OBJECTIVE: This study implemented a piecewise volumetric modulated arc therapy (P-VMAT) for realizing whole-brain radiation therapy (WBRT) with simultaneous integrated boost (SIB) for multiple brain metastases (> 40 metastases) with a conventional C-arm linear accelerator.
METHODS: This study retrospectively analyzed 10 patients with multiple brain metastases (40-120 metastases, median 76), who underwent WBRT and SIB using helical tomotherapy (HT). The prescribed doses were 40 Gy/20 f and 60 Gy/20 f for WBRT and SIB, respectively. Corresponding new HT plans were designed with P-VMAT using 7 arcs. For each arc, the collimator was rotated to 45°, and the field width was limited to 2.5 cm with 0.5 cm overlap with adjacent arcs. Thus, each arc covered only one section of the brain target volume. A conventional dual arc VMAT (DA-VMAT) plan was also designed. HT, P-VMAT, and DA-VMAT plans were compared using dose distribution reviews and dosimetric parameters. ArcCHECK phantom measurements were performed for verification of P-VMAT plans.
RESULTS: No significant differences in the mean coverage of the whole-brain target and metastases were observed between HT and P-VMAT (p > 0.05). The conformity index for the whole-brain target improved with P-VMAT compared with HT (p < 0.05). Furthermore, the volume of 44 Gy V44 (110% of prescribed dose for WBRT) received for whole-brain significantly reduced with P-VMAT from 38.2 ± 12.9% to 23.3 ± 9.4% (p < 0.05), and the maximum dose for organs at risks such as the hippocampus, optical nerve, optical chiasm, and spinal cord declined with P-VMAT (p < 0.05). Unlike HT and P-VMAT, DA-VMAT was clinically unacceptable because V44 in the whole-brain was too high (54.7 ± 8.2%). The mean absolute dose gamma passing rate for P-VMAT plans was 97.6 ± 1.1% (3%/3 mm criterion, 10%).
CONCLUSIONS: P-VMAT is favorable for WBRT and SIB for multiple brain metastases. It provides comparable coverage of whole-brain target and SIB, with better conformity, lower V44, and better dose sparing of organs at risk compared with HT. Furthermore, results show that DA-VMAT fails clinical practice even for a relatively large number of brain metastases with a high degree of plan complexity. The patient specific verification demonstrates the feasibility of P-VMAT for clinical application.

Frequency sweeping interferometry (FSI) based absolute distance ranging has high precision and no ranging blind area. It can be used to realize large-scale and non-cooperative target measurement. However, the nonlinear frequency modulation of the laser seriously affects the ranging accuracy. In this manuscript, a measurement method assisted by Hilbert Transform (HT) and Chirp-z Transform (CZT) is proposed, which can realize the phase unwrapping of the beat signal, the length reduction in the delay fiber of auxiliary optical path, and the improvement of the frequency resolution. The narrow-band frequency suitable for HT is further studied. In the experiment, the ranging resolution is 70 μm and the standard deviation is 12.6 μm within a distance of 4005 mm.

The glutamic acid decarboxylase 65 antibody (GAD65-Ab) is an autoimmune marker in some diseases such as diabetes or autoimmune disorders of the central nervous system such as stiff-man syndrome. It can appear with other pancreatic autoantibodies, such as insulin autoantibodies (IAA), presenting as early signs of pancreatic islet β-cells impairing, and play roles in the pathogenesis of type1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA). Positive GAD65-Ab is rarely observed in insulin-dependent diabetic patients with other acquired autoimmune diseases, such as Sjogren\'s syndrome (SS). Besides, LADA revealed by islet autoantibodies such as GAD65-Ab can also be complicated with Hashimoto\'s thyroiditis (HT), another autoimmune thyroid disease. To date, whether GAD65-Ab positive in patients with autoimmune diseases predicts the onset or progression to T1D or LADA remains unknown. Herein, two unique cases of middle-aged Chinese Han women free from diabetes for three years are described despite their blood tests persistently testing positive for GAD65-Ab or IAA. Both patients suffered from HT and SS. Follow-up OGTTs (oral glucose tolerance test) for three years revealed that the patients had a well-controlled glycemic level and normal pancreatic function. However, one of the patients had a temporary increase of postprandial glucose after a short-term loss of diet control. The presence of auto-immune antibodies in these patients had little impact on glucose tolerance or insulin secretion in 3 years. The study postulate that both the primary immune injury caused by serum GAD65-Ab positive, an autoimmune marker, and increased body weight contribute to the progression of LADA.

