Cranioplasty with Direct Revascularization in Hemorrhagic Moyamoya Disease: 2-Dimensional Operative Video.

Moyamoya disease is a progressive nonatherosclerotic stenosis of the terminal segments of the arteries of the Circle of Willis. Hemorrhagic presentation is a life-threatening condition, associated with an increased risk of rebleeding and ischemic events.1-7 We present the case of a 65-year-old woman with a right intracerebral hemorrhage who underwent emergency hematoma evacuation without bone flap replacement (Video 1). The investigation confirmed the diagnosis of Moyamoya disease and demonstrated hypoperfusion of the right cerebral hemisphere. Late angiography depicted no transdural collaterals through the bone defect and demonstrated preservation of the superficial temporal artery (STA). Next, it was chosen to perform 1-stage cranioplasty with direct revascularization. We detached the temporal fascia from the muscle and created a window through the fascia to give STA passage in a corridor through the temporal muscle until the brain's surface. Vascular anastomosis was performed with an interrupted suture line employing a 10-0 nylon thread. Flow within the right middle cerebral artery was retrograde, coming from branches of the posterior cerebral artery, and the end-to-side anastomosis was placed to orientate the STA flow in the same direction as in the middle cerebral artery. We used a custom-made titanium plate for the cranioplasty and gave enough room inferiorly for the course of STA. In the end, we sutured the temporal fascia to the titanium plate for a better cosmetic result. To avoid additional unnecessary procedures, the performance of direct revascularization during the cranioplasty is feasible and deserves additional investigation as a tool to prevent new hemorrhagic or ischemic events. Informed consent was obtained from the patient for the procedure and publication of this operative video.

Insights into the immunomodulatory regulation of matrix metalloproteinase at the maternal-fetal interface during early pregnancy and pregnancy-related diseases.

Trophoblast immune cell interactions are central events in the immune microenvironment at the maternal-fetal interface. Their abnormalities are potential causes of various pregnancy complications, including pre-eclampsia and recurrent spontaneous abortion. Matrix metalloproteinase (MMP) is highly homologous, zinc(II)-containing metalloproteinase involved in altered uterine hemodynamics, closely associated with uterine vascular remodeling. However, the interactions between MMP and the immune microenvironment remain unclear. Here we discuss the key roles and potential interplay of MMP with the immune microenvironment in the embryo implantation process and pregnancy-related diseases, which may contribute to understanding the establishment and maintenance of normal pregnancy and providing new therapeutic strategies. Recent studies have shown that several tissue inhibitors of metalloproteinases (TIMPs) effectively prevent invasive vascular disease by modulating the activity of MMP. We summarize the main findings of these studies and suggest the possibility of TIMPs as emerging biomarkers and potential therapeutic targets for a range of complications induced by abnormalities in the immune microenvironment at the maternal-fetal interface. MMP and TIMPs are promising targets for developing new immunotherapies to treat pregnancy-related diseases caused by immune imbalance.

Use of Superior Petrosal Venous Complex to Transpose the Superior Cerebellar Artery in Microvascular Decompression for Trigeminal Neuralgia: 2-Dimensional Operative Video.

Trigeminal neuralgia is a cause of severe facial pain, usually provoked by a neurovascular conflict, commonly involving the superior cerebellar artery (SCA).1 The superior petrosal venous complex is in the way toward the nerve through a retrosigmoid approach and can narrow the working area around trigeminal nerve.2-4 Nonetheless, instead an obstacle it can be faced in selected cases as an adjunct to help to transpose the offending arterial loop, avoiding undesired venous sacrifice. We present a case of a 64-year-old man with left-sided severe shock-like pain in the V3 territory suggestive of trigeminal neuralgia (Video 1). Preoperative imaging depicted a neurovascular conflict between SCA and trigeminal nerve root. A retrosigmoid approach was implemented, and stimulation of the compression point was consistent with the preoperative referred pain.5 Considering the thick superior petrosal vein (SPV), we transposed the offending artery and anchored it over a SPV tributary.6 In this way no prosthetic material was placed in contact with trigeminal nerve, minimizing chance of recurrence.7-9 No abnormality on neurophysiological monitoring was reported, and postoperative imaging demonstrated no edema or hemorrhage, as well successful displacement of SCA. Patient presented complete resolution of pain and no new neurological deficit after 1 year of follow-up. This case is an uncommon report depicting a helpful intraoperative decision to be considered in selected cases to avoid venous sacrifice and preclude prosthetic material in contact with the nerve. Anatomical pictures courtesy of the Rhoton Collection, American Association of Neurological Surgeons (AANS)/Neurosurgical Research and Educational Foundation (NREF).

