As few cerebral venous thrombosis (CVT) patients with primary Sjögren’s syndrome (pSS) have been reported, little is known about the characteristics of this rare complication. This study is aimed at describing the clinical features, treatment, and outcome of CVT combined with pSS. We reported five patients of CVT and pSS admitted to our hospital and searched the relevant case reports in PubMed for literature review. We reviewed a total of twelve patients with pSS and CVT. Among them, five patients were from our report in the present paper, and seven other patients were from the case reports searched in PubMed. In total twelve patients, eleven patients were female. The twelve patients had an average age of 43.7 ± 8.3 years (age range, 26–57 years). The symptoms of pSS included multiple caries (50

This report details a rare case where a patient simultaneously suffered from Sjogren's syndrome (SS) and Meige's syndrome (MS). SS, an autoimmune disorder, and MS, a rare neurological condition characterized by involuntary eyelid closure, presented in a 73-year-old male. The patient had been experiencing dry eye symptoms for the past 5 years, with the onset of eyelid spasms and tetanic eye closure occurring 3 years ago. Traditional treatments, including subthalamic nucleus deep brain stimulation, provided only temporary relief. Diagnostic evaluations, including blood tests and imaging, confirmed SS and MS coexistence. Treatment involved a combination of steroids, immunosuppressants, and immunoglobulin, leading to significant symptom relief. This case suggests a potential association between SS and the development of MS, highlighting the importance of immunomodulatory therapy in managing neurological symptoms. Further research is needed to explore the relationship between these two conditions and to develop more effective treatment strategies.

Objective: The aim of this study was to explore if the single nucleotide polymorphism (SNP) of IL-6 was related to the susceptibility, severity of neurological deficit and the recurrence risk of cerebral infarction (CI). Methods: Three hundred and eighty-two patients with CI and 385 healthy controls were selected for IL-6 gene promotor region-174G /C, -572C/G, -597G/A polymorphism by SNaPshot SNP typing. The National Institute of Health Stroke Scale (NIHSS) and Essen Stroke Risk Score (ESRS) were adopted to evaluate the neurological deficit and stroke relapse risk in CI patients. Results: The rs1800796 polymorphism of the IL-6 gene showed a significant correlation with CI, and its GG genotype increased the risk of CI (CG+GG vs CC, P=0. 019). The dominant model of rs1800796 was related to severity of neurological deficit and the recurrence risk of cerebral infarction (CG+GG vs CC. P =0. 048 and P= 0. 019). No association was observed between rs1800795/rs1800797 and CI. Conclusion: IL-6 genetic polymorphism serves as a potential biomarker to determine the susceptibility of CI, neurological deficit and the risk of stroke recurrence.

Aim: The authors aimed to investigate whether polymorphisms of PON-1 were associated with the susceptibility to and severity of ischemic stroke (IS). Methods: In this study, 302 IS patients and 303 healthy controls were enrolled. Polymorphisms rs854560 and rs854572 of PON-1 were detected using SNaPshot single-nucleotide polymorphism typing technology. Results: The rs854572 polymorphism of the PON-1 gene showed a significant correlation with IS, and its GG genotype reduced the risk of IS (recessive model, p = 0.001). The GG genotype was also associated with mild stroke (p = 0.032). No association was observed between rs854560 and IS. Conclusion:PON-1 rs854572 polymorphism was related to the risk of IS and could be a biomarker to access the severity of IS.

Objectives The collateral circulation near the cerebral artery occlusion can contribute to the relief of the symptoms and signs of stroke. Genetic factors play a decisive role in the difference in collateral circulation. Survivin, encoded by the baculoviral inhibitor of apoptosis (IAP) repeat-containing 5 gene (BIRC5), plays an important role in maintaining long-term endothelial integrity and homeostasis and as an angiogenic factor in the treatment of vascular diseases. We hypothesized that genetic variations in the BIRC5 gene may contribute to severity by influencing the collateral circulation. This study aimed at examining how the polymorphism of the BIRC5 gene correlated with the collateral circulation and severity of large artery atherosclerotic stroke. Methods This study enrolled 428 patients with large artery atherosclerotic stroke. There are no statistical differences in age, sex, social behavior, such as smoking and drinking, between the groups classified by the collateral circulation and by the severity of stroke (P > 0.01). Direct sequencing was performed for the genotyping of single nucleotide polymorphism (SNP) of BIRC5 (rs2071214). The enrolled patients were divided into several subgroups based on the collateral flow grading system from the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR), the results of the National Institutes of Health Stroke Survey (NIHSS) (6 as a threshold), and the score of the modified Rankin scale (mRS) (for the prediction of prognosis, 2 as a threshold). Differences among subgroups were identified through logistic regression. Results The analysis of collateral circulation revealed the significant correlation of SNP of rs2071214 with the development of poor collateral circulation of large artery atherosclerotic stroke in the additive model (GG vs. AA, odds ratio (OR) = 3.592, 95% confidence interval (CI) = 1.410–9.150, and P=0.007) and the recessive model (GG vs. AA/GA, OR = 3.313, 95% CI = 1.420–7.727, and P=0.006). The analysis of stroke severity exposed the significant role of the SNP of rs2071214 in increasing stroke severity in the dominant model (GA/GG vs. AA, OR = 1.658, 95% CI = 1.017–2.703, and P=0.043) and the additive model (GA vs. AA, OR = 1.717, 95% CI = 1.021–2.888, and P=0.042). However, the analysis of the short-term outcome indicated that three genetic models were not associated with short-term outcomes in the additive model (GA vs. AA, P=0.815, GG vs. AA, and P=0.336), the dominant model (GA/GG vs. AA and P=0.589), and the recessive model (GG vs. AA/GA and P=0.342). Conclusion Our findings identified the SNP of rs2071214 of the BIRC5 gene as a risk factor for the poor compensatory ability of collateral circulation and a predictor of stroke severity in large artery atherosclerotic stroke, which suggested that the SNP of rs2071214 can serve as an innovative therapeutic target for patients with acute ischemic stroke.

Background: Somatic mutations in WT1 and TET2 were separately perceived as contributors to hematopoietic disorders and thought to have a mutually exclusive effect in acute myeloid leukemia (AML). Here, we report a case in which WT1 and TET2 mutations co-existed at different stages in an AML patient with t(9;11)(p21.3;q23.3), and without abnormal WT1 expression, which did not synchronize with the patient's tumor state. Hence, the origins and prognostic value of these two mutations were investigated. Methods: Bone marrow (BM) and buccal mucosal cells were obtained from a 27-year-old male AML patient, and next-generation sequencing (NGS), targeting multiple genes, was performed after DNA extraction. Single nucleotide variant (SNV) and insertion-deletion (Indel) associated with AML were identified in these two samples by using SAM tools. Then, peripheral blood or buccal mucosal cells were obtained from the patient’s relatives, and NGS targeting multiple genes was applied. Besides, the relationship between overall survival (OS) and alteration of these two genes in AML patients was analyzed by using cBioPortal and UALCAN databases, respectively. Results: SNV of WT1 (NM_024426:exon7:c.1109G>C；p.Arg370Pro) and TET2 (NM_001127208:exon11:c.5530G>A；p.Asp1844Asn) were present in the BM of the patient, and these two mutations were also observed in his buccal mucosal cells, which suggested that they were germline mutations. Variation analysis of samples from other relatives indicated that WT1 (NM_024426:exon7:c.1109G>C;p.Arg370Pro) and TET2 (NM_001127208:exon11:c.5530G>A;p.Asp1844Asn) were also present in his father and mother, respectively. The patient’s brother also carried TET2 (NM_001127208:exon11:c.5530G>A；p.Asp1844Asn) mutations. Bioinformatic analysis suggested that mutations in the WT1 and TET2 genes are both associated with a poor prognosis of AML, and abnormal TET2 expression is associated with a poorer prognosis than abnormal WT1 expression. Conclusion: It is firstly report that WT1 p.Arg370Pro and TET2 p.Asp1844Asn mutations co-existed in an AML patient with t(9;11)(p21.3;q23.3) and no WT1 abnormal expression, which highlight the importance of the identification and prognostic evaluation of germline mutations in clinical practice for AML.

Therapeutic transplantation of autologous bone marrow mesenchymal stem cells (BMSCs) holds great promise for ischemic stroke, yet the efficacy is negatively impacted by aging. Here, we examined whether hypoxia conditioning could enhance aged human BMSCs-induced neuroprotection via secretome action. Primary cultured mouse neurons were exposed to oxygen glucose deprivation (OGD) to mimic ischemic stroke in vitro, then randomized into a hypoxia conditioned aged human BMSCs-conditioned medium (BMSC-hypoCM) versus normoxia conditioned (BMSC-norCM). After 22 h of reperfusion, cell viability was significantly increased in neurons treated with BMSC-hypoCM rather than BMSC-norCM. ELISA revealed that hypoxia conditioning enhanced vascular endothelial growth factor (VEGF) release into BMSC-derived CM. Blocking the VEGF receptor negated BMSC-hypoCM-induced protection for neurons against OGD insult. Altogether, our data indicates that hypoxia conditioning improves aged human BMSCs’ therapeutic efficacy for neurons with ischemic challenge, in part via promoting secretion of VEGF.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid neoplasms in adults. Through the decades, rituximab, cyclophosphamide, doxorubicin, prednisone, and vincristine (R-CHOP) therapy has dramatically improved the clinical outcome due to the introduction of rituximab. Even so, still about 30–40% of patients ultimately relapse or progress, which become difficult to manage. A study has shown that patients with primary refractory DLBCL or early relapse after rituximab-containing therapy have a very poor prognosis,[1] which makes the introduction of novel drugs to DLBCL regimen definitely an urge demand. The history of immunomodulatory drugs (IMiDs) was originated from the application of thalidomide to prevent nausea during pregnancy in 1950s. A few years later, it was withdrawn because deformed infants with phocomelia began to surface. The inhibition of thalidomide on new formations led to the discovery of new pharmacological antiangiogenic effect and its new application in tumor therapy. The clinical outcomes in the treatment of malignant diseases were impressive, especially in hematological malignant diseases. Lenalidomide, one of the second-generation IMiDs, had shown its efficacy on multiple myeloma (MM), myelodysplastic syndrome (MDS) associated with deletion 5q, and mantle cell lymphoma in various clinical trials. Consequently, lenalidomide has been approved by Food and Drug Administration for the treatment of those diseases. Notably, the latest National Comprehensive Cancer Network guideline recommended lenalidomide as the regimen of the first-line treatment of MM and MDS associated with del(5q). Based on its mechanisms that have been explored, several clinical trials have been executed to explore the efficacy of lenalidomide on B-cell lymphoma,[2] especially R/R DLBCL. Until now, lenalidomide has shown impressive activity in both monotherapy and combination therapy on R/R DLBCL patients, especially in elderly patients. This review highlights the new insight into its mechanism on treating lymphoma and the studies exploring efficiencies of lenalidomide on DLBCL patients for salvage, maintenance, and introduction, both as a single agent and in combinations. Lenalidomide, an analog of thalidomide, makes itself distinct from both traditional chemotherapy and monoclonal antibody-based therapy. The mechanism that has been demonstrated includes antiproliferative, immunomodulatory, and antiangiogenic properties. Cereblon (CRBN), a substrate adaptor of E3 ubiquitin ligase, was identified as the primary target for lenalidomide-induced teratogenesis.[3] The pharmacologic mechanism of action includes binding to the CRL4CRBN E3 ubiquitin ligase complex (E3 complex) through CRBN and modulating substrates (such as IKZF1 and IKZF3), which leads to the interference with life circle of cells. IKZF1 and IKZF3 encode two transcription factors IKAROS and AIOLOS, respectively, regulating the vital transcriptional network. In particular, IKZF3 regulates the expression of interferon regulatory factor 4, which is in dominate position of a positive feedback loop with MYC as well as many other genes essential to cell survival. In addition, a study[4] has shown that the ETS transcription factor SPI-B, which is overexpressed in ABC-DLBCL and required for its survival, is one of the targets of IKAROS. The reduction of IKZF1 by lenalidomide leads to downregulating the level of SPI-B mRNA and resulting in the subsequent death of ABC-DLBCL cells. The mechanism of immunomodulation has been shown to involve three different aspects: cytokine modulation, T-cell co-stimulation, and antibody-dependent cellular cytotoxicity (ADCC) regulation.[5] Some studies suggest that the immunomodulation property depends on the proper functioning of E3 complex.[6] The level of IKZF1 and IKZF3 has been shown to affect the production of interleukin-2 and other cytokines,[7] subsequently enhance the antigen presentation by dendritic cells (DC), promote the interaction between T cells and DC, and alter the shift of T helper differentiation. ADCC has been increased by IMiDs through enhancing natural killer (NK) cells through the stimulation of DC and modification of the cytokine microenvironment.[8] IMiDs upregulate the abundance of monocyte chemotactic protein-1, tumor necrosis factor-α, and interferon-γ[9] to stimulate the expression of functional receptors on NK cells. The first generation of IMiDs drew attention mostly because of the reports of deformed infants with phocomelia; the growth of limbs has been restricted due to the deficiency of new blood capillaries. Both the bad reputation and its withdrawal led to the discovery of the antiangiogenic mechanism. A research showed that IMiDs exhibited antiangiogenic effects on lymphoma in mice.[9] With the upregulation of SPARC, a tumor-suppressor gene that displays antiproliferative, antiadhesive, and antiangiogenic properties in 5q– syndrome, lenalidomide was considered antiangiogenesis in vivo.[10] In 2009, Dredge et al.[11] revealed that lenalidomide inhibited the phosphorylation of vascular endothelial growth factor-induced Akt-1 in endothelial cells and offered more solid proof for this mechanism. However, based on clinical outcomes that have been published, the application of lenalidomide on the treatment of solid tumor seems not promising. Research on deeper understanding of its molecular mechanism is still needed. In 2008, Wiernik et al.[12] reported the first clinical trial about lenalidomide monotherapy in R/R aggressive non-Hodgkin's lymphoma. The efficacy of lenalidomide treatment for R/R DLBCL patients was first demonstrated, and safety was claimed manageable. After that, most researchers started with relapsed and refractory patients. Czuczman et al.[13] reported a trial that 102 R/R DLBCL patients received lenalidomide (25 mg/d, 21 days of 28-day cycle) or investigator's choice (R-CHOP, R-ICE, R-DHAP, R-GemOx, etc). Patients in lenalidomide arm had an overall response rate (ORR) of 27.5% versus 11.8% with IC treatment, and median progression-free survival (PFS) of patients received lenalidomide was increased with greater improvements in non-Germinal Center B (GCB, cell-like lymphoma) patients compared with GCB cell-like lymphoma. Treatment-emergent adverse events (TEAEs) in both arms were similar and acceptable. Although the IC arm could be a limitation, these results were promising, proving both better efficacy and safety of lenalidomide compared with current clinical treatments. The combination with traditional regimens also demonstrated its potential, according to Wang's Phase 2 clinical trial.[14] After lenalidomide-rituximab therapy, ORR and the rate of complete response (CR) of 32 enrolled patients were 28% and 22%, respectively. The combination was claimed well tolerated and effective. The efficacy of lenalidomide-rituximab therapy could serve as a framework for further rational combination with other agents, and stem cell translation after lenalidomide-rituximab was claimed associated with prolonged response duration. The combination of lenalidomide and rituximab therapy for elderly patients showed high and continuous CR, according to Zinzani et al.'s trial.[15] Twenty-three elderly patients with R/R DLBCL were enrolled and given lenalidomide and rituximab as induction treatment, and ORR was 35% (n = 8). Ten patients were enrolled in lenalidomide maintenance afterward, 8 of them achieved CR. The updated outcomes[7] revealed the median duration of CR were 5 years and a disease-free survival was 75% at 6 years. Six patients (26%) obtained a very long-term continuous CR which may represent an indication of high efficacy of the combination maintenance. These trials showed impressive outcomes for R/R DLBCL. Moreover, some other clinical trials of salvage treatment for patients with R/R DLBCL since 2010 are listed in Table 1. The rate of CR and duration of PFS differ greatly probably because of the different design and small sample.Table 1: Selected studies of lenalidomide in R/R DLBCLWith the encouraging benefit obtained from salvage treatment of lenalidomide alone or with other regimes, it is conceivable that lenalidomide could be added into maintenance therapy. Rituximab, targeted agents enzastaurin and everolimus, used to be involved as maintenance therapies. However, no reports showed more efficacy than risk[20] for DLBCL patients. Compared with those drugs mentioned above, lenalidomide is a kind of oral medicine with better tolerance, meaning better compliance and controllability. The REMARC study,[21] which was a multicenter, double-blind, randomized, placebo-controlled Phase III trial, explored the difference between lenalidomide and placebo as maintenance in responding elderly patients with previously untreated DLBCL. Six hundred and fifty patients (60–80 years old) were enrolled, and median PFS was not reached for lenalidomide arm. However, in placebo arm, the median PFS was 58.9 months. The study demonstrated that lenalidomide maintenance significantly prolonged PFS in elderly patients, with no more TEAEs. However, this trial showed almost no difference among subtypes and was lack of overall survival (OS) benefit. Based on the conclusion of recent trials that lenalidomide provided more benefits for R/R and responding patients in sequence treatment, researchers have expected efficacy of lenalidomide in induction treatment. A Phase 2 study[22] showed the safety and efficiency of lenalidomide plus R-CHOP (R2CHOP) in newly diagnosed DLBCL (subtype was non-GCB). Sixty patients received R2CHOP. The ORR was 98% and CR was 80%. OS rates at 24 months were 78%. The R2CHOP therapy showed no difference in PFS or OS between subgroups of GCB and non-GCB, which may lead to a wider application despite different subtypes. With the difficulty of improving the outcome of R-CHOP on ABC-type DLBCL, the introduction of lenalidomide may be the key to the revolution. ROBUST,[23] a clinical trial protocol focused on the upgrading results of R2CHOP over placebo on ABC-type DLBCL, is enrolling at centers in different continents. Solid data and probably promising outcomes could be expected. More clinical trials with large sample and randomized double-blind design are needed for better evidence-based medicine. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Acknowledgment We thank CQ Xia, MD. PhD and Mr. Will Donelan, for critical reading and assistance with the manuscript.

Peri- menopausal syndrome is one of the most common diseases. It means various syndromes of menopause,menopausal disorders,Baihe disease,depression and hysteria and others in traditional Chinese medicine. Traditional Chinese medicine theories are based on kidney controlling reproduction,water out of kidney and others,raising that kidney Qi declines and Tiangui is gradually dried up and Chong and Ren meridians gradually become deficiency and essence and blood are deficiency and internal organs fail to be nourshied,leadin to body's Yin- Yang imbalance which can lead to this disease. This paper presents an exploration of the etiology,syndrome,therapy and recipe of perimenopausal syndrome according to the clinical experiences and literature research from the viewpoint of Dr. LI Yunbo. The pathogenesis of five Zang- organs illustrations based on the Yin and Yang are not transferred,putting forward by the five elements theories of conditioning five internal organs treatment and providing clinical treatment of perimenopausal syndrome with the reference.