OBJECTIVE: We aimed to formulate a practical clinical treatment algorithm for Holmes\'s tremor (HT) by reviewing currently published clinical data.
METHODS: We performed a systematic review of articles discussing the management of HT published between January 1990 and December 2018. We examined data from 89 patients published across 58 studies detailing the effects of pharmacological or surgical interventions on HT severity. Clinical outcomes were measured by a continuous 1-10 ranked scale. The majority of studies addressing treatment response were case series or case reports. No randomized control studies were identified.
RESULTS: Our review included 24 studies focusing on pharmacologic treatments of 25 HT patients and 34 studies focusing on the effect of deep brain stimulation (DBS) in 64 patients. In the medical intervention group, the most commonly used drugs were levetiracetam, trihexyphenidyl, and levodopa. In the surgically treated group, the thalamic ventralis intermedius nucleus (VIM) and globus pallidus internus (GPi) were the most common brain targets for neuromodulation. The two targets accounted for 57.8% and 32.8% of total cases, respectively. Overall, compared to the medically treated group, DBS provided greater tremor suppression (p = 0.025) and was more effective for the management of postural tremor in HT. Moreover, GPi DBS displayed greater benefit in the resting tremor component (p = 0.042) and overall tremor reduction (p = 0.022).
CONCLUSIONS: There is a highly variable response to different medical treatments in HT without randomized clinical trials available to dictate treatment decisions. A variety of medical and surgical treatment options can be considered for the management of HT. Collaborative reseach between different institutions and researchers are warranted and needed to improve our understanding of the pathophysiology and management of this condition. In this review, we propose a practical treatment algorithm for HT based on currently available evidence.

To examine the preoperative patients with cervical spondylotic myelopathy (CSM): (1) whether cervical sagittal parameters are related to the progress of patients with CSM, and (2) whether cervical sagittal parameters can predict disease progression or prognosis in patients with CSM.
From 2015 to 2018, 126 preoperative patients with CSM were enrolled. The inclusion criteria included cervical lateral radiograph, flexion (F), extension (E), and some clinical function scores (visual analog score, modified Japanese Orthopedic Association, Neck Disability Index [NDI], the Medical Outcomes Study 36-Item Short-Form Health Survey, Patient Health Questionnaire-9). Health Transition was used to evaluate the patient\'s disease progress. The following radiographic parameters were measured: (1) C0-C2 lordosis, (2) C2-C7 lordosis, (3) C7 slope, (4) T1 slope, (5) C2-C7 sagittal vertical axis, (6) cervical tilt, (7) cranial tilt, (8) cervical curvature index (CCI), and (9) CCI change constant (CCI-CC). Of the 126 patients, 101 chose surgical treatment. We followed up for 1 year and grouped the patients with the C2-C7 Cobb angle (F) > 29°. We compared the prognosis of the surgical group and the disease progression of the nonsurgical group.
In preoperative patients with CSM, modified Japanese Orthopedic Association was positively correlated with cervical tilt (E), cervical tilt (range of motion), and CCI (range of motion). The larger CCI-CC is the only independent risk factor for the NDI increase. High C2-7F, low cervical tilt, and low cervical tilt (F) values are independent predictors of high Health Transition scores. Whether in the surgical group or the nonsurgical group, the recovery of patients with C2-7F > 29° was better than that of patients with C2-7F ≤ 29°.
In preoperative patients with CSM, the larger CCI-CC is the only independent risk factor for the NDI increase. When the patient has a C2-C7 Cobb angle (F) > 29°, the patient\'s condition progresses slowly.

Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke (AIS) who are treated with tissue plasminogen activator (tPA). HT is associated with high morbidity and mortality, but no effective treatments are currently available to reduce the risk of HT. Therefore, methods to prevent HT are urgently needed. In this study, we used IM-12, an inhibitor of glycogen synthase kinase 3β (GSK-3β), to evaluate the role of the Wnt-β-catenin signaling pathway in recombinant tPA (rtPA)-induced HT. Sprague-Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) model of ischemic stroke, and then were either administered rtPA, rtPA combined with IM-12, or the vehicle at 4 h after stroke was induced. Our results indicate that rats subjected to HT had more severe neurological deficits, brain edema, and blood-brain barrier (BBB) breakdown, and had a greater infarction volume than the control group. Rats treated with IM-12 had improved outcomes compared with those of rats treated with rtPA alone. Moreover, IM-12 increased the protein expression of β-catenin and downstream proteins while suppressing the expression of GSK-3β. These results suggest that IM-12 reduces rtPA-induced HT and attenuates BBB disruption, possibly through activation of the Wnt-β-catenin signaling pathway, and provides a potential therapeutic strategy for preventing tPA-induced HT after AIS.

Objectives: To compare treatment plans of intensity modulated radiotherapy (IMRT), volumetric modulated arc radiotherapy (VMAT), and helical tomotherapy (HT) with simultaneous integrated boost (SIB) technique for esophageal cancer (EC) of different locations using dosimetry and radiobiology. Methods: Forty EC patients were planned for IMRT, VMAT, and HT plans, including 10 cases located in the cervix, upper, middle, and lower thorax, respectively. Dose-volume metrics, conformity index (CI), homogeneity index (HI), tumor control probability (TCP), and normal tissue complication probability (NTCP) were analyzed to evaluate treatment plans. Results: HT showed significant improvement over IMRT and VMAT in terms of CI (p = 0.007), HI (p < 0.001), and TCP (p < 0.001) in cervical EC. IMRT yielded more superior CI, HI and TCP compared with VMAT and HT in upper and middle thoracic EC (all p < 0.05). Additionally, V30 (27.72 ± 8.67%), mean dose (1801.47 ± 989.58cGy), and NTCP (Niemierko model: 0.44 ± 0.55%; Lyman-Kutcher-Burman model: 0.61 ± 0.59%) of heart in IMRT were sharply reduced than VMAT and HT in middle thoracic EC. For lower thoracic EC, the three techniques offered similar CI and HI (all p > 0.05). But VMAT dramatically lowered liver V30 (9.97 ± 2.84%), and reduced NTCP of lungs (Niemierko model: 0.47 ± 0.48%; Lyman-Kutcher-Burman model: 1.41 ± 1.07%) and liver (Niemierko model: 0.10 ± 0.08%; Lyman-Kutcher-Burman model: 0.17 ± 0.17%). Conclusions: HT was a good option for cervical EC with complex target coverage but little lungs and heart involvement as it achieved superior dose conformity and uniformity. Due to potentially improving tumor control and reducing heart dose with acceptable lungs sparing, IMRT was a preferred choice for upper and middle thoracic EC with large lungs involvement. VMAT could ameliorate therapeutic ratio and lower lungs and liver toxicity, which was beneficial for lower thoracic EC with little thoracic involvement but being closer to heart and liver. Individually choosing optimal technique for EC in different location will be warranted.

Tissue plasminogen activator (t-PA) remains to be the only FDA-approved drug for ischaemic stroke, but it has a restrictive therapeutic window with 4.5 hours. Beyond the golden time window, thrombolytic treatment carries the risk of haemorrhagic transformation (HT). The blood-brain barrier (BBB) disruption is a critical step in the t-PA-mediated HT. Although large efforts are made to explore the mechanisms of the BBB disruption and HT, the underlying mechanisms are largely unknown. Thrombolytic treatment for recanalization could produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) and mediate cerebral ischaemia-reperfusion injury. RNS, including nitric oxide (NO) and peroxynitrite (ONOO-), are important players in cerebral ischaemia-reperfusion injury. In particular, ONOO- and its derivatives could mediate neurovascular unit damages and induce the BBB disruption and HT possibly through interacting with different cellular signalling pathways including matrix metalloproteinase (MMPs), high mobility group Box 1 (HMGB1), toll-like receptor2/4, poly(ADP-ribose) polymerase, Src, ROCK, and GSK-3β. Herein, we review current progress about the roles of ONOO- in mediating those signalling pathways and their impacts on the t-PA-induced BBB disruption and HT. Subsequently, we discuss the values of natural compounds with the properties of scavenging ONOO- as adjunctive therapies to extend the therapeutic window of t-PA and attenuate haemorrhage transformation in ischaemic stroke.

BACKGROUND: The altered expression of circulating miRNAs has been discovered in many autoimmune diseases (ADs). With rare existing research, it is still unclear in Hashimoto\'s thyroiditis (HT). We detected plasma miRNA expression of HT patients in this three-stage designed study.
METHODS: Differently expressed miRNAs (4 HT pools vs. 1 normal control pool) were identified using quantitative reverse transcription polymerase chain reaction (qRT-PCR) based Exiqon panel (miRCURY-Ready-to-Use- PCR-Human- panel-I+II-V1.M) in the initial discovery stage. These miRNAs were then confirmed in the training stage and further validated in the testing stage using qRT-PCR with 64 (32 HT vs. 32 NCs) and 136 samples (68 HT vs. 68 NCs), respectively.
RESULTS: A total of 10 miRNAs showed differential expression through the training stage. For further validation in the testing stage, expression of 6 miRNAs (miR-205, miR-20a-3p, miR-375, miR-296, miR-451, miR-500a) were consistent with those in the training stage. Combination results showed that these 6 miRNAs were significantly up-regulated in peripheral plasma of HT patients compared with normal controls (P<0.05). In addition, the six-miRNA signature was evaluated to be a potential diagnostic marker of HT. The areas under the receiver operating characteristic curve of the signature were 0.80, 0.75 and 0.69 for the training, testing and the combined stages, respectively. Three miRNAs were associated with TSH levels in HT patients (miR-451, P=0.043; miR-375, P=0.043; miR-500a, P=0.043). Additionally, miR-20a-3p was related with TgAb level (P=0.046).
CONCLUSIONS: We identified a miRNA signature including six dysregulated plasma miRNAs which could act as a diagnostic marker in plasma of HT, providing more evidence and better understanding for the association between circulating miRNAs and autoimmune diseases.

Hashimoto\'s thyroiditis (HT) is one of the most common organ-specific autoimmune diseases. Increasing evidence indicates that HT may be characterized by an imbalance in the helper T cell subsets Th1 and Th2. Traditional Chinese Medicine (TCM) considers HT as a chronic exhaustion disease, leading to deficiency of qi. In TCM, qi indicates the functional power of the organs of the human body; hence TCM recommends focusing the treatment of HT so as to increase qi production. Ginseng is a well-known herbal medicine exhibiting a variety of efficacies, its main function-being to generate qi. Ginseng\'s principal active component is ginsenoside, and modern pharmacology has shown that ginsenoside demonstrates biphasic immunomodulatory effects that can be utilized for the treatment of immune disorders. Previous work demonstrated that ginsenoside has a therapeutic effect on HT, but its mechanism is unknown. Experimental autoimmune thyroiditis rats were produced in order to investigate whether ginsenoside can modulate Th1/Th2 imbalance, the direct objective being to examine modulation of IFN-γ and IL-4 by ELISA, and the gene and protein expression of T-bet and GATA-3 by real-time PCR and Western blot. IFN-γ levels were increased while IL-4 levels decreased in EAT rats; treatment with ginsenoside led to decreased peripheral blood IFN-γ levels, with low doses statistically significant. Ginsenoside produced a biphasic effect on IL-4, with low and moderate doses promoting and high doses inhibiting secretion. Both protein and mRNA levels of T-bet were markedly reduced, while GATA-3 was significantly increased by ginsenoside.