and sepsis-related organ damage, including sepsis-associated encephalopathy, septic cardiomyopathy, sepsis-associated acute kidney injury, sepsis-associated acute lung injury, and sepsis-induced acute liver injury. Moreover, compounds that inhibit ferroptosis exert potential therapeutic effects in the context of sepsis-related organ damage. This review summarizes the mechanism by which ferroptosis contributes to sepsis and sepsis-related organ damage. We focus on the emerging types of therapeutic compounds that can inhibit ferroptosis and delineate their beneficial pharmacological effects for the treatment of sepsis-related organ damage. The present review highlights pharmacologically inhibiting ferroptosis as an attractive therapeutic strategy for sepsis-related organ damage.

Case report: Alexander's disease with "head drop" as the main symptom and literature review.

Alexander's disease (AxD) is a rare autosomal dominant hereditary disorder that is caused by the mutations in the GFAP gene, which encodes the glial fibrillary acidic protein (GFAP). This neurogenerative disease has many clinical manifestations, and the onset of disease spans a wide range of ages, from newborns to children, adults, and even the elderly. An overaccumulation of the expression of GFAP has a close causal relationship with the pathogenesis of Alexander's disease. Usually, the disease has severe morbidity and high mortality, and can be divided into three distinct subgroups that are based on the age of clinical presentation: infantile (0-2 years), juvenile (2-13 years), and adult (>13 years). Children often present with epilepsy, macrocephaly, and psychomotor retardation, while adolescents and adults mainly present with muscle weakness, spasticity, and bulbar symptoms. Atonic seizures are a type of epilepsy that often appears in the Lennox-Gastaut syndrome and myoclonic-astatic epilepsy in early childhood; however, the prognosis is often poor. Atonic episodes are characterized by a sudden or frequent reduction in muscle tone that can be local (such as head, neck, or limb) or generalized. Here, we report a 4-year-old girl whose main symptoms were intermittent head drop movements, which could break the frontal frame and even bleed in severe conditions. A video-encephalography (VEEG) showed that the nodding movements were atonic seizures. A head magnetic resonance imaging (MRI) revealed abnormal signals in the bilateral paraventricular and bilateral subfrontal cortex. The gene detection analyses indicated that the GFAP gene exon 1 c.262 C>T was caused by a heterozygous mutation, as both her parents were of the wild-type. The girl had no other abnormal manifestations except atonic seizures. She could communicate normally and go to kindergarten. After an oral administration of sodium valproate, there were no atonic attacks. Although epilepsy is a common symptom of Alexander's disease, atonic seizures have not been reported to date. Therefore, we report a case of Alexander's disease with atonic seizures as the main symptom and provide a review of the literature.

Positive antithyroid antibody predicts severity of neuromyelitis optica spectrum disorder in children.

BACKGROUND: Neuromyelitis optica spectrum disease (NMOSD) is a rare autoimmune disease, which can coexist with autoimmune thyroid diseases (AITDS). There has been no report on the clinical characteristics of NMOSD in children with positive anti-thyroid antibodies (ATAbs). The aim of this study is to evaluate thyroid function and detect the difference between ATAbs seropositive and seronegative NMOSD children. METHODS: 108 children with a confirmed diagnosis of NMOSD who were admitted to Shengjing Hospital of China Medical University from January 2015 to September 2020 were enrolled and their thyroid functions were evaluated. They were divided into two groups by ATAbs abnormalities. Their demographic characteristics, clinical symptoms, laboratory and MRI scan results of the brain and spinal cord were assessed. RESULTS: ATAbs positive rate was higher in children with NMOSD when compared with healthy controls (P < 0.05). Most NMOSD children with positive ATAbs were female (P < 0.01). The expanded disability status scale (EDSS) score was significantly higher in the ATAbs positive group (P < 0.01). There were statistically significant differences for the incidence of bulbar area postrema symptoms, spinal cord symptoms, and fever of unknown origin of the first onset between the ATAbs positive and negative group (P < 0.05). The ANA and MOG antibody positive rate, longitudinally extensive transverse myelitis (LETM), and electroencephalogram (EEG) were significantly higher in ATAbs positive group (P < 0.05). CONCLUSION: MOG antibody-positive is a unique marker of aggravation of neurological dysfunction in ATAbs-positive NMOSD children. Monitoring ATAbs may play an important role in predicting the prognosis of NMOSD.