A High-Performance Transmitarray Antenna with Thin Metasurface for 5G Communication Based on PSO (Particle Swarm Optimization).

A 5G metasurface (MS) transmitarray (TA) feed by compact-antenna array with the performance of high gain and side-lobe level (SLL) reduction is presented. The proposed MS has two identical metallic layers etched on both sides of the dielectric substrate and four fixed vias connecting two metallic layers that works at 28 GHz to increase the transmission phase shift range. The proposed planar TA consisting of unit cells with different dimensional information can simulate the function as an optical lens according to the Fermat's principle, so the quasi-spherical wave emitted by the compact Potter horn antenna at the virtual focal point will transform to the quasi-plane wave by the phase-adjustments. Then, the particle swarm optimization (PSO) is introduced to optimize the phase distribution on the TA to decrease the SLL further. It is found that the optimized TA could achieve 27 dB gain at 28 GHz, 11.8% 3 dB gain bandwidth, -30 dB SLL, and aperture efficiency of 23% at the operating bandwidth of 27.5-29.5 GHz, which performs better than the nonoptimized one. The advanced particularities of this optimized TA including low cost, low profile, and easy to configure make it great potential in paving the way to 5G communication and radar system.

Combined Application of Arachnoid Membrane and Petrosal Dura to Transpose Dual Offending Arteries in Microvascular Decompression for Trigeminal Neuralgia: Two-Dimensional Operative Video.

Trigeminal neuralgia is featured by episodic and severe unilateral facial pain triggered usually by innocuous cutaneous stimuli.1-4 Microvascular decompression (MVD) is a safe and effective treatment for cases refractory to medical treatment caused by neurovascular conflicts.1,5-7 This Video 1 demonstrates MVD using arachnoid membrane and petrosal dura to transpose dual offending arteries. Informed consent was obtained from the patient for publication of this operative video. The patient was a 64-year-old woman with refractory right trigeminal neuralgia (V2 territory). Preoperative magnetic resonance imaging demonstrated simultaneous conflict between the right trigeminal nerve (TN) and superior cerebellar (SCA) and anterior inferior cerebellar arteries (AICA). Due to progressive and refractory symptoms, MVD was indicated, with aid of neurophysiologic monitoring. A right retrosigmoid approach was employed and after exposure of the TN root, both AICA and SCA were identified conflicting with the nerve. The AICA was displaced inferolaterally and attached to the petrosal dura between the VII/VIII and IX cranial nerves using a USP #0 silk thread. The SCA was mobilized into a fissure created in the lateral pontomesencephalic arachnoid membrane and fixed with shredded Teflon (polytetrafluoroethylene). Another piece of Teflon was positioned between the TN and the proximal segment of AICA to lighten the pulling force from the thread. Postoperative imaging demonstrated no signs of cerebellar contusion or hemorrhage. The patient presented complete resolution of her pain, and no neurologic deficits were observed. We demonstrate MVD with 2 different transposition techniques that can be considered for trigeminal neuralgia with dual offending arteries (AICA, SCA).

Toll-like receptor 4 gene is associated with recurrent spontaneous miscarriage in Uygur and Han women in Xinjiang.

Toll-like receptor 4 (TLR4), a recently identified vertebrate receptor, serves a pivotal role in immune responses. The aim of the present study was to investigate the association between the human TLR4 gene and recurrent spontaneous miscarriage (RSM). A total of 306 RSM patents and 306 age-matched controls were genotyped for four single-nucleotide polymorphisms (SNPs) of the human TLR4 gene (rs1927914, rs1927911, rs4986790 and rs4986791). Data were analyzed for Uygur and Han women separately using a haplotype-based case-control study. There were significant differences between the distributions of rs1927914, rs1927911 and rs4986790 SNPs between RSM patients and the controls (P=0.001, P<0.001 and P=0.015, respectively) were identified in Uygur women, and significant differences between the distributions of the rs1927914 and rs1927911 SNPs between RSM patients and the controls (P<0.001 and P<0.001, respectively) were identified in Han women. Results of the logistic regression analysis indicated that rs1927914, rs1927911 and rs4986790 SNPs were significantly higher in the RSM patients compared with the control individuals (P=0.012, P=0.024 and P=0.035, respectively) in Uygur women. Furthermore, significantly higher frequency was noted for the A-G-G haplotype (SNP1-SNP2-SNP3) (P=0.016) in RSM patients compared with the controls in Uygur women. The results indicate that rs1927914, rs1927911, rs4986790 and the A-G-G haplotype (SNP1-SNP2-SNP3) of the human TLR4 gene may be genetic markers for RSM in Uygur women, while rs1927914 and rs1927911 SNPs of the human TLR4 gene are most likely associated with RSM in Han women in Xinjiang.

