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This study was to investigate clinical applicability of diffusion spectrum imaging (DSI) for quantitative detection of visual pathway abnormalities to predict the degree of visual field defects (VFD) in patients with pituitary adenomas. Sixty-five patients with pituitary adenomas and 33 healthy controls underwent conventional MRI and DSI scanning that allowed high-angular-resolution fiber tracking. Optic chiasmal compression and VFD were confirmed in all patients via radiological and neuro-ophthalmological examinations. Quantitative assessments of chiasmal lift, VFD, and DSI parameters from the optic nerve, optic tract, and optic radiation were performed. Group comparisons and correlation analyses were conducted in patients and controls. Using the 5-fold cross-validation method, the support vector machine classifiers were constructed to predict the degree of visual defects. The mean values of quantitative anisotropy and generalized fractional anisotropy in optic nerve and optic tract showed significant differences between patients and controls (p < 0.05). These parameters were also significantly correlated with the chiasmal lift distance and degree of visual defects (p < 0.05). All patients were divided into mild (n = 42) and severe (n = 23) VFD groups, using the mean deviation value of −8 dB as the threshold. The classifiers achieved an accuracy of 0.83, sensitivity of 0.78, and specificity of 0.86 to discriminate patients with mild and severe visual defects. Using high-angular-resolution fiber tracking, DSI may provide quantitative information to detect visual pathway abnormalities and be a potential diagnostic tool for determining the degree of visual field defects in pituitary adenomas. • Abnormal QA and GFA values of optic nerve and optic tract in adenoma patients • Close relationship between DSI parameters and VFD degree in adenoma patients • The classifiers achieved an accuracy of 0.83, sensitivity of 0.78, and specificity of 0.86 to discriminate patients with mild and severe VFD

Chronic inflammation of autoimmune diseases, including type 1 diabetes (T1D), is mainly mediated by memory T(Tm) cells, predominantly effector memory T (Tem) cells. The roles of the programmed death-1 (PD-1) receptor on lymphocytes have been well studied in tumor and other infection models. However, little is known about the relationship between the expression of PD-1 on CD8+ Tem cells and the pathogenesis of T1D. A total of 52 patients diagnosed with T1D and 39 gender-, age-, and ethnically matched health control individuals were enrolled in this study. Peripheral blood mononuclear cells from these individuals were isolated and analyzed by flow cytometry. We evaluated the frequencies of PD-1+ CD8+ memory T cell subsets from patients' peripheral blood with T1D and the spleen cells of nonobese diabetic (NOD) mice in the present study. We also investigated the effects of blocking PD-1/PD-L1 pathway on islet’s inflammation in NOD mice. Frequencies of PD-1+ CD8+ Tem cells were decreased significantly in PBMC of patients with T1D (40.73 ± 12.72 vs 47.43 ± 15.56, *p

Angiogenesis is an integral process in many ischemic disorders, and vascular endothelial growth factor (VEGF) plays an important role in it. Protein arginine methyltransferase 4 (PRMT4), a member of the type I PRMT family, is involved in various biological activities, but its role in endothelial cell (EC) remains elusive. Here, we aimed to investigate the role of PRMT4 in ischemic angiogenesis and explore the possible underlying mechanism. We found that PRMT4 was upregulated in ischemic muscles, and VEGF treatment potentiated its expression in ECs. In vitro, adenovirus-mediated PRMT4 overexpression promoted, while its gene disruption inhibited, EC proliferation, migration, and tube formation. In an in vivo hindlimb ischemia model, forced expression of PRMT4 in ECs showed accelerated blood flow recovery and increased capillary density, whereas its knockdown exhibited the opposite effect. Mechanistically, PRMT4 activated the transcription of VEGF via the interaction with Y-box binding protein-1 (YB1), leading to accelerated angiogenesis. Interestingly, the loss of YB1 partially abolished PRMT4-mediated angiogenesis in vitro. Collectively, our data revealed that PRMT4 promoted angiogenesis through interacting with YB1 and the consequential VEGF upregulation, suggesting that PRMT4 may present as a potential therapeutic target in ischemic angiogenesis. KEY MESSAGES: •PRMT4 is induced by VEGF and upregulated in a hindlimb ischemia model. •PRMT4 promotes angiogenesis both in vitro and in vivo. •PRMT4 regulates VEGF expression through interacting with YB1. •YB1 knockdown retards PRMT4-mediated angiogenic effects in vitro.

Background Accurately predicting the risk level for a lymph node metastasis is critical in the treatment of non-small cell lung cancer (NSCLC). This study aimed to construct a novel nomogram to identify patients with a risk of lymph node metastasis in T1-2 NSCLC based on positron emission tomography/computed tomography (PET/CT) and clinical characteristics. Methods From January 2011 to November 2017, the records of 318 consecutive patients who had undergone PET/CT examination within 30 days before surgical resection for clinical T1-2 NSCLC were retrospectively reviewed. A nomogram to predict the risk of lymph node metastasis was constructed. The model was confirmed using bootstrap resampling, and an independent validation cohort contained 156 patients from June 2017 to February 2020 at another institution. Results Six factors [age, tumor location, histology, the lymph node maximum standardized uptake value (SUVmax), the tumor SUVmax and the carcinoembryonic antigen (CEA) value] were identified and entered into the nomogram. The nomogram developed based on the analysis showed robust discrimination, with an area under the receiver operating characteristic curve of 0.858 in the primary cohort and 0.749 in the validation cohort. The calibration curve for the probability of lymph node metastasis showed excellent concordance between the predicted and actual results. Decision curve analysis suggested that the nomogram was clinically useful. Conclusions We set up and validated a novel and effective nomogram that can predict the risk of lymph node metastasis for individual patients with T1-2 NSCLC. This model may help clinicians to make treatment recommendations for individuals.

Aim: To derive an echocardiography-based prognostic score for a 3-year risk of mortality in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD). Methods: 173 ESRD patients hospitalized in the second affiliated hospital of Soochow University from January 1, 2010, to July 31, 2016, were enrolled and followed up for 3 years. All subjects began to receive HD from recruitment. Baseline clinical and echocardiographic parameters were collected and screened for risk factors using univariate and multivariate analysis. The prognostic value of echocardiographic indexes was determined by concordance indexes and reclassification assay. Restricted cubic spline models (RCS) and forest plots were employed to visualize the association between risk factors and all-cause mortality. A multivariate nomogram including the identified factors was developed to estimate the prognosis. Results: After multivariate adjustment for advanced age, hypertension, diabetes, and decreased hemoglobin (Hb), echocardiographic indexes including left atrial diameter index (LADI), cardiac valvular calcification, and moderate to severe cardiac valve regurgitation were independently associated with the risk of 3-year mortality in HD patients. RCS showed that age, Hb, and LADI were positively associated with the risk of mortality. Adding multiple echocardiographic indexes to a basic model containing age, hypertension, diabetes, and Hb increased the concordance index and improved reclassification. A multivariate Cox model-derived nomogram showed the association between each factor and mortality by the end of follow-up. Conclusions: Echocardiographic indexes showed independent predictive power for mortality in ESRD patients and may constitute a promising prognostic tool in this population.

Touch can positively influence cognition and emotion, but the underlying mechanisms remain unclear. Here, we report that tactile experience enrichment improves memory and alleviates anxiety by remodeling neurons along the dorsoventral axis of the dentate gyrus (DG) in adult mice. Tactile enrichment induces differential activation and structural modification of neurons in the dorsal and ventral DG, and increases the presynaptic input from the lateral entorhinal cortex (LEC), which is reciprocally connected with the primary somatosensory cortex (S1), to tactile experience-activated DG neurons. Chemogenetic activation of tactile experience-tagged dorsal and ventral DG neurons enhances memory and reduces anxiety respectively, whereas inactivation of these neurons or S1-innervated LEC neurons abolishes the beneficial effects of tactile enrichment. Moreover, adulthood tactile enrichment attenuates early-life stress-induced memory deficits and anxiety-related behavior. Our findings demonstrate that enriched tactile experience retunes the pathway from S1 to DG and enhances DG neuronal plasticity to modulate cognition and emotion., Touch can positively modulate cognitive performance and emotional response. Here the authors demonstrate that enriched tactile experience improves memory and reduces anxiety in adult mice by remodelling the pathway from the primary somatosensory cortex to the dentate gyrus.

AIM To evaluate the efficacy and safety of polyethylene glycol loxenatide (PEX168) monotherapy in type 2 diabetes (T2D) patients in China. MATERIALS AND METHODS In a multicentred, randomized, double-blinded, placebo-controlled phase 3a clinical trial, 361 patients with inadequate glycaemic control (HbA1c 7.0%-10.5%, fasting plasma glucose

The migration sources and pathways of Sogatella furcifera (Horváth) in topologically complex regions like Yunnan, China, and adjacent montane areas have long been a challenging task and a bottleneck in effective pest forecast and control. The present research reinvestigated this issue using a combination of mtDNA and long‐term historical wind field data in an attempt to provide new insights. Genetic analyses showed that the 60 populations of S. furcufera collected across Myanmar, Thailand, Laos, Vietnam, Yunnan, Guizhou, and Sichuan lack genetic structure and geographic isolation, while spatial analysis of haplotype and diversity indices discovered geographic relevance between populations. Migration rate analysis combined with high‐resolution 10‐year wind field analysis detected the following migration sources, pathways, and impacted areas which could explain the outbreak pattern in Yunnan. (a) Dominating stepwise northward migrations originated from northern Indochina, southern Yunnan, and central‐eastern Yunnan, impacting their northern areas. (b) Concurring summer–autumn southward (return) migration originated from nearly all latitude belts of Sichuan and Yunnan mainly impacting central and southern Yunnan. (c) Regular eastward and summer–autumn westward migrations across Yunnan. The northward migration reflects the temporal rhythm of gradual outbreaks from the south to the north in a year, while the return migration may explain the repeated or very severe outbreaks in the impacted areas. To form a better pest forecast and control network, attention must also be paid to the northern part of Yunnan to suppress the impact of return migration in summers and autumns.

Craniopharyngioma is an uncommon intracranial tumor that primarily occurs in the sella turcica. Giant cystic craniopharyngioma is rare in general and extremely rare in adults. We report a rare case of giant cystic craniopharyngioma in the anterior pontine cisterna and suprasellar cisterna. A 27-year-old man presented with double vision, and craniocerebral MRI revealed cystic masses in the anterior pontine cisterna and suprasellar cisterna. The masses were removed surgically and diagnosed as large cystic craniopharyngiomas by pathology and MRI. Giant cystic craniopharyngioma is rare in adults. Through this case report, we hope to increase awareness of this disease among various clinicians, including radiologists.

Background Dexmedetomidine induces a sedative response that is associated with rapid arousal. To elucidate the underlying mechanisms, the authors hypothesized that dexmedetomidine increases the activity of dopaminergic neurons in the ventral tegmental area, and that this action contributes to the unique sedative properties of dexmedetomidine. Methods Only male mice were used. The activity of ventral tegmental area dopamine neurons was measured by a genetically encoded Ca2+ indicator and patch-clamp recording. Dopamine neurotransmitter dynamics in the medial prefrontal cortex and nucleus accumbens were measured by a genetically encoded dopamine sensor. Ventral tegmental area dopamine neurons were inhibited or activated by a chemogenetic approach, and the depth of sedation was estimated by electroencephalography. Results Ca2+ signals in dopamine neurons in the ventral tegmental area increased after intraperitoneal injection of dexmedetomidine (40 μg/kg; dexmedetomidine, 16.917 [14.882; 21.748], median [25%; 75%], vs. saline, –0.745 [–1.547; 0.359], normalized data, P = 0.001; n = 6 mice). Dopamine transmission increased in the medial prefrontal cortex after intraperitoneal injection of dexmedetomidine (40 μg/kg; dexmedetomidine, 10.812 [9.713; 15.104], median [25%; 75%], vs. saline, –0.498 [–0.664; –0.355], normalized data, P = 0.001; n = 6 mice) and in the nucleus accumbens (dexmedetomidine, 8.543 [7.135; 11.828], median [25%; 75%], vs. saline, –0.329 [–1.220; –0.047], normalized data, P = 0.001; n = 6 mice). Chemogenetic inhibition or activation of ventral tegmental area dopamine neurons increased or decreased slow waves, respectively, after intraperitoneal injection of dexmedetomidine (40 μg/kg; delta wave: two-way repeated measures ANOVA, F[2, 33] = 8.016, P = 0.002; n = 12 mice; theta wave: two-way repeated measures ANOVA, F[2, 33] = 22.800, P < 0.0001; n = 12 mice). Conclusions Dexmedetomidine activates dopamine neurons in the ventral tegmental area and increases dopamine concentrations in the related forebrain projection areas. This mechanism may explain rapid arousability upon dexmedetomidine sedation. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase1,2 probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain–spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention. Neuronal activities in the central amygdala and paraventricular nucleus are transmitted via the splenic nerve to increase plasma cell formation after immunization, and this process can be behaviourally enhanced in mice.

The long-armed scarab (Cheirotonus gestroi) is an endangered large insect in southwestern China and neighboring countries; however, limited information is available regarding its population genetics, hindering conservation efforts. Therefore, we investigated the population genetic structure and evolutionary history of C. gestroi in southwestern China. Twenty-five haplotypes were obtained from 47 specimens across five populations. The Dawei Mountain (DWS) population differed from other populations by a high genetic distance. Population structure analysis generated three distinct clades, corresponding to Hengduan Mountains (HM), Ailao Mountains (AM), and Dawei Mountains (DM), and high-level genetic diversity was found in two HM populations. Collectively, the strong genetic differentiation among populations might be due to limited gene flow, geographical isolation, and habitat fragmentation. Therefore, while developing a conservation strategy, HM, AM, and DM groups should be defined as separate management units. Additionally, the DWS population should be given priority protection due to its uniqueness and low genetic diversity.

Aims Painful diabetic neuropathy (PDN) is a refractory complication of diabetes. The study aimed to investigate the role of α‐lipoic acid (ALA) on the regulation of transient receptor potential vanilloid‐1 (TRPV1) in dorsal root ganglion (DRG) neurons of rats with diabetes. Methods Whole‐cell patch‐clamp recordings were employed to measure neuronal excitability in DiI‐labeled DRG neurons of control and streptozotocin (STZ)‐induced diabetic rats. Western blotting and immunofluorescence assays were used to determine the expression and location of NF‐κBp65 and TRPV1. Results STZ‐induced hindpaw pain hypersensitivity and neuronal excitability in L4‐6 DRG neurons were attenuated by intraperitoneal injection with ALA once a day lasted for one week. TRPV1 expression was enhanced in L4‐6 DRGs of diabetic rats compared with age‐matched control rats, which was also suppressed by ALA treatment. In addition, TRPV1 and p65 colocated in the same DRG neurons. The expression of p65 was upregulated in L4‐6 DRGs of diabetic rats. Inhibition of p65 signaling using recombinant lentiviral vectors designated as LV‐NF‐κBp65 siRNA remarkably suppressed TRPV1 expression. Finally, p65 expression was downregulated by ALA treatment. Conclusion Our findings demonstrated that ALA may alleviate neuropathic pain in diabetes by regulating TRPV1 expression via affecting NF‐κB.

The TIM family comprises of eight genes in the mouse, three of which are conserved in humans (TIM-1, TIM-3, and TIM-4). Previous studies have revealed the relationships between Tim3+ Tregs and autoimmune disease. There was little study about the expression of Tim1 and Tim4 surface molecules on Tregs. We evaluated the frequency of the Tim1+Tregs and Tim4+Tregs in type 1 diabetes (T1D) in the present study. A total of 28 patients with T1D and 14 gender-, age-, and ethnically matched healthy volunteers were recruited. PBMCs from these individuals were isolated and analyzed by flow cytometry. Splenocytes from mice were also analyzed by flow cytometry. There is no difference in the frequency of Treg cells in peripheral blood isolated from T1D patients. Tim1 on CD4+CD25+ T cells decreased significantly in PBMC of patients with T1D(1.19 ± 0.17% vs 2.78 ± 0.38%, 95% CI:0.87–2.31, P

The mitogenomes of two insular subspecies of Pazala, G. (P.) eurous asakurae and G. (P.) mullah chungianus from Taiwan Island, are reported. Both mitogenomes are circular, 15,228 bp and 15,240 bp i...

Stepwise escalation of glucose-lowering therapy to more intensive regimens is an integral component of type 2 diabetes management (1). Early blood glucose control is associated with beneficial effects on long-term micro- and macrovascular outcomes (2). Understanding factors associated with time to therapy escalation following an elevated glycated hemoglobin (HbA1c) may inform interventions to facilitate timely control. We used linked real-world data to examine time to therapy escalation following a recorded HbA1c ≥8.0% (64 mmol/mol) and associated factors. The EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45 Study) is an Australian population-based linked data study in which participants of the 45 and Up Study have been linked to the Medicare Benefits Schedule (MBS), providing data on government-subsidized medical services, the Pharmaceutical Benefits Scheme (PBS), providing prescription claims data, and community laboratory databases (among others) (3). The 45 and Up Study comprises 267,153 individuals aged ≥45 years living in New South Wales (NSW), Australia, recruited between July 2006 and December 2009. Ethical approval for the EXTEND45 Study was obtained from the NSW Population & Health Services Research Ethics Committee (HREC/13/CIPHS/49). In EXTEND45, 24,430 individuals with diabetes between 2006 and 2014 have been identified using multiple linked data sources (3). In the current study, therapy escalation was assessed during the 6 months following all linked HbA1c results ≥8.0% occurring in non–treatment-naive, non–insulin-using individuals presumed to have type 2 diabetes. As a result, the unit of analysis was the elevated HbA1c, with individuals able to contribute multiple results to the analysis. A threshold of 8.0% was used to reflect the typically higher HbA1c targets recommended for older people (4). To ensure that all included HbA1c results represented separate instances of an elevated HbA1c in the same individual, those results ≥8.0% that occurred …

Aim. DNA methylation is thought to be involved in regulating the expression of key genes and inducing diabetic peripheral neuropathy (DPN). However, clinically, the level of whole-genome DNA methylation and its relationship with DPN remains unclear. Methods. 186 patients with type 2 diabetes mellitus (T2DM) admitted to the Second Affiliated Hospital of Soochow University since Jul. 2016 to Oct. 2017 were enrolled in the study, including 100 patients in the DPN group and 86 patients in the non-DPN group, diagnosed with Toronto Clinical Scoring System (TCSS). Clinical and biochemical characteristics between the two groups were compared, and the correlations with TCSS scores were analyzed. Furthermore, the levels of genomic DNA methylation of leukocytes, measured with high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), were also analyzed between the two groups. Results. Age, duration, triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), creatinine, uric acid (UA), blood urea nitrogen (BUN), and C-reactive protein (CRP) were significantly higher in the DPN group. Estimated glomerular filtration rate (eGFR) and the level of genomic DNA methylation were much lower in the DPN group. Spearman correlation analysis showed that TCSS was positively correlated with age, duration, UA, and CRP and was negatively correlated with body mass index (BMI), eGFR, and the level of genomic DNA methylation. Interestingly, multiple stepwise regression analysis showed that only duration, genomic DNA methylation, and eGFR had impacts on TCSS. The results also showed that the levels of genomic DNA methylation did not change significantly whether or not there was renal injury. Another multiple stepwise regression analysis showed that TCSS and BMI were the influencing factors of genomic DNA methylation. Finally, we found that genomic DNA methylation levels were decreased significantly in the DPN group compared with the non-DPN group when the duration is ≥5 years or BMI≥25 kg/m2. Conclusion. Low level of genomic DNA methylation is a relative specific risk factor of diabetic peripheral neuropathy in patients with type 2 diabetes.

A subgroup analysis of the nationwide, cross-sectional 3B STUDY was performed to understand the current blood pressure (BP) control status and treatment patterns in Chinese diabetes patients as well as to identify factors associated with BP control. The demographic data, anthropometric parameters, and laboratory results were collected from 24 512 type 2 diabetes patients. The BP goal was a systolic BP

OBJECTIVE Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. RