Bone Marrow Mesenchymal Stem Cells (BMSCs) Enhance Endometrial Stromal Cell Migration and Epithelial-Mesenchymal Transition in Adenomyosis Through Upregulation of Neuropilin 1

Hormone support (estrogen and progesterone) is a key factor in decidualization and embryo implantation. Elevated levels of estrogen lead to luteal phase defects through Neuropilin 1, a membranecytoskeleton junction protein. This study aimed to explore the effect of BMSCs on endometrial stromal cells (ESCs) in adenomyosis. ESCs obtained from patients with adenomyosis were cocultured with BMSCs in the absence of presence of Neuropilin 1 inhibitor followed by analysis of expression of decidualization-related genes by RT-qPCR and western blot, cell viability by MTT assay, cell invasion and migration by Transwell assay, oxidative stress factors by ROS kit. Treatment with Neuropilin 1 inhibitor significantly decreased ESC proliferation and invasion, blocked epithelialmesenchymal transition (EMT) process, and restrained decidualization with a downregulation of decidualization-related genes. Furthermore, inhibition of Neuropilin 1 exerted effects through estrogen regulation. However, co-culture with BMSCs restored ESC activity by promoting Neuropilin expression and enhanced intrauterine ESC decidualization. In conclusion, Neuropilin 1 inhibitor restrains decidualization through estrogen regulation which can be abrogated by estrogen receptor antagonists. BMSCs restore the damaged ESC decidualization through increasing Neuropilin 1 expression, which provides new insights into the adverse effect of Neuropilin 1 on human ESCs, suggesting that BMSC is a potential therapeutic drug candidate for adenomyosis.

SUDEP in adults and children

Sudden unexpected death in epilepsy (SUDEP) represents an important cause of death in patients with epilepsy and it exceeds the expected rate of sudden death in the general population by nearly 24 times. We searched the electronic databases (Cochrane, EMBASE, Scopus, Medline, Pubmed) for studies related to etiology and risk stratification of SUDEP including data on Takotsubo cardiomyopathy (TKC) following seizures resulting in death or near death.: SUDEP is more common among males in the fourth decade of life. Risk for SUDEP is increased by early onset of seizures, low IQ, generalised tonic clonic seizures, nocturnal seizures and seizure frequency. Nonadherance to antiepileptic medications, absence of therapeutic drug level monitoring, presence of neuropathological lesions on imaging and certain subgroups like Dravet syndrome increase its risk. The risk for premature death in patients undergoing temporal lobe resection for drug resistant epilepsy decreased over time but remained above the standard population. Prolonged postictal electroencephalographic suppression was a risk factor for SUDEP in patients with generalised seizures which may indicate a cerebral electrical shutdown. Documented ictal/postictal hypoventilation, laryngeal spasm and cardiac rhythm abnormalities prior to SUDEP may suggest central apnea, neurogenic pulmonary edema, cardiac arrhythmia, or a combination of the above as a cause. Seizure triggered TKC does not seem to play a major role in the pathogenesis of SUDEP.

Notoginsenoside R1 Facilitated Wound Healing in High-Fat Diet/Streptozotocin-Induced Diabetic Rats

Diabetic ulcers bring about high morbidity and mortality in patients and cause a great economic burden to society as a whole. Since existing treatments cannot fulfil patient requirements, it is urgent to find effective therapies. In this study, the wound healing effect of topical notoginsenoside R1 (NR1) treatment on diabetic full-thickness wounds in type II diabetes mellitus (T2DM) was induced by the combination of a high-fat diet and streptozotocin (STZ) injection. NR1 significantly increased the wound closure rate, enhanced extracellular matrix (ECM) secretion, promoted collagen growth, increased platelet endothelial cell adhesion molecule-1 (CD31) expression, and decreased cleaved caspase-3 expression. RNA-Seq analysis identified ECM remodeling and inflammation as critical biological processes and Timp1 and Mmp3 as important targets in NR1-mediated wound healing. Further experiments showed that NR1-treated wounds demonstrated higher expression of tissue inhibitor of metalloproteinase 1 (TIMP1) and transforming growth factor-β1 (TGFβ1) and lower expression of matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 3 (MMP3), interleukin-1β (IL-1β), and interleukin-6 (IL-6) than diabetic wounds. These investigations promote the understanding of the mechanism of NR1-mediated diabetic wound healing and provide a promising therapeutic drug to enhance diabetic wound healing.

Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.