The Clinical Utility of TIMP3 Expression in ACTH-Secreting Pituitary Tumor.

In recent years, the tissue inhibitor of metalloproteinase-3 (TIMP3) plays a pivotal role in tumorigenesis, while the role of TIMP3 in adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas remains unclear. In this study, 86 sporadic pituitary tumor specimens, including ACTH (40), GH (18), PRL-secreting (8), and non-functioining (20) and non-tumorous pituitary samples (n = 10) were available, and then, the mRNA and protein expression of TIMP3 was quantified by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry, respectively. Our findings showed that TIMP3 expression was significantly correlated with Ki-67 expression and the invasiveness of pituitary adenomas. TIMP3 mRNA and protein expression were reduced in ACTH-secreting pituitary adenomas and the other three types of pituitary adenomas compared to adjacent non-tumorous pituitary tissues (all p < .01). On the other hand, the expression of TIMP3 was negatively correlated with tumor size and Ki-67 in ACTH-secreting pituitary adenomas. TIMP3 mRNA expression was significantly lower in invasive pituitary adenomas than that in noninvasive ones (1.92-fold, p < .05). TIMP3 protein levels were also significantly lower in the majority of invasive adenomas (1.41-fold, p < .05) Furthermore, TIMP3 mRNA and protein expression were significantly lower in pituitary giant adenomas than those in microadenomas (2.58-fold, p < .05). In conclusion, the expression of TIMP3 is low in pituitary adenomas including ACTH-secreting pituitary adenomas and negatively associated with tumor aggressiveness. TIMPs may play a potential role in the progression of ACTH-secreting pituitary adenomas and be useful as a biomarker of invasiveness.

STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion.

Pituitary somatotroph adenomas result in dysregulated growth hormone (GH) hypersecretion and acromegaly; however, regulatory mechanisms that promote GH hypersecretion remain elusive. Here, we provide evidence that STAT3 directly induces somatotroph tumor cell GH. Evaluation of pituitary tumors revealed that STAT3 expression was enhanced in human GH-secreting adenomas compared with that in nonsecreting pituitary tumors. Moreover, STAT3 and GH expression were concordant in a somatotroph adenoma tissue array. Promoter and expression analysis in a GH-secreting rat cell line (GH3) revealed that STAT3 specifically binds the Gh promoter and induces transcription. Stable expression of STAT3 in GH3 cells induced expression of endogenous GH, and expression of a constitutively active STAT3 further enhanced GH production. Conversely, expression of dominant-negative STAT3 abrogated GH expression. In primary human somatotroph adenoma-derived cell cultures, STAT3 suppression with the specific inhibitor S3I-201 attenuated GH transcription and reduced GH secretion in the majority of derivative cultures. In addition, S3I-201 attenuated somatotroph tumor growth and GH secretion in a rat xenograft model. GH induced STAT3 phosphorylation and nuclear translocation, indicating a positive feedback loop between STAT3 and GH in somatotroph tumor cells. Together, these results indicate that adenoma GH hypersecretion is the result of STAT3-dependent GH induction, which in turn promotes STAT3 expression, and suggest STAT3 as a potential therapeutic target for pituitary somatotroph adenomas.

[Correlation between Expression of Signal Transducer and Activator of Transcription 3 and Pituitary Adenoma Subtypes].

OBJECTIVE: To investigate the correlation between signal transducer and activator of transcription 3 (STAT3) expression and pituitary adenoma subtypes. METHOD: The STAT3 expression profiles in different pituitary adenomas from 74 patients were determined using quantificational real-time polymerase chain reaction,Western blot,and immunohistochemistry. RESULTS: Expression of STAT3 was observed in all pituitary adenoma subtypes. The STAT3 expression level was highest in growth hormone adenoma when compared with other tumors including prolactin,follicle-stimulating hormone/luteinizing hormone-secreting adenoma,and adrenocorticotrophic hormone-secreting adenoma. The follicle-stimulating hormone/luteinizing hormone adenomas exhibited the lowest STAT3 expression levels. CONCLUSION: STAT3 is differentially expressed in pituitary adenoma subtypes, suggesting the cell-specific features of STAT3 regulation,although further investigations are still warranted to clarify the underlying mechanisms.

[A cross-sectional study of infertility prevalence and influencing factors in Uygur and Kazak women, Xinjiang Uygur autonomous region].

OBJECTIVE: To investigate the prevalence of infertility and related factors in Uygur and Kazak women in Xinjiang Uygur autonomous region (Xinjiang). METHODS: Questionnaire survey and pelvic examination were conducted among 535 Uygur women and 322 Kazak women at reproductive age who were selected through stratified cluster random sampling in Sansan and Fuhai counties in Xinjiang. The data were analyzed with software SPSS 17.0. RESULTS: The prevalence of infertility among the Uygur and Kazak women were 26.5% and 21.7% respectively, the difference was not statistically significant (P>0.05). The prevalence of primary infertility among the Uygur and Kazak women were 14.7%, and 8.7%, respectively, the difference was statistically significant (P<0.05). The prevalence of secondary infertility among the Uygur and Kazak women were 11.8% and 13.0%, respectively, the difference was not statistically significant (P>0.05). The prevalence of infertility in the Uygur women was correlated with household income, pelvic inflammation, endometriosis and BMI, while the prevalence of infertility in the Kazak women was correlated with age of marriage, endometriosis and the history of ectopic pregnancy. CONCLUSION: The prevalence of infertility was high among the Uygur and Kazak women at reproductive age in Xinjiang. The influencing factors varied with ethnic group. It is necessary to conduct targeted health education and provide early diagnosis and effective treatment.

Downregulation of Insulin-like growth factor binding protein 6 is associated with ACTH-secreting pituitary adenoma growth.

BACKGROUND: Adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome, called Cushing disease, is caused by a corticotroph tumor of the pituitary gland. Insulin-like growth factor binding protein 6 (IGFBP6), which regulates insulin-like growth factor (IGF) activity and inhibits several IGF2-dependent cancer growths, plays a pivotal role in the tumorigenesis of malignancy, but its roles in ACTH-secreting pituitary adenomas remain unclear. OBJECTIVE: To investigate IGFBP6 expression in ACTH-secreting pituitary adenomas, and its involvement in tumor growth. METHODS: Sporadic ACTH-secreting pituitary adenomas specimens (n = 41) and adjacent non-tumorous pituitary tissues (n = 9) were collected by transphenoidal surgery. IGFBP6 expression was assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and validated by Western blotting. Associations of IGFBP6 expression with maximum tumor diameter or Ki-67 labeling index were evaluated in ACTH-secreting pituitary adenomas. RESULTS: IGFBP6 mRNA and protein expression were both decreased in ACTH-secreting pituitary adenomas, compared to adjacent non-tumorous pituitary tissues (P < 0.01). IGFBP6 expression was correlated inversely with maximum tumor diameter (Rho = -0.53, P < 0.0001) and Ki-67 levels (Rho = -0.52, P < 0.05). Moreover, IGFBP6 downregulation activated PI3 K-AKT-mTOR pathway in ACTH-secreting pituitary adenomas. CONCLUSIONS: IGFBP6 attenuation in ACTH-secreting pituitary adenomas is associated with tumor growth, through activation of PI3K-AKT-mTOR pathway. The finding underlies IGFBP6 roles in Cushing disease and would potentially provide a novel target of medical therapies.

Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis.

OBJECTIVE: The aryl hydrocarbon receptor interacting protein gene (AIP) is associated with pituitary adenoma (PA). AIP has not been sequenced in East Asian PA populations, so we performed this study in a Han Chinese cohort. DESIGN: Our study included six familial PA pedigrees comprising 16 patients and 27 unaffected relatives, as well as 216 sporadic PA (SPA) patients and 100 unrelated healthy controls. METHODS: AIP sequencing was carried out on genomic DNA isolated from blood samples. Multiplex ligation-dependent probe amplification and microsatellite marker analyses on DNA from the paired tumor tissues were performed for loss of heterozygosity analysis. RESULTS: We identified three common and four rare single nucleotide polymorphisms (SNPs), one intron insertion, one novel synonymous variant, four novel missense variants, and a reported nonsense mutation in three familial isolated PA (FIPA) cases from the same family. Large genetic deletions were not observed in the germline but were seen in the sporadic tumor DNA from three missense variant carriers. The prevalence of AIP pathogenic variants in PA patients here was low (3.88%), but was higher in somatotropinoma patients (9.30%), especially in young adults (≤30 years) and pediatric (≥18 years) paients (17.24% and 25.00% respectively). All AIP variant patients suffered from macroadenomas. However, the AIP mutation rate in FIPA families was low in this cohort (16.67%, 1/6 families). CONCLUSION: AIP gene mutation may not be frequent in FIPA or SPA from the Han Chinese population. AIP sequencing and long-term follow-up investigations should be performed for young patients with large PAs and their families with PA predisposition.

Pyrimethamine sensitizes pituitary adenomas cells to temozolomide through cathepsin B-dependent and caspase-dependent apoptotic pathways.

Invasive pituitary adenomas (PAs) are generally refractory to conventional therapy and salvage treatment with temozolomide (TMZ). In addition to antiprotozoan effects, pyrimethamine (PYR) has recently shown its strong antitumor activity as an antineoplastic agent or in combination with TMZ in metastatic melanoma cells. In this study, the effects of TMZ, PYR or TMZ/PYR combination on rat/mouse PA cell lines αT3-1, GH3, MMQ and ATt-20 as well as GH3 xenograft tumor model were evaluated. TMZ/PYR combination synergistically inhibited proliferation, invasion and induced apoptosis of these PA cell lines in vitro. Strikingly, combination treatment with TMZ and PYR produced synergistic antitumor activity and enhanced the survival rate of GH3 xenograft tumor models without increasing systemic side effects. In addition, TMZ/PYR induced cell cycle arrest, increased DNA damage, upregulated the expression of cathepsin B, BAX, cleaved PARP and phosphorylated histone H2AX as well as elevated caspase3/7, 8 and 9 activities. The decreased expression of Bcl-2, MMP-2 and MMP-9 alone with cytochrome c release from mitochondria into the cytosol was also observed in the TMZ/PYR combination group. The increase in cell apoptosis due to combination with PYR was rescued by leucovorin. These data suggest that PYR may enhance the efficacy of TMZ via triggering both cathepsin B-dependent and caspase-dependent apoptotic pathways. Therefore, combination of PYR and TMZ may provide a novel regimen for invasive PAs refractory to standard therapy and TMZ.

Folate receptor-mediated boron-10 containing carbon nanoparticles as potential delivery vehicles for boron neutron capture therapy of nonfunctional pituitary adenomas.

Invasive nonfunctional pituitary adenomas (NFPAs) are difficult to completely resect and often develop tumor recurrence after initial surgery. Currently, no medications are clinically effective in the control of NFPA. Although radiation therapy and radiosurgery are useful to prevent tumor regrowth, they are frequently withheld because of severe complications. Boron neutron capture therapy (BNCT) is a binary radiotherapy that selectively and maximally damages tumor cells without harming the surrounding normal tissue. Folate receptor (FR)-targeted boron-10 containing carbon nanoparticles is a novel boron delivery agent that can be selectively taken up by FR-expressing cells via FR-mediated endocytosis. In this study, FR-targeted boron-10 containing carbon nanoparticles were selectively taken up by NFPAs cells expressing FR but not other types of non-FR expressing pituitary adenomas. After incubation with boron-10 containing carbon nanoparticles and following irradiation with thermal neutrons, the cell viability of NFPAs was significantly decreased, while apoptotic cells were simultaneously increased. However, cells administered the same dose of FR-targeted boron-10 containing carbon nanoparticles without neutron irradiation or received the same neutron irradiation alone did not show significant decrease in cell viability or increase in apoptotic cells. The expression of Bcl-2 was down-regulated and the expression of Bax was up-regulated in NFPAs after treatment with FR-mediated BNCT. In conclusion, FR-targeted boron-10 containing carbon nanoparticles may be an ideal delivery system of boron to NFPAs cells for BNCT. Furthermore, our study also provides a novel insight into therapeutic strategies for invasive NFPA refractory to conventional therapy, while exploring these new applications of BNCT for tumors, especially benign tumors.