ABSTRACT
BACKGROUND: Approximately 2%-8% of non-small-cell lung cancer (NSCLC) harbors concurrent epidermal growth factor receptor (EGFR) sensitizing mutation and mesenchymal-epithelial transition factor (MET) amplification prior to EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy. This study aimed to investigate the optimal first-line therapeutic options for patients with concurrent EGFR-mutant, MET-overexpressed/amplified advanced NSCLC. METHODS: A total of 104 treatment-naïve patients with EGFR-mutant de novo MET-overexpressed advanced NSCLC were identified using immunohistochemistry and stratified to four groups according to treatment regimen: EGFR-TKI monotherapy (n = 48), EGFR-TKI combined with either crizotinib (n = 9) or chemotherapy (n = 12), and chemotherapy (n = 35). A subpopulation of 28 patients was also tested with next-generation sequencing (NGS). Objective response rate (ORR) and progression-free survival (PFS) outcomes were analyzed according to treatment strategies and molecular features. RESULTS: All the patients (n = 104) achieved ORR of 36.5% and median PFS (mPFS) of 7.0 months. Baseline clinicopathologic characteristics were similar among the four treatment groups. Compared with chemotherapy, EGFR-TKI monotherapy or EGFR-TKI combination therapy achieved significantly higher ORR (P < 0.001) and longer mPFS (P = 0.003). No ORR or PFS difference was observed between EGFR-TKI monotherapy and combination therapy. In the NGS-identified population (n = 28), patients who received EGFR-TKI plus crizotinib (n = 9) achieved similar ORR (88.9% versus 57.9%, P = 0.195) and mPFS (9.0 versus 8.5 months, hazard ratio 1.10, 95% confidence interval 0.43-2.55, P = 0.45) than those who received EGFR-TKI monotherapy (n = 19), regardless of MET copy number status. Grade 3/4 rashes were significantly more among patients who received EGFR-TKI plus crizotinib (P = 0.026). CONCLUSIONS: Our findings provided clinical evidence that patients with concurrent EGFR sensitizing mutation and de novo MET amplification/overexpression could benefit from first-line EGFR-TKI monotherapy.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
OBJECTIVE: To evaluate the efficacy of tunnel technique (TUN) in treatment of teeth with adjacent gingival regression (GR) combined with noncarious cervical lesions (NCCL). METHODS: We collected data from 21 patients (79 teeth) undergoing TUN surgery for GR combined with NCCL. According to GR depth (GRD) and lesion depth (LD) of NCCL, the teeth were divided into group 1 with GRD≤3 mm and LD≤1 mm; group 2 with GRD≤3 mm and LD>1mm; group 3 with GRD>3 mm and LD≤1 mm; and group 4 with GRD>3 mm and LD>1 mm. The mean root coverage (MRC) rate, complete root coverage (CRC) rate, keratinized gingival width, and keratinized gingival thickness were compared among the 4 groups after TUN surgery. RESULTS: The keratinized gingival width and thickness were significantly improved after the surgery in the 4 groups. When the GRD was below 3 mm, the MRC was not significantly different between group 1 and group 2 (8.55% vs 95.45%, P>0.05); When the GRD was beyond 3 mm, the MRC and CRC rates were both decreased in group 3 and group 4, especially in group 4, where the CRC rate (25%) was significantly lower than those in the other 3 groups (P < 0.01). CONCLUSION: In patients with GR combined with NCCL, TUN surgery can obviously improve keratinized gingival width and thickness. GRD has a greater effect on the outcome of root coverage than LD, suggesting that NCCL restoration before TUN surgery may not be necessary. Both GRD and LD should be considered in the evaluation of the clinical efficacy of TUN surgery.