Overexpression of Human Aspartyl (Asparaginyl) ß-hydroxylase in NSCLC: Its Diagnostic Value by Means of Exosomes of Bronchoalveolar Lavage.

The human aspartyl ß-hydroxylase (ASPH) is overexpressed in tumor tissues. Bronchoalveolar lavage (BAL) is a diagnostic procedure for infections and malignancies. The aim of this study was to investigate whether tumor exosomes carrying ASPH gene marker were present in bronchoalveolar fluid of patients with non-small cell lung cancer (NSCLC). A tissue microarray analysis was applied to explore the expression of ASPH in different histologic NSCLC. The human NSCLC cell lines and normal bronchial cell lines were used to study exosomal ASPH exprerssion. A total of 27 NSCLC, 21 benign tumor, and 15 healthy controls underwent BAL. Immunohistochemistry was performed to study the ASPH expression in malignant and normal lung tissues. The expression characteristics of ASPH in different NSCLC and normal bronchial cells and pneumocytes were confirmed by cell blocks. A reverse transcription-quantitative polymerase chain reaction was carried out to study the levels of exosomal ASPH expression. Immunohistochemical staining of tissue microarray demonstrated that overexpression of ASPH was found in NSCLC tissues including adenocarcinoma, large cell carcinoma, and squamous cell carcinoma, but absent in adjacent normal tissues. All NSCLC specimens exhibited high levels of ASPH immunoreactivity, while nonmalignant and normal lung tissues exhibited a very low level of expression. Overexpression of ASPH was found in exosomes from NSCLC cell lines but absent from the normal bronchial cell line NL-20. ASPH level from BAL exosomes was significantly increased in NSCLC patients compared with that from nonmalignant or health group. Our method of isolation of BAL exosomes was easily performed in the clinical laboratory. BAL exosomal ASPH can be a potential biomarker for NSCLC diagnosis.

Case Report: A Case of Eyelid Myoclonic Status With Tonic-Clonic Seizure and Literature Review.

Eyelid myoclonus with or without absence epilepsy is a rare and usually misdiagnosed disease in the neurology department. It is an idiopathic general epileptic syndrome, the onset period is 6-8 years, and is more common in girls. It is characterized by rapid abnormal eye blinking, accompanied by upward rolling of the eye and slight backward movement of the head, with eye closure sensitivity and photosensitivity. The seizure is frequent and short, dozens or even hundreds of times a day; a small number of patients may have eyelid myoclonus status. We report a patient who visits the hospital for the first time with eyelid myoclonic problem; the patient continued to wink the eyes, eye rolled up, and backward movement of the head, accompanied by impairment of consciousness. Video electroencephalography (VEEG) suggests continued spike slow-wave, polyspike slow-wave. After the patient had 2, 4, 6, 8, 10, 12, and 14 Hz of intermittent photic stimulation (IPS), her seizures and epileptic discharges reduced or stopped. Seven min after giving stimulation at 20 Hz, the child developed an occipital-initiated tonic-clonic seizure, which demonstrated that after sufficient IPS stimulation, the occiput cortex became excited and initiated a brain network, leading to diffuse brain discharge and tonic-clonic seizures. At 1 h after onset, the child developed a nonconvulsive state, with impairment of consciousness despite no eyelid myoclonic movements, and VEEG suggested a large number of epileptic discharges. After 10 min of administrating midazolam, the patient's EEG immediately became normal, and the patient regained consciousness. Therefore, this paper presents an eyelid myoclonus status patient with occipital origin seizure, we recorded the whole course of the disease and the treatment effect, and reviewed the literature accordingly.

Life Cycle Impact Assessment of Garbage-Classification Based Municipal Solid Waste Management Systems: A Comparative Case Study in China.

Confronted with a series of problems caused by surging generation of municipal solid waste (MSW), the Chinese central and local governments have promulgated and implemented policies to deal with them, including promotions of the classification of MSW. However, to date, practical knowledge and understanding about benefits for garbage classification from its environmental performance perspective is still limited. The present study is purposed to comprehensively investigate the environmental effects of garbage classification on municipal solid waste management (MSWM) systems based on three proposed garbage classification scenarios in China, via a comparative life cycle impact assessment (LCIA). Taking advantage of Impact Assessment of Chemical Toxics (IMPACT) 2002+ method, this comparative LCIA study can quantitatively evaluate midpoint, endpoint, and single scored life cycle impacts for the studied MSWM systems. A Monte Carlo uncertainty analysis is carried out to test the effectiveness and reliabilities of the LCIA results. The LCIA and uncertainty analysis results show that MSWM systems based on various garbage classification scenarios have significant variations in the studied midpoint, endpoint, and single scored environmental impacts. Different garbage classification scenarios have their individual environmental-friendly superiority for specific impact categories. Overall, results of this study demonstrate that MSW treatment systems integrated with garbage classification are more environmentally friendly by comparison with non-classification; and that the more elaborate the level of MSW classification, the smaller its impacts on the environment.

Life Cycle Assessment on Wave and Tidal Energy Systems: A Review of Current Methodological Practice.

Recent decades have witnessed wave and tidal energy technology receiving considerable attention because of their low carbon emissions during electricity production. However, indirect emissions from their entire life cycle should not be ignored. Therefore, life cycle assessment (LCA) has been widely applied as a useful approach to systematically evaluate the environmental performance of wave and tidal energy technologies. This study reviews recent LCA studies on wave and tidal energy systems for stakeholders to understand current status of methodological practice and associated inherent limitations and reveal future research needs for application of LCA on wave and tidal technologies. The conformance of the selected LCAs to ISO 14040 (2006) and 14044 (2006) are critically analyzed in strict accordance with the ISO stepwise methodologies, namely, goal and scope definition, life cycle inventory (LCI) analysis, as well as life cycle impact assessment (LCIA). Our systematically screening of these studies indicates that few of the selected studies are of strict conformance with ISO 14040 and 14044 standards, which makes the results unreliable and thus further reduces the confidence of interested stakeholders. Further, our review indicates that current LCA practice on wave and tidal energies is lacking consideration of temporal variations, which should be addressed in future research, as it causes inaccuracy and uncertainties.

Efficacy of postoperative intraperitoneal hyperthermic perfusion chemotherapy with oxaliplatin + 5-Fluorouracil in the treatment of gastric cancer patients with peritoneal carcinomatosis.

PURPOSE: To explore the effect of palliative laparoscopic resection of gastric cancer combined with intraperitoneal hyperthermic perfusion chemotherapy (IHPC) with oxaliplatin + 5-fluorouracil (5-FU) on gastric cancer patients with peritoneal carcinomatosis (PC). METHODS: 90 patients definitely diagnosed with gastric adenocarcinoma and PC and admitted to our hospital from March 2013 to March 2016 were collected and divided into IHPC group (n=45) and control group (n=45). In IHPC group, IHPC with oxaliplatin + 5-FU was carried out for the first time on the first day after operation, and then it was conducted once every other day for a total of 4 times. The clinical efficacy, quality of life, adverse reactions, postoperative tumor recurrence and survival of the patients were observed and recorded. RESULTS: The total effective rates in IHPC group and control group were 62.2% (28/45) and 55.6% (25/45), respectively (p>0.05). In both groups, the curative effect was the best in moderately differentiated adenocarcinoma and worst in signet ring cell carcinoma. Besides, the effective rates of Karnofsky performance status (KPS) in the two groups after operation were 82.2% (37/45) and 75.6% (34/45), respectively (p=0.606). However, the renal function indexes, serum creatinine (sCr) and blood urea nitrogen (BUN) in the two groups of patients after operation were increased, and those in the IHPC group were higher than those in the control group (p=0.016, p=0.010). Moreover, follow-up results of patients' survival revealed that the OS and PFS in the IHPC group were significantly higher than those in the control group (p=0.041, p=0.045). CONCLUSIONS: Palliative laparoscopic resection of gastric cancer combined with IHPC with oxaliplatin +5-FU has a definite therapeutic effect on gastric cancer with PC, which can achieve a better short-term clinical therapeutic effect and better postoperative quality of life.

Efficient extraction and characterization of pectin from orange peel by a combined surfactant and microwave assisted process.

Surfactant and microwave assisted extraction (S-MAE) was used for pectin extraction from orange peel. First, we optimized the conditions of microwave assisted extraction (MAE), e.g., irradiation time, liquid-to-solid ratio (LSR), and pH on pectin yield (PY), galacturonic acid (GA) content, and degree of esterification (DE) using a Box-Behnken design. Under optimal conditions (pH 1.2, 7.0 min, and 21.5 v/w LSR), we obtained a PY of 28.0 ±â€¯0.5%, which was close to the predicted value (31.1%). Second, we analyzed the effect of surfactant on microwave extraction of pectin. Among the surfactants investigated, Tween-80 (8 g/L, w/v) increased PY by 17.0%. Compared with conventional solvent extraction, S-MAE is a novel and efficient method for pectin extraction, which generated a higher (p < 0.05) PY (32.8%), GA content (78.1%), DE (69.8%), and Mw (286.3 kDa).

Association between clinical features and YMDD mutations in patients with chronic hepatitis B following lamivudine therapy.

The aim of the present study was to investigate the correlation between feature and genotype with regard to the tyrosine-methionine-aspartate-aspartate (YMDD) mutation in chronic hepatitis B patients after lamivudine (LAM) therapy. A total of 30 patients with chronic hepatitis B were recruited, who underwent one year of LAM therapy. The patients' alanine aminotransferase (ALT) level and hepatitis B envelope antigen (HBeAg) seroconversion were evaluated, hepatitis B virus (HBV) DNA was genotyped using a new genotyping method and YMDD mutations were analyzed prior to treatment and at 6 and 12 months after LAM treatment. Furthermore, the secondary protein structure of the HBV DNA polymerase gene (P gene) was analyzed. Following treatment, the results suggested that LAM therapy improved ALT normalization. There was no correlation between clinical effects and ALT level before treatment. After 12 months treatment, the rate of HBeAg loss increased and the rate of HBeAg seroconversion decreased linearly with the rise of baseline ALT level. While ALT normalization and HBeAg seroconversion were highest in patients with HBV genotype B, HBeAg loss and HBVDNA loss were highest in those with genotype C. The effect was predominant in genotype D. No YMDD mutations were identified prior to 6 months of LAM therapy. The rate of YMDD mutations after 12 months LAM therapy was 12.12%. Two patients with rtM204V + rtL180M belonged to genotype C and another patient with rtL180M alone belonged to genotype D. The turn of secondary protein structure of P gene changed to ß sheet when a rtM204V mutation occurred, and no change of secondary protein structure was associated with the rtL180M mutation. Thus, the present results indicate that one year of LAM therapy is able to improve ALT normalization. Long-term LAM therapy may induce YMDD mutation and drug resistance.

Apoptotic events induced by high glucose in human hepatoma HepG2 cells involve endoplasmic reticulum stress and MAPK's activation.

To investigate whether endoplasmic reticulum (ER) stress participates in the induction of apoptosis in HepG2 cells exposed to high glucose and explore its probable mechanism. A series of experiments were performed following HepG2 cells treated with different concentrations of glucose for 48 h. The apoptosis was detected by means of Hoechst staining and flow cytometry. Caspase-3 activity assay was performed by measuring the pNA (p-nitroaniline) to indirectly reveal the catalytic activity of caspase-3. The expression levels of apoptosis-, ER stress-associated proteins and MAPKs were analyzed by western blot. To further characterize the molecular mechanisms, the effects of antioxidant alpha-lipoic acid (ALA) and specific inhibitors for JNK and p38 (SP600125 and SB203580, respectively) were examined by Hoechst staining, immunofluorescence, and western blot. After HepG2 cells were incubated with high glucose for 48 h, both Hoechst staining and flow cytometry analyses unveiled the apoptosis of HepG2 cells. Caspase-3 activity assay revealed that the activity of caspase-3 was enhanced. Western blot showed an enhancement of pro-caspase-9 degradation, a reduction of Bcl-2/Bax ratio, a decrease in GRP78 expression, and increases in CHOP and p47/phox levels. In addition, western blot analysis presented that phosphorylation of p38 and JNK was triggered and that the expression of ASK1 was elevated. In the case of the contributions of oxidative stress and the MAPK signaling pathways, all ALA, SP600125 and SB203580 were able to largely rescue high glucose-induced apoptosis. High glucose induced the apoptosis in HepG2 cells through the activation of ASK1-p38/JNK pathway mediated by ER stress and oxidative stress.