Application of RNS in refractory epilepsy: Targeting insula.

Although responsive neurostimulation (RNS) is approved for treatment of resistant focal epilepsy in adults, little is known about response to treatment of specific cortical targets. We describe the experience of RNS targeting the insular lobe. We identified patients who had RNS implantation with at least one electrode within the insula between April 2014 and October 2015. We performed a retrospective review of preoperative clinical features, imaging, electrocardiogram (EEG), intraoperative electrocorticography (ECoG), and postoperative seizure outcome. Eight patients with at least 6 months of postimplant follow-up were identified. Ictal localization was inconclusive with MRI or scalp EEG findings. Intracranial EEG monitoring or intraoperative ECoG demonstrated clear ictal onsets and/or frequent interictal discharges in the insula. Four patients demonstrated overall 50-75% reduction in seizure frequency. Two patients did not show appreciable seizure improvement. One patient has experienced a 75% reduction of seizure frequency, and another is nearly seizure free postoperatively. There were no reported direct complications of insular RNS electrode placement or stimulation, though two patients had postoperative complications thought to be related to craniotomy (hydrocephalus and late infection). Our study suggests that insular RNS electrode placement in selected patients is relatively safe and that RNS treatment may benefit selected patients with insular epilepsy

Characterization of two functional NKX3.1 binding sites upstream of the PCAN1 gene that are involved in the positive regulation of PCAN1 gene transcription

<p>Abstract</p> <p>Background</p> <p><it>NKX3.1 </it>and <it>PCAN1 </it>are both prostate-specific genes related to prostate development and prostate cancer. So far, little is known about the regulatory mechanisms of the expression of these two genes. In the present study, we found that NKX3.1 upregulated <it>PCAN1 </it>gene transcription in LNCaP prostate cancer cells. To understand the regulatory mechanisms, our work focused on identifying the functional NKX3.1 binding sites upstream of the <it>PCAN1 </it>gene, which might be involved in the positive regulation of <it>PCAN1 </it>expression by NKX3.1.</p> <p>Results</p> <p>We cloned and characterized a 2.6 kb fragment upstream of the <it>PCAN1 </it>gene. Analysis of the 2.6 kb sequence with MatInspector 2.2 revealed five potential binding sites of NKX3.1 transcription factor. Luciferase reporter assays, electrophoretic mobility shift assays, chromatin immunoprecipitation and RNA interference were performed to study the effects of NKX3.1 on <it>PCAN1 </it>gene expression in prostate cancer cells. Our results showed that <it>PCAN1 </it>promoter activity and mRNA expression were increased by transfection with the <it>NKX3.1 </it>containing plasmid (pcDNA3.1-<it>NKX3.1</it>) and that <it>PCAN1 </it>mRNA expression was decreased by RNA interference targeting human <it>NKX3.1 </it>in LNCaP prostate cancer cells. The results of electrophoretic mobility shift assays and chromatin immunoprecipitation showed that NKX3.1 bound to NBS1 (-1848 to -1836) and NBS3 (-803 to -791) upstream of the <it>PCAN1 </it>gene. The luciferase reporter assays showed that NBS1 and NBS3 enhanced the promoter activity in pGL₃-promoter vector with cotransfection of the <it>NKX3.1 </it>containing plasmid. Furthermore, the deletion of NBS1 or both NBS1 and NBS3 reduced <it>PCAN1 </it>promoter activity and abolished the positive regulation of <it>PCAN1 </it>expression by NKX3.1.</p> <p>Conclusion</p> <p>Our results suggested that two functional NKX3.1 binding sites located at -1848 to -1836 and -803 to -791 upstream of the <it>PCAN1 </it>gene were involved in the positive regulation of <it>PCAN1 </it>gene transcription by NKX3.1.</p

New insights on hyperglycemia in 17-hydroxylase/17,20-lyase deficiency

ObjectiveThe adrenal glands of patients with 17-hydroxylase/17,20-lyase deficiency (17OHD) synthesize excessive 11-deoxycorticosterone(DOC) and progesterone, and produce less amount of sex steroid production. Mineralocorticoids and sex hormones play an important role in regulating glucose homeostasis. This study aimed to describe the glucose metabolism in 17OHD patients diagnosed at Peking Union Medical College Hospital (PUMCH).Design/methodsA total of 69 patients diagnosed with 17OHD after adolescence in PUMCH from 1995 to June in 2021. Among them 23 patients underwent a 3-hours oral glucose tolerance test (3hOGTT) after being diagnosed with 17OHD. Insulin response in patients with normal glucose tolerance (NGT) were further compared between the study two groups with different kalemia status. Another 19 patients were followed up to 30 years and older. All clinical data were obtained from the hospital information system of PUMCH.ResultsBaseline: (1) The average body mass index(BMI) of all patients at baseline was 20.3 ± 3.7kg/m2. Twenty-three patients underwent 3hOGTT, of whom three were diagnosed with diabetes mellitus, and one with impaired glucose tolerance (IGT). Positive correlation between the ratio of progesterone to upper limit of normal range (P times) and hyperglycaemia was exist(r=0.707, P=0.005). (2) In 19 NGT patients, the insulin concentrations at 0 minute, results of the homeostasis model assessment for β-cell function and insulin resistance were lower in the hypokalaemia group than in the normal kalemia group(7.0(5.8-13.2) vs 12.4(8.9-14.9) μIU/ml, P=0.017; 115.5(88.2-240.9) vs 253.1(177.2-305.8), P=0.048; 1.54(1.17-2.61) vs 2.47(1.91-2.98), P=0.022, respectively). Follow-up: Four patients had IGT, while seven patients had diabetes mellitus. Of the 19 patients,11 had hyperglycaemia. P times was significantly higher(7.6(5.0-11.0) vs 3.75(2.2-5.3), P=0.008) in hyperglycemia group than in the normal glucose group.ConclusionsAbnormal glucose metabolism was common in 17OHD patients, which was possibly associated with hypokalaemia and high progesterone levels. Routine monitoring on glucose metabolism in 17OHD patient should be conducted

Health-Related Quality of Life and Health Service Use among Multimorbid Middle-Aged and Older-Aged Adults in China: A Cross-Sectional Study in Shandong Province

(1) Background: The management of multiple chronic diseases challenges China&rsquo;s health system, but current research has neglected how multimorbidity is associated with poor health-related quality of life (HRQOL) and high health service demands by middle-aged and older adults. (2) Methods: A cross-sectional study was conducted in Shandong province, China in 2018 across three age groups: Middle-aged (45 to 59 years), young-old (60 to 74 years), and old-old (75 or above years). The information about socio-economic, health-related behaviors, HRQOL, and health service utilization was collected via face-to-face structured questionnaires. The EQ-5D-3L instrument, comprising a health description system and a visual analog scale (VAS), was used to measure participants&rsquo; HRQOL, and &chi;2 tests and the one-way ANOVA test were used to analyze differences in socio-demographic factors and HRQOL among the different age groups. Logistic regression models estimated the associations between lifestyle factors, health service utilization, and multimorbidity across age groups. (3) Results: There were 17,867 adults aged 45 or above in our sample, with 9259 (51.82%) female and 65.60% living in rural areas. Compared with the middle-aged adults, the young-old and old-old were more likely to be single and to have a lower level of education and income, with the old-old having lower levels than the young-old (P &lt; 0.001). We found that 2465 (13.80%) suffered multimorbidities of whom 75.21% were older persons (aged 60 or above). As age increased, both the mean values of EQ-5D utility and the VAS scale decreased, displaying an inverse trend to the increase in the number of chronic diseases (P &lt; 0.05). Ex-smokers and physical check-ups for middle or young-old respondents and overweight/obesity for all participants (P &lt; 0.05) were positively correlated with multimorbidity. Drinking within the past month for all participants (P &lt; 0.001), and daily tooth-brushing for middle (P &lt; 0.05) and young-old participants (P &lt; 0.001), were negatively associated with multimorbidity. Multimorbidities increased service utilization including outpatient and inpatient visits and taking self-medicine; and the probability of health utilization was the lowest for the old-old multimorbid patients (P &lt; 0.001). (4) Conclusions: The prevalence and decline in HRQOL of multimorbid middle-aged and older-aged people were severe in Shandong province. Old patients also faced limited access to health services. We recommend early prevention and intervention to address the prevalence of middle-aged and old-aged multimorbidity. Further, the government should set-up special treatment channels for multiple chronic disease sufferers, improve medical insurance policies for the older-aged groups, and set-up multiple chronic disease insurance to effectively alleviate the costs of medical utilization caused by economic pressure for outpatients and inpatients with chronic diseases

Mutational Profile and Potential Molecular Therapeutic Targets of Pheochromocytoma

PurposePheochromocytoma/paraganglioma (PCC/PGL; collectively known as PPGL) can be driven by germline and somatic mutations in susceptibility genes. We aimed to investigate the mutation profile and clinical features of pathogenic genes in highly genetically heterogeneous PPGL and to preliminary explore molecular therapeutic targets in PPGL.MethodsWe established a panel of 260 genes, including susceptibility genes of PPGL and other important tumorigenic genes to sequence 107 PPGL tissues.ResultsOverall, 608 genomic mutations were identified in 107 PPGL tissues. Almost 57% of PPGL tissue samples exhibited pathogenic mutations, and the most frequently mutated gene was SDHB (15/107, 14%). SDHB and HRAS were the most commonly mutated genes in germline-mutated PPGL (25/107, 23%) and nongermline-mutated PPGL (36/107, 34%), respectively. In addition, novel pathogenic mutations were detected in sporadic PPGL. PPGL with mutations in the hypoxia pathway had an earlier onset and higher norepinephrine level than those in the kinase pathway. Receptor tyrosine kinase (RTK; 22%, 24/107), mitogen-activated protein kinase (MAPK; 14%, 15/107), and tyrosine kinase (TK; 2%, 2/107) pathways were the most frequently mutated pathways in PPGL.ConclusionOur results provided the genetic mutation profile in PPGL tissues. Genetic mutations in PPGL were mainly concentrated in the RTK, TK, and MAPK pathways, suggesting potential molecular therapeutic targets for PPGL

The role of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia

<p>Abstract</p> <p>Background</p> <p>We have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE ₂and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE ₂is the central factor downstream of TLR4 signaling that promotes intestinal tumorigenesis. To further elucidate critical downstream pathways involving TLR4-mediated intestinal tumorigenesis, we examined the effects of exogenously administered PGE ₂in TLR4-/- mice to see if PGE ₂bypasses the protection from colitis-associated tumorigenesis.</p> <p>Method</p> <p>Mouse colitis-associated neoplasia was induced by azoxymethane (AOM) injection followed by two cycles of dextran sodium sulfate (DSS) treatment. Two different doses of PGE ₂(high dose group, 200 μg, n = 8; and low dose group, 100 μg, n = 6) were administered daily during recovery period of colitis by gavage feeding. Another group was given PGE ₂during DSS treatment (200 μg, n = 5). Inflammation and dysplasia were assessed histologically. Mucosal Cox-2 and amphiregulin (AR) expression, prostanoid synthesis, and EGFR activation were analyzed.</p> <p>Results</p> <p>In control mice treated with PBS, the average number of tumors was greater in WT mice (n = 13) than in TLR4-/- mice (n = 7). High dose but not low dose PGE ₂treatment caused an increase in epithelial proliferation. 28.6% of PBS-treated TLR4-/- mice developed dysplasia (tumors/animal: 0.4 ± 0.2). By contrast, 75.0% (tumors/animal: 1.5 ± 1.2, P < 0.05) of the high dose group and 33.3% (tumors/animal: 0.3 ± 0.5) of the low dose group developed dysplasia in TLR4-/- mice. Tumor size was also increased by high dose PGE ₂treatment. Endogenous prostanoid synthesis was differentially affected by PGE ₂treatment during acute and recovery phases of colitis. Exogenous administration of PGE ₂increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE ₂treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2.</p> <p>Conclusions</p> <p>These results highlight the importance of PGE ₂as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.</p

Review of solar energetic particle models

Solar Energetic Particle (SEP) events are interesting from a scientific perspective as they are the product of a broad set of physical processes from the corona out through the extent of the heliosphere, and provide insight into processes of particle acceleration and transport that are widely applicable in astrophysics. From the operations perspective, SEP events pose a radiation hazard for aviation, electronics in space, and human space exploration, in particular for missions outside of the Earth’s protective magnetosphere including to the Moon and Mars. Thus, it is critical to improve the scientific understanding of SEP events and use this understanding to develop and improve SEP forecasting capabilities to support operations. Many SEP models exist or are in development using a wide variety of approaches and with differing goals. These include computationally intensive physics-based models, fast and light empirical models, machine learning-based models, and mixed-model approaches. The aim of this paper is to summarize all of the SEP models currently developed in the scientific community, including a description of model approach, inputs and outputs, free parameters, and any published validations or comparisons with data.</p

Methyl Parathion Exposure Induces Development Toxicity and Cardiotoxicity in Zebrafish Embryos

Methyl parathion (MP) has been widely used as an organophosphorus pesticide for food preservation and pest management, resulting in its accumulation in the aquatic environment. However, the early developmental toxicity of MP to non-target species, especially aquatic vertebrates, has not been thoroughly investigated. In this study, zebrafish embryos were treated with 2.5, 5, or 10 mg/L of MP solution until 72 h post-fertilization (hpf). The results showed that MP exposure reduced spontaneous movement, hatching, and survival rates of zebrafish embryos and induced developmental abnormalities such as shortened body length, yolk edema, and spinal curvature. Notably, MP was found to induce cardiac abnormalities, including pericardial edema and decreased heart rate. Exposure to MP resulted in the accumulation of reactive oxygen species (ROS), decreased superoxide dismutase (SOD) activity, increased catalase (CAT) activity, elevated malondialdehyde (MDA) levels, and caused cardiac apoptosis in zebrafish embryos. Moreover, MP affected the transcription of cardiac development-related genes (vmhc, sox9b, nppa, tnnt2, bmp2b, bmp4) and apoptosis-related genes (p53, bax, bcl2). Astaxanthin could rescue MP-induced heart development defects by down-regulating oxidative stress. These findings suggest that MP induces cardiac developmental toxicity and provides additional evidence of MP toxicity to aquatic organisms