Subject(s)
Gingival Recession , Gingival Recession/surgery , HumansABSTRACT
Objective: To examine treatment outcomes of breast phyllodes tumors and the prognosis factors of local recurrence. Methods: This retrospective cohort study included 276 patients who underwent surgical resection at Breast Center, Peking University People's Hospital from January 2011 to December 2019. Tumor subtype and histopathological features were determined from pathology reports, and the deadline of follow-up was September 30th, 2020. All 276 patients underwent open surgery, including 17 patients of mastectomy, and 259 patients of lumpectomy. The enrolled patients were all female, with age of (41.5±11.3) years (rang: 11 to 76 years), and tumor diameter of 35(28) mm (M(QR)). The Kaplan-Meier method and Log-rank test were used for survival analysis. The multivariate analysis was implemented using the Cox proportional hazard model. Results: According the pathologic test, there were 191 patients of benign phyllodes tumor, 67 patients of borderline tumor and 18 patients of malignant tumor. There were 249 patients with a follow-up of more than 6 months, and 14.1% (35/249) had local recurrence. The time-to-recurrence was (28.6±22.2) months (range: 2 to 96 months), (29.1±18.1) months (range: 2 to 80 months), (32.1±30.1) months (range: 5 to 96 months) and (12.0±6.9) months (range: 8 to 20 months) for benign, borderline and malignant phyllodes tumors. Tumor diameter (≥100 mm vs.<50 mm, HR=3.968, 95%CI: 1.550 to 10.158, P=0.004) and malignant heterologous element (yes vs. no, HR=26.933, 95%CI: 3.105 to 233.600, P=0.003) were prognosis factors of local recurrence. One death from malignant phyllodes occurred after distant metastasis. The 3-year disease-free survival rates of benign, borderline and malignant phyllodes tumor were 88.2%, 81.7% and 81.4% (P=0.300). Conclusion: Phyllodes tumors have a considerable local recurrence rate, which may be associated with tumor diameter and malignant heterologous element.
Subject(s)
Breast Neoplasms , Neoplasm Recurrence, Local/diagnosis , Phyllodes Tumor , Adult , Breast Neoplasms/surgery , Female , Humans , Mastectomy , Middle Aged , Phyllodes Tumor/surgery , Prognosis , Retrospective StudiesABSTRACT
To improve and perfect the quality standards and propose recommendations for the revision of quality standards for Andrographis Herba and its processed slices in Chinese Pharmacopoeia(ChP)(2020 edition) based on the problems and limitations in ChP(2015 edition). TLC identification method with andrographolide and control herbs as references was established using silica gel G thin layer plate, with chloroform-methylbenzene-methanol(8â¶1â¶1) as developing solvent, and 10% sulfuric acid ethanol solution as colour-developing agent. This method has good reproducibility, strong specificity and high sensitivity. As compared with the original method in ChP 2015, this method has better development effect and clearer spots. Based on the previous research, a quantitative analysis of multi-components by single-marker(QAMS) method with andrographolide as the internal reference substance was developed to simultaneously determine the contents of 4 diterpene lactones: andrographolide(S), neoandrographolide(A), 14-deoxyandrographolide(B), and dehydroandrographolide(C). The relative correction factors of f_(A/S), f_(B/S), and f_(C/S) were determined as 1.12, 0.79, and 0.63, respectively. The relative retention time of t_(A/S), t_(B/S), and t_(C/S) was 1.95, 2.18, and 2.25, respectively. According to the content determination results in 46 batches of crude drugs and 38 batches of processed slices, it was stipulated that the total contents of 4 diterpene lactones should not be less than 1.5% and 1.2% in crude drugs and processed slices, respectively. As compared with the original method in ChP 2015, the present QAMS method could not only reduce the detection cost and improve the efficiency, but also can be used to evaluate the quality of Andrographis Herba and its processed slices more comprehensively and objectively. Diterpene lactones are generally recognized as the effective components in Andrographis Herba, and their contents in leaves were much higher than those in stems. However, almost all of the current commercial processed slices are processed from stems, so their quality is gene-rally poor and the efficacy is hard to be guaranteed. Therefore, the weight percentage of leaves should be added into the inspection items of the processed slices and it should not be less than 25%.
Subject(s)
Andrographis , Drugs, Chinese Herbal , Chromatography, High Pressure Liquid , Diterpenes/analysis , Reproducibility of ResultsABSTRACT
Objective: To study the clinicopathologic features and the key points of differential diagnosis of appendiceal diverticulosis (AD) and low-grade mucinous neoplasm (LAMN) to avoid over-diagnosis. Methods: The clinical data, pathologic features and follow-up information of 20 patients with AD, who were diagnosed in the Peking University Third Hospital from January 2010 to November 2019 were collected and compared with 44 cases of LAMN which were diagnosed during the same period. Results: Among the 20 cases of AD, hypermucinous epithelium, filiform villi or undulating epithelium and mucosa atrophy were observed in 10 (50.0%), 4 (20.0%) and 14 (70.0%) cases, respectively, however, focally loss of lamina propria and mucosa/submucosa fibrosis were observed only in 1 (5.0%) and 4 (20.0%) cases, respectively. Extramural mucin deposits were seen in 11 (55.0%) cases, all were acellular mucin. Mucosal Schwann cell hyperplasia were present in 12 (60.0%) cases. Nine (45.0%) and 5 (25.0%) cases were associated with acute diverticulitis or acute suppurative appendicitis, respectively. In comparison with AD, LAMN cases more frequently showed hypermucinous epithelium (42/44, 95.5%), filiform villi or undulating epithelium (43/44, 97.7%), loss of lamina propria (43/44, 97.7%) and fibrosis and hyalinization of appendiceal wall (44/44, 100.0%), whereas mucosal atrophy (4/44, 9.1%) and Schwann cell hyperplasia(11/44, 25.0%) were less frequently seen (P<0.05). Follow-up information was available for 10 AD patients and 27 LAMN patients; all were alive without evidence of recurrence. Conclusions: Epithelial hyperplasia, loss of lamina propria, fibrosis of the appendiceal wall and extramural mucin deposits may occur focally in AD and should be distinguished from LAMN. The preservation of normal appendiceal mucosa architecture, lack of diffuse appendiceal wall fibrosis and hyalinization, and no definite neoplastic epithelium are the key point for preventing over-diagnosis.
Subject(s)
Adenocarcinoma, Mucinous , Appendiceal Neoplasms , Appendix , Diverticulum , Humans , MucinsABSTRACT
ABSTRACT: The number of death from insulin overdose, including accidental poisoning, suicide and homicide, is increasing these years. The forensic diagnosis of death from insulin overdose is a tough task. Glucose is the main energy source of the brain. Therefore, hypoglycemic brain damage is considered to be the main reason of death from insulin overdose. Recently, research of hypoglycemic brain damage caused by insulin overdose is gradually being paid attention in the field of forensic medicine. This paper summarizes the neuropathologic changes, pathophysiologic process and potential neural molecular markers of hypoglycemic brain damage caused by insulin overdose in terms of forensic neuropathology, providing reference for the research and practice in forensic medicine related fields.
Subject(s)
Brain , Drug Overdose , Humans , Hypoglycemic Agents , Insulin , NeuropathologyABSTRACT
ABSTRACT: Objective To summarize the characteristics of cases of electrocution due to direct current ï¼DCï¼ electronic hunter, and to provide references for forensic identification. Methods Four cases of electrocution due to DC electronic hunter were collected. Statistical analysis was carried out from the perspective of the scene and electric marks distribution, damage characteristics and histopathological changes. Results All the 4 cases of electrocution were accidental events. There were multiple electric marks, most of which were located in the lower limbs with serious damage. Some strip type electric marks were visible. Conclusion The distribution, morphological characteristics and severity of the electric marks caused by DC electronic hunter are different from those of the ordinary low-voltage alternating current damage. It is alerting that there would be actions of destroying the scene and abandoning the corpse in such cases.
Subject(s)
Electric Injuries/mortality , Electricity/adverse effects , Cadaver , Electric Injuries/pathology , Fatal Outcome , Forensic Pathology/methods , Humans , Lower ExtremityABSTRACT
BACKGROUND AND PURPOSE: Flow diversion is an established method to treat complex intracranial aneurysms. The natural history of flow-diversion treatment failure resulting in aneurysm remnants is not well-defined. We aimed to delineate the clinical and angiographic features of this entity. MATERIALS AND METHODS: Review of a prospectively maintained Pipeline Embolization Device data base from inception to October 2017 was performed for aneurysms that demonstrated residual filling on follow-up imaging. Procedural and follow-up clinical details were recorded. Independent, blinded, angiographic assessment of occlusion was performed on the basis of the O'Kelly-Marotta scale. Aggregated outcomes were analyzed using the Fisher exact and Mann-Whitney U tests for categoric and continuous variables, respectively (statistical significance, α = .05). RESULTS: During the study period, 283 sequential patients were treated; 87% (246/283) were women. The median patient age was 55 years (interquartile range, 47-65 years). Six-month follow-up imaging was available in 83.7% (237/283) of patients, which showed 62.4% (148/237) complete occlusion (class D, O'Kelly-Marotta grading scale). Adjunctive coiling (P = .06), on-label Pipeline Embolization Device use (P = .04), and multiple device constructs (P = .02) had higher rates of complete occlusion at 6 months. Aneurysm remnants were identified in 25 cases on long-term follow-up imaging (median, 16 months; interquartile range, 12-24 months). No patient with an aneurysm remnant after flow diversion presented with delayed rupture or other clinical sequelae, with a median clinical follow-up of 31 months (interquartile range, 23-33 months). CONCLUSIONS: Aneurysm remnants after flow diversion are infrequent with minimal clinical impact. When appropriate, the presence of overlapping devices and possibly adjunctive coiling may result in higher rates of complete occlusion.
Subject(s)
Blood Vessel Prosthesis , Endovascular Procedures/instrumentation , Endovascular Procedures/methods , Intracranial Aneurysm/pathology , Intracranial Aneurysm/therapy , Adult , Aged , Female , Humans , Longitudinal Studies , Male , Middle Aged , Retrospective Studies , Treatment OutcomeABSTRACT
High-risk human papillomavirus (HPV) is an important pathogenic factor for cervical cancer and understanding the mechanism of HPV gene transcription is important for the prevention and therapy of HPV related cervical cancer. This study aimed to investigate the role of nitric oxide (NO) in the regulation of HPV gene transcription. SiHa cells containing integrated HPV16 were treated with NO donor DETA-NO and cell proliferation and cytotoxicity were determined. HPV gene transcription was detected by real-time PCR. We found no significant cytotoxic effects on SiHa cells when the concentration of DETA-NO was less than 0.5 mmol/l. The transcription of HPV E6 gene was inhibited by DETA-NO in a dose-dependent manner and the best inhibitory effect was observed at 0.5 mmol/l DETA-NO. In addition, ERK inhibitor U0126 decreased the transcription of HPV E6 gene at the concentration of 30 µmol/l. In conclusion, NO inhibits the transcription of HPV E6 gene and probably involves MAPK signaling pathway. Keywords: SiHa cells; nitric oxide; MAPK pathway; HPV transcription.
Subject(s)
Nitric Oxide , Oncogene Proteins, Viral , Papillomaviridae , Cell Line, Tumor , Humans , Nitric Oxide/pharmacology , Oncogene Proteins, Viral/genetics , Papillomaviridae/drug effectsABSTRACT
Distributed compressed sensing techniques are applied to enhance sparse channel estimation performance in underwater acoustic multiband systems. The core idea is to use receptions from multiple sub-bands to enhance the detection of channel tap positions. A known variant of the orthogonal matching pursuit (OMP) algorithm based on the distributed compressed sensing principle is simultaneous orthogonal matching pursuit (SOMP). However, the impulse responses across multiple sub-bands may have different arrival structures, although they often show a certain level of similarity. To address such differences at the sub-bands, a multiple selection strategy is applied to select multiple candidates at individual sub-bands at each iteration. This is different from the conventional OMP and SOMP algorithms that select only one candidate at each iteration. When the multiple selection strategy is combined with the SOMP algorithm, the proposed algorithm is referred to as JB-MSSOMP algorithm. To take advantage of channel coherence between adjacent data blocks from different sub-bands, the multiple selection strategy is further used over time. This leads to JBT-MSSOMP algorithm. Computer simulations show improved channel estimation performance of the proposed JB-MSSOMP and JBT-MSSOMP algorithms over the OMP or SOMP algorithms. Communication data from a recent acoustic experiment demonstrates improved receiver performance with the proposed channel estimators.
ABSTRACT
While it has been recognized that the multipath structure of the underwater acoustic (UWA) channel offers the potential for compressed sensing (CS) sparsity exploitation, the rapidly time varying arrivals induced by highly dynamic surfaces unfortunately pose significant difficulties to channel estimation. From the viewpoint of underwater acoustic propagation, with the exception of the highly time varying arrivals caused by dynamic surface, generally there exist relatively stationary or slowly changing arrivals caused by direct path or bottom reflection, which imply the adoption of a discriminate estimation method to handle sparse components with different time variation scale. By modeling the time varying UWA channels as a sparse set consisting of constant and time-varying supports, in this paper, estimation of time varying UWA channel is transformed into a problem of dynamic compressed sensing sparse recovery. The combination of a Kalman filter and compressed sensing is adopted to pursue the solution of it. Numerical simulations demonstrate the superiority of the proposed algorithm. In the form of a channel-estimation-based decision-feedback equalizer, the experimental results with the field data obtained in a shallow water acoustic communication experiment indicate that the proposed dynamic compressed sensing algorithm outperforms classic algorithms as well as CS algorithms.
ABSTRACT
BACKGROUND: The aim of this study was to determine whether the protective effects of brief and repeated ischemic postconditioning (IPoC) are associated with the modulation of cystathionine γ-lyase (CSE) expression after renal ischemia/reperfusion (I/R) injury in diabetes mellitus (DM). METHODS: We subjected diabetic rats to 45 minutes of ischemia followed by reperfusion at 24 hours. Before reperfusion, diabetic rats were treated with 3 cycles of 6 seconds of reperfusion, followed by 6 seconds of ischemia. DL-Propargylglycine (PAG, a CSE inhibitor) was administered to the diabetic rats to investigate its effects on the severity of renal I/R injury in diabetes mellitus (DM). Blood samples and left kidneys were collected for the measurement of blood urea nitrogen (BUN) and serum creatinine (SCr) levels and renal pathologic changes. Western blot and immunochemistry techniques were also performed for the localization of CSE. Levels of superoxidase dismutase (SOD), malonyldialdehyde (MDA), tumor necrosis-alpha (TNF-α), and hydrogen sulfide (H2S) were quantified using commercially available kits. RESULTS: The results showed that BUN and SCr levels increased on renal ischemia/reperfusion injury (RI/RI) in the DM group. Diabetic rats treated with IPoC exhibited significantly less renal damage on I/R. Kit measurements showed that IPoC could markedly inhibit the levels of MDA and TNF-α and also improve SOD and H2S levels. Western blot and immunochemistry showed that expression of CSE was downregulated on I/R in the DM group and IPoC upregulated CSE expression, whereas PAG treatment resulted in opposite effects. CONCLUSION: Our findings show that brief and repeated IPoC increased the expression of CSE after I/R in DM, and the modulation of CSE may underlie the renoprotective effect of IPoC.
Subject(s)
Cystathionine gamma-Lyase/metabolism , Diabetes Mellitus, Experimental/pathology , Ischemic Postconditioning/methods , Kidney/pathology , Reperfusion Injury/pathology , Animals , Diabetes Mellitus, Experimental/enzymology , Kidney/enzymology , Male , Rats , Rats, Sprague-Dawley , Reperfusion Injury/enzymologyABSTRACT
Insulin as a common clinical hypoglycemic agent can effectively control serves to lower the concentration of blood glucose. However, insulin overdose can lead to death. In the whole fatal cases of insulin overdose, medical accident is the most common, followed by suicide. Though insulin homicide is extremely rare, it deserves great attention. Though there are some researches about insulin poisoning on forensic toxicology and pathology, it is still a difficult task in forensic practice. In this paper, the mechanism of death, pathological changes, detection methods and diagnose criteria of insulin overdose will be discussed in the view of forensic toxicology and pathology. We hope that this paper could enhance relative knowledges of insulin poisoning for medical examiners.
Subject(s)
Drug Overdose , Forensic Toxicology , Hypoglycemic Agents/poisoning , Insulins/poisoning , Poisoning/pathology , Accidents , Death , Homicide , Humans , Hypoglycemic Agents/therapeutic use , Insulins/therapeutic use , SuicideABSTRACT
Objective: To investigate the prevalence of galactosemia(GAL), and the characteristics of genotype and phenotype of newborns who were confirmed with GAL in newborn screening in Zhejiang province. Method: The number of all live births, newborn screened infants and all clinical data of confirmed newborns with GAL from October 2013 to March 2015 were retrospectively analyzed by reviewing the data of Zhejiang Province screening center database. And the characteristics of genes and the clinical data of GAL cases who were confirmed by correlative gene test and enzyme activity measurement were analyzed. Result: The prevalence of GAL in Zhejiang province was 1/189 857. Among them, there was 1 case confirmed with GAL typeâ (prevalence, 1/759 428), with mutations of c. 904+ 1G>T and c. 687G>A, the enzyme activity of galactose-1-phosphate uridyltransferase (GALT) was 56.4% of controls. And there was 1 case of GAL typeâ ¡(prevalence, 1/759 428), with mutations of c. 85G>T and c. 502G>A. There were 2 cases confirmed with GAL type â ¢(prevalence, 1/379 714), with mutations of c. 505C>T, c. 452G>A, c. 280G>A and c. 925G>A, the enzyme activity of UDP-galactose-4'-epimerase (GALE) were 42% and 38% of controls, respectively. All cases had different abnormal biochemical marks of liver function, and 1 case had combined hyperlactacidemia or hyperammonemia or increase of multiple kinds of amino acids, respectively. The newborn of GAL type â ¡ had phacoscotasmus before treatment. All the cases were fed with lactose free milk powder, and all the abnormal parameters were improved during following up. Conclusion: The disease of GAL is rare in Zhejiang province, and its genotype distribution is scattered with comparatively mind clinical manifestations, and the cases with early treatment with lactose free milk powder have good prognosis. All cases needed to be treated and followed up for a life-long time. It is recommended that the high risk cases with GAL should be screened as soon as possible.
Subject(s)
Galactosemias/diagnosis , Neonatal Screening , Genetic Testing , Genotype , Humans , Infant , Infant, Newborn , Mutation , Phenotype , Prevalence , UDPglucose 4-Epimerase , UTP-Hexose-1-Phosphate UridylyltransferaseABSTRACT
BACKGROUND AND PURPOSE: Cerebral thermoregulation remains poorly understood. Temperature dysregulation is deeply implicated in the potentiation of cerebrovascular ischemia. We present a multiphasic, MR thermographic study in a nonhuman primate model of MCA infarction, hypothesizing detectable brain temperature disturbances and brain-systemic temperature decoupling. MATERIALS AND METHODS: Three Rhesus Macaque nonhuman primates were sourced for 3-phase MR imaging: 1) baseline MR imaging, 2) 7-hour continuous MR imaging following minimally invasive, endovascular MCA stroke induction, and 3) poststroke day 1 MR imaging follow-up. MR thermometry was achieved by multivoxel spectroscopy (semi-localization by adiabatic selective refocusing) by using the proton resonance frequency chemical shift. The relationship of brain and systemic temperatures with time and infarction volumes was characterized by using a mixed-effects model. RESULTS: Following MCA infarction, progressive cerebral hyperthermia was observed in all 3 subjects, significantly outpacing systemic temperature fluctuations. Highly significant associations were observed for systemic, hemispheric, and global brain temperatures (F-statistic, P = .0005 for all regressions) relative to the time from stroke induction. Significant differences in the relationship between temperature and time following stroke onset were detected when comparing systemic temperatures with ipsilateral (P = .007), contralateral (P = .004), and infarction core (P = .003) temperatures following multiple-comparisons correction. Significant associations were observed between infarction volumes and both systemic (P ≤ .01) and ipsilateral (P = .04) brain temperatures, but not contralateral brain temperature (P = .08). CONCLUSIONS: Successful physiologic and continuous postischemic cerebral MR thermography was conducted and prescribed in a nonhuman primate infarction model to facilitate translatability. The results confirm hypothesized temperature disturbance and decoupling of physiologic brain-systemic temperature gradients. These findings inform a developing paradigm of brain thermoregulation and the applicability of brain temperature as a neuroimaging biomarker in CNS injury.
Subject(s)
Body Temperature Regulation/physiology , Infarction, Middle Cerebral Artery/physiopathology , Magnetic Resonance Imaging/methods , Stroke/physiopathology , Thermometry/methods , Animals , Disease Models, Animal , Female , Macaca mulatta , Male , TemperatureABSTRACT
Objective: To investigate the incidence, clinical, biochemical and gene mutation characteristics of short chain acyl-coenzyme A dehydrogenase deficiency (SCADD). Method: From January, 2009 to October, 2015, a retrospective analysis of the urine organic acids and acyl-coenzyme A dehydrogenase (ACADS) gene mutation characteristics of patients diagnosed as SCADD by newborn screening using tandem mass spectrometry in Department of Genetics and Metabolism (Newborn screening Center of Zhejiang Province), Children's Hospital, Zhejiang University School of Medicine. Dietary guidance, life management and supplementation of L-carnitine were conducted, and growth and intelligence development were observed during follow-up among the SCADD patients. Result: A total of 1 430 024 neonates, seventeen cases were diagnosed with SCADD with an incidence of 1/84 117. All patients had no clinical symptoms, and intelligence and physical development were normal. Blood butylacyl-carnitine (C4) levels and the ratios increased, C4 0.713.14 µmol/L(reference value 0.03-0.48 µmol/L), C4/C2 0.07-0.23(reference value 0.01-0.04), C4/C3 0.65-2.04(reference value 0.05-0.39). Thirteen with increased urinary ethyl malonic acid (9.30-90.99 mg/g creatinine (reference value 0-6.20 mg/g creatinine )), one patient was accompanied by increased methyl succinic acid (12.33 mg/g creatinine(reference value 0-6.40 mg/g creatinine)), one subject with increased acetylglycine (3.52 mg/g creatinine(reference value 0-0.70 mg/g creatinine)). A total of 13 known mutations were detected in the ACADS gene, 1 homozygous mutation (c.1031A>G), the others are compound heterozygous mutations. One frameshift mutation (c.508_509delGC) and 12 missense mutations were detected. Common mutation were c. 1031A>G(35.3%), c. 164C>T(20.6%) and c. 991G>A(11.8%). SCADD in newborn screening program had no clinical symptoms and normal growth development after 8-42 months follow-up. Conclusion: Cases with SCADD had no clinical symptoms with an incidence of 1/84117. The c. 164C>T and c. 1031A>G may be the common mutations.
Subject(s)
Acyl-CoA Dehydrogenase/deficiency , Amino Acid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/genetics , Neonatal Screening/methods , Acyl-CoA Dehydrogenase/blood , Acyl-CoA Dehydrogenase/genetics , Amino Acid Metabolism, Inborn Errors/blood , Amino Acid Metabolism, Inborn Errors/ethnology , Carnitine/blood , Child , China/epidemiology , Homozygote , Humans , Incidence , Infant, Newborn , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/ethnology , Male , Mutation , Retrospective Studies , Tandem Mass SpectrometryABSTRACT
BACKGROUND: ACAT-related enzyme 2 required for viability 1 (ARV1) is a putative lipid transporter of the endoplasmic reticulum that is conserved across eukaryotic species. The ARV1 protein contains a conserved N-terminal cytosolic zinc ribbon motif known as the ARV1 homology domain, followed by multiple transmembrane regions anchoring it in the ER. Deletion of ARV1 in yeast results in defective sterol trafficking, aberrant lipid synthesis, ER stress, membrane disorganization and hypersensitivity to fatty acids (FAs). We sought to investigate the role of Arv1 in mammalian lipid metabolism. METHODS: Homologous recombination was used to disrupt the Arv1 gene in mice. Animals were examined for alterations in lipid and lipoprotein levels, body weight, body composition, glucose tolerance and energy expenditure. RESULTS: Global loss of Arv1 significantly decreased total cholesterol and high-density lipoprotein cholesterol levels in the plasma. Arv1 knockout mice exhibited a dramatic lean phenotype, with major reductions in white adipose tissue (WAT) mass and body weight on a chow diet. This loss of WAT is accompanied by improved glucose tolerance, higher adiponectin levels, increased energy expenditure and greater rates of whole-body FA oxidation. CONCLUSIONS: This work identifies Arv1 as an important player in mammalian lipid metabolism and whole-body energy homeostasis.
ABSTRACT
BACKGROUND AND PURPOSE: Current nonhuman primate stroke models are limited by either stroke variability or survivability. A new nonhuman primate stroke model was developed by using endovascular trapping techniques to limit collateral vessels with serial MR imaging and neurologic assessments. MATERIALS AND METHODS: Eight adult rhesus monkeys (female, 7-13 years of age) underwent MR imaging and Spetzler neurologic assessment followed by endovascular stroke induction consisting of superselective endovascular placement of surgical silk sutures into the right MCA by using a trapping technique. Two initial subjects were euthanized immediately following postocclusion MR imaging. The subsequent 6 subjects recovered and underwent follow-up MR imaging and Spetzler neurologic assessments at 48 hours, with 4 being followed to 96 hours. Stroke infarct volumes were measured, and the longitudinal Spetzler clinical neurologic scores were assessed. The brain tissues were harvested and prepared with hematoxylin-eosin staining. RESULTS: Focal permanent cerebral ischemia was induced in the targeted right MCA territory in all subjects. The volumes of the ischemic lesions at 6, 48, and 96 hours were 3.18 ± 1.007 mL (standard error of the mean) (n = 8), 6.70 ± 1.666 mL (standard error of the mean) (n = 6), and 7.23 ± 1.371 mL (standard error of the mean) (n = 4). For the survival animals, the immediate postsurgical Spetzler grading score improved from 60.7 at 24 hours to 68.7 at 48 hours. CONCLUSIONS: We report a trapping modification to an established endovascular suture stroke model that yielded reproducible ischemia and clinically quantifiable neurologic deficits with no strokes in nontarget areas. This technique may be useful in evaluating translational stroke and penumbral imaging research in addition to preclinical testing of neuroprotective therapies.