Prefrontal cortical dopamine deficit may cause impaired glucose metabolism in schizophrenia.

The brain neurotramsmitter dopamine may play an important role in modulating systemic glucose homeostasis. In seven hundred and four drug- naïve patients with first-episode schizophrenia, we provide robust evidence of positive associations between negative symptoms of schizophrenia and high fasting blood glucose. We then show that glucose metabolism and negative symptoms are improved when intermittent theta burst stimulation (iTBS) on prefrontal cortex (PFC) is performed in patients with predominantly negative symptoms of schizophrenia. These findings led us to hypothesize that the prefrontal cortical dopamine deficit, which is known to be associated with negative symptoms, may be responsible for abnormal glucose metabolism in schizophrenia. To explore this, we optogenetically and chemogenetically inhibited the ventral tegmental area (VTA)-medial prefrontal cortex (mPFC) dopamine projection in mice and found both procedures caused glucose intolerance. Moreover, microinjection of dopamine two receptor (D2R) neuron antagonists into mPFC in mice significantly impaired glucose tolerance. Finally, a transgenic mouse model of psychosis named Disc1tr exhibited depressive-like symptoms, impaired glucose homeostasis, and compared to wild type littermates reduced D2R expression in prefrontal cortex.

Factors Influencing the Answerability and Popularity of a Health-Related Post in the Question-and-Answer Community: Infodemiology Study of Metafilter.

BACKGROUND: The web-based health question-and-answer (Q&A) community has become the primary and handy way for people to access health information and knowledge directly. OBJECTIVE: The objective of our study is to investigate how content-related, context-related, and user-related variables influence the answerability and popularity of health-related posts based on a user-dynamic, social network, and topic-dynamic semantic network, respectively. METHODS: Full-scale data on health consultations were acquired from the Metafilter Q&A community. These variables were designed in terms of context, content, and contributors. Negative binomial regression models were used to examine the influence of these variables on the favorite and comment counts of a health-related post. RESULTS: A total of 18,099 post records were collected from a well-known Q&A community. The findings of this study include the following. Content-related variables have a strong impact on both the answerability and popularity of posts. Notably, sentiment values were positively related to favorite counts and negatively associated with comment counts. User-related variables significantly affected the answerability and popularity of posts. Specifically, participation intensity was positively related to comment count and negatively associated with favorite count. Sociability breadth only had a significant impact on comment count. Context-related variables have a more substantial influence on the popularity of posts than on their answerability. The topic diversity variable exhibits an inverse correlation with the comment count while manifesting a positive correlation with the favorite count. Nevertheless, topic intensity has a significant effect only on favorite count. CONCLUSIONS: The research results not only reveal the factors influencing the answerability and popularity of health-related posts, which can help them obtain high-quality answers more efficiently, but also provide a theoretical basis for platform operators to enhance user engagement within health Q&A communities.

Bandwidth extension method based on the field-shunting effect in a high-gain photoelectric receiver circuit.

In the high-gain photoelectric receiver circuit, the method based on the field-shunting effect is applied to improve the bandwidth of the transimpedance amplifier. This method is implemented by adding a ground trace under the gain resistor, which reduces the parasitic capacitance of the gain resistor and thus increases the bandwidth. To obtain the specific impact of this method on bandwidth, a series of simulations are carried out, including electromagnetic simulations of a three-dimensional structure of circuit gain part and simulation program with integrated circuit emphasis (SPICE) simulations of the high-gain voltage-current feedback transimpedance amplifier. Finally, the optimal simulation result shows that selecting a 1206 size chip fixed resistor and setting the ground trace width to 1.1 mm can greatly reduce the influence of resistor parasitic effects on the circuit, thereby achieving the best performance of bandwidth extension. Further, the comparative experiment also verifies the effectiveness of the method for bandwidth enhancement.

Aggregating large-scale databases for PubMed author name disambiguation.

OBJECTIVE: PubMed has suffered from the author ambiguity problem for many years. Existing studies on author name disambiguation (AND) for PubMed only used internal metadata for development. However, some of them are incomplete (eg, a large number of names are only abbreviated and their full names are not available) or less discriminative. To this end, we present a new disambiguation method, namely AggAND, by aggregating information from external databases. MATERIALS AND METHODS: We address this issue by exploring Microsoft Academic Graph, Semantic Scholar, and PubMed Knowledge Graph to enhance the built-in name metadata, and extend the internal metadata with some external and more discriminative metadata. RESULTS: Experimental results on enhanced name metadata demonstrate comparable performance to 3 author identifier systems, as well as show superiority over the original name metadata. More importantly, our method, AggAND, incorporating both enhanced name and extended metadata, yields F1 scores of 95.80% and 93.71% on 2 datasets and outperforms the state-of-the-art method by a large margin (3.61% and 6.55%, respectively). CONCLUSIONS: The feasibility and good performance of our methods not only help better understand the importance of external databases for disambiguation, but also point to a promising direction for future AND studies in which information aggregated from multiple bibliographic databases can be effective in improving disambiguation performance. The methodology shown here can be generalized to broader bibliographic databases beyond PubMed. Our code and data are available online (https://github.com/carmanzhang/PubMed-AND-method).

Gamma ray-induced glial activation and neuronal loss occur before the delayed onset of brain necrosis.

Radiotherapy is one of the most effective treatments for head and neck tumors. However, delayed radiation-induced brain necrosis (RN) remains a serious issue due to the lack of satisfying prevention and effective treatment. The pathological role of radiation in the delayed onset of brain necrosis is still largely unknown, and the traditional animal model of whole brain irradiation, although being widely used, does not produce reliable and localized brain necrosis mimicking clinical features of RN. In this study, we demonstrated a successful RN mouse model using optimized gamma knife irradiation in male C57BL/6 mice. On the premise that brain necrosis started to appear at 6 weeks postirradiation in our RN model, as confirmed by both MRI and histopathological examinations, we systematically examined different time points before the onset of RN for the histopathological changes and biochemical indicators. Our initial results demonstrated that in the ipsilateral hemisphere of the irradiated brains, a significant decrease in neuronal numbers that occurred at 4 weeks and a sustained increase in TNF-α, iNOS, and other inflammatory cytokines beginning at 1-week postirradiation. Changes of cell morphology and cell numbers of both microglia and astrocytes occurred as early as 1-week postirradiation, and intervention by bevacizumab administration resulted in reduced microglia activation and reduction of radiation-induced lesion volume, indicating that chronic glial activation may result in subsequent elevation of inflammatory factors, which led to the delayed onset of neuronal loss and brain necrosis. Since C57BL/6 is the most widely used strain of genetic engineered mouse model, our data provide an invaluable platform for the mechanistic study of RN pathogenesis, identification of potential imaging and biological biomarkers, and the development of therapeutic treatment for the disease.

Pulsed light time-of-flight measurement based on a differential hysteresis timing discrimination method.

In the pulsed light time-of-flight (ToF) measurement, the timing point generated in the receiver channel is very important to the measurement accuracy. Therefore, a differential hysteresis timing discrimination method is proposed to generate timing points of the receiver channel. This method is based on utilizing the unbalanced characteristics of the fully differential operational amplifier circuit as well as introducing extra hysteresis levels to achieve the stable generation of timing points. With this method, fewer circuit components are consumed and the dynamic range of the receiver channel is not limited by its linear range. The experiments demonstrate that a receiver channel applying the proposed discrimination reaches better single shot accuracy compared to that using leading-edge timing discrimination. This method is also suitable for the timing walk error compensation by means of pulse width. Finally, these results verify the effectiveness of the proposed method in pulsed light ToF measurement.

(S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal.

Gastric cancer (GC), a common gastrointestinal malignancy worldwide, has poor prognosis and frequent recurrence. There is a great need to identify effective therapy for GC. Crizotinib is a multi-targeted, clinically available oral tyrosine kinase inhibitor approved for lung cancer, but its use for the highly heterogeneous disease of GC is unknown. The goal of this study was to investigate the anti-cancer mechanisms of the (S)-crizotinib in inhibiting GC growth. Human GC cell lines (SGC-7901 and BGC-823) and the (S)-crizotinib-resistant BGC-823/R were cultured for determining the effects of (S)-crizotinib on cell viability, apoptosis, oxidant generation, and cell cycle progression. Involvement of ROS, Akt signaling, MTH1, and DNA damage was tested with respective pharmacological blockade. The in vivo anti-tumor effects of (S)-crizotinib were determined using xenograft tumor mice. Results indicated that (S)-crizotinib decreased GC cell viability, induced growth arrest and apoptosis, and increased levels of γH2AX and Ser1981-phosphorylated ATM, which were inhibited by NAC. The anti-cancer mechanism of (S)-crizotinib was independent of MTH1. Moreover, ATM-activated Akt, a pro-survival signal, whose inhibition further enhanced (S)-crizotinib-induced inhibition of GC cell growth and tumor growth in xenograft mice, and re-sensitized resistant GC cells to (S)-crizotinib. (S)-crizotinib reduced GC cell and tumor growth through oxidative DNA damage mechanism and triggered pro-survival Akt signaling. We conclude that inclusion of Akt inhibition (to block the survival signaling) with (S)-crizotinib may provide an effective and novel combination therapy for GC in the clinical setting.

Identification and characterization of two novel PTCH1 splice variants.

Patched-1 (PTCH1), one of the key molecules involved in the Hedgehog (HH) signaling pathway, acts as the receptor of the HH ligand. PTCH1 also inhibits the positive signal transducer Smoothened (SMO). Several PTCH1 splice variants have been identified and confirmed to play critical roles in HH pathway regulation. In the present study, two novel alternatively spliced variants of PTCH1 transcripts, designated PTCH1-Δ10 and PTCH1-Δ15, were found in humans, mice and zebrafish using RT-PCR, direct sequencing and ribonuclease protection assays. PTCH1-Δ10 lacks exon 10, which encodes part of the sterol-sensing domain (SSD), while PTCH1-Δ15 lacks 166 bp of exon 15, which causes a frame shift that generates a premature stop codon leading to a truncated PTCH1 protein. Different truncated PTCH1 proteins localized in the cytoplasm were capable of internalizing the N-terminal fragment of Sonic hedgehog (SHH-N), which was visualized using immunofluorescence microscopy. Exon skipping dramatically influenced the steady states of the proteins, with the levels of PTCH1-1B and PTCH1-Δ10 being significantly higher than those of PTCH1-Δ15, as detected using western blot. These results imply that the pronounced inhibitory signaling properties of PTCH1-1B and PTCH1-Δ10 may be partially due to high protein expression in addition to intrinsic functional differences. All isoforms examined worked as functional receptors of SHH. However, the isoforms PTCH1-1B and PTCH1-Δ10 inhibited SMO and the pathway transcription factor glioma 1 (GLI1) to a greater extent than did PTCH1-Δ15. In addition, PTCH1-1B and PTCH1-Δ10 (but not PTCH1-Δ15) can be negative regulators of the HH pathway. These results indicate that the SSD domain and the C-terminal region are essential for maximal repressor function of PTCH1. Additionally, SMO inhibition by PTCH1 occurred through a nonstoichiometric, catalytic mechanism, indicating that this inhibition was less dependent on the dose of the PTCH1 protein. Finally, all these isoforms have been revealed to inhibit GLI1 activation by either the classical HH signaling pathway or a new pathway not reliant on both SMO and apoptosis. Thus, our study clearly demonstrated the unique involvement of the two novel PTCH1 splice variants in HH signal transduction.

Clinical Outcomes of Impending Nasal Skin Necrosis Related to Nose and Nasolabial Fold Augmentation with Hyaluronic Acid Fillers.

BACKGROUND: Although there are several case reports of facial skin ischemia/necrosis caused by hyaluronic acid filler injections, no systematic study of the clinical outcomes of a series of cases with this complication has been reported. METHODS: The authors report a study of 20 consecutive patients who developed impending nasal skin necrosis as a primary concern, after nose and/or nasolabial fold augmentation with hyaluronic acid fillers. The authors retrospectively reviewed the clinical outcomes and the risk factors for this complication using case-control analysis. RESULTS: Seven patients (35 percent) developed full skin necrosis, and 13 patients (65 percent) recovered fully after combination treatment with hyaluronidase. Although the two groups had similar age, sex, filler injection sites, and treatment for the complication, 85 percent of the patients in the full skin necrosis group were late presenters who did not receive the combination treatment with hyaluronidase within 2 days after the vascular complication first appeared. In contrast, just 15 percent of the patients in the full recovery group were late presenters (p = 0.004). CONCLUSIONS: Nose and nasolabial fold augmentations with hyaluronic acid fillers can lead to impending nasal skin necrosis, possibly caused by intravascular embolism and/or extravascular compression. The key for preventing the skin ischemia from progressing to necrosis is to identify and treat the ischemia as early as possible. Early (<2 days) combination treatment with hyaluronidase is associated with the full resolution of the complication. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Prevalence estimates for primary brain tumors in China: a multi-center cross-sectional study.

BACKGROUND: Although the first leading cause of death in China was malignant neoplasms (mortality, 374.1 per 100,000 person-years), the full impact of primary brain tumors (PBT) on the healthcare system is not completely described because there are a few well documented reports about the epidemiologic features of brain tumors. This study aimed to report a comprehensive assessment on the prevalence of PBT. METHODS: A multicenter cross-sectional study on brain tumor (MCSBT) in China was initiated in five regional centers: Daqing (northeast), Puyang (north of China), Shiyan (center of China), Ma'anshan (center of China) and Shanghai (southeast). Prevalence rate was calculated by counting the number of people living with a PBT between October 1, 2005 and September 30, 2006 and dividing by the total population of the five communities at January 1, 2006. Estimates of prevalence were expressed as percentages and grouped according to gender and to age in fifteen-year categories. Within these strata, the rates were estimated with 95% confidence intervals (CI) using the accurate calculation of CI for Poisson distribution. A chi-square test was used to compare the various frequencies with α < 0.05. Age-standardized prevalence with the direct method was calculated with the ten-year age-specific prevalence and the age distribution of the Chinese population in 2010, obtained from World population prospects: the 2008 revision. RESULTS: We estimated that the overall prevalence of PBT was 24.56 per 100,000 (95%CI, 14.85 to 34.27), and the overall prevalence of PBT in female population (30.57 per 100,000 and its 95%CI ranged from 19.73 to 41.41) was higher than that in male population (18.84 per 100,000 and its 95%CI ranged from 10.33 to 27.35). However, the discrepancy between genders was not statistically significant because the 95%CI overlapped. Of 272 cases of newly diagnosed PBT, the proportion of histological subtypes by age groups, gender was statistically different (χ(2) = 52.6510, P < 0.0001). More than half of all reported tumors (52.57%) were either gliomas or meningiomas. For the youngest (aged from 0 - 19) strata of the population, glioma appeared to occur more than other subtypes, accounting for 55.56% of all of cases. The majority of brain tumors presented in those aged from 20 to 59 years was pituitary adenomas (45.12%) and gliomas (31.10%). Opposed to brain tumors in adults and teenage, gliomas only accounted for 22.22%. Meanwhile, the median ages at diagnosis of the patients with PBT were similar between males and females except for pituitary adenomas (male: 59 years old; female: 45 years old). CONCLUSIONS: Age standardized prevalence of PBT is 22.52 per 100,000 (95%CI, 13.22 to 31.82) for all populations, 17.64 per 100,000 (95%CI, 9.41 to 25.87) for men, and 27.94 per 100,000 (95%CI, 17.58 to 38.30) for women. Age standardization to China's 2010 population yielded an estimated population of 304 954 cases with PBT. Our prevalence estimates provide a conservative basis on which to plan health care services and to develop programmatic strategies for surviving. In the future, it would be helpful to have long-term observed survival rates that would make the assumptions and the resulting imprecision in the current estimates unnecessary.

Intraarterial thrombolysis and stent placement for acute basilar artery occlusion.

PURPOSE: To study retrospectively the prognostic factors for acute basilar artery occlusion treated with intraarterial thrombolysis and stent placement. MATERIALS AND METHODS: Within 3-48 hours of disease onset, 52 patients with basilar artery occlusion were treated with emergency intraarterial thrombolysis with recombinant tissue plasminogen activator (rtPA) or urokinase (UK) or intraarterial thrombolysis combined with stent placement. Sixteen patients simultaneously received stent placement for the partial recanalization of basilar artery occlusion after intraarterial thrombolysis. The National Institutes of Health Stroke Scale (NIHSS) scores and the modified Rankin Scale (mRS) scores of the patients were estimated. RESULTS: A favorable clinical outcome occurred in 22 patients (42.3%), and 20 patients (38.5%) died. The survival rate was 61.5% (32 patients). Successful recanalization of basilar artery occlusion was achieved in 24 patients (46.2%), and partial recanalization was achieved in 16 patients (30.7%). The rate of recanalization was 76.9%. NIHSS scores less than 14, treatment time window less than 24 hours, and a good recanalization were markedly correlated with good clinical prognosis. NIHSS scores less than 14 and treatment time window less than 24 hours were significantly correlated with recanalization. NIHSS scores less than 14 and good recanalization could act as independent predictors for clinical prognosis. CONCLUSIONS: NIHSS scores less than 14 on admission and successful recanalization can predict favorable outcome for patients with basilar artery occlusion. This study shows that intraarterial thrombolysis and stent placement may be a useful treatment for acute basilar artery occlusion.

[Influence of electromagnetic irradiation on P450scc mRNA expression in rat testis tissues and protective effect of the shield].

OBJECTIVE: To study the influence of electromagnetic irradiation on cytochrome P450 cholesterol side chain lyase (P450scc) in adult rat testis tissues and to assess the protective effect of the copper shield. METHODS: Healthy male Wistar rats were randomized into a control group, an electromagnetic irradiation group and a wholly shielded group (with the copper shielding net). The electromagnetic irradiation group and the shielded group were set for 4 phases of 3, 6, 24 and 72 hours after irradiation, 15 rats for each phrase. The testosterone contents in the serum of the irradiated rats at 3, 6, 24 and 72 hours and in that of the controls were measured by radioimmunoassay(RIA), and so was the level of the P450scc mRNA in the testis tissues by semi-quantitative RT-PCR. And the effect of the copper shielding net on testosterone and P450scc mRNA was observed. RESULTS: The contents of testosterone and the P450scc mRNA level in the irradiated group were significantly lower than in the control rats, decreased by 83.9% and 56.9% at 3 hours (P < 0.01), 54.8% and 27.3% at 6 hours (P < 0.01), restored to normal at 24 hours, but again reduced by 60.1% and 56.1% respectively (P < 0.01). While in the shielded group, no significant change was observed either in the testosterone of the serum or in the P450scc mRNA expression in the testis tissues. CONCLUSION: Electromagnetic irradiation may affect the transcription of P450scc in adult rat Leydig cells and thereby decrease the testosterone synthesis. Whole-body shielding with the copper net may achieve satisfactory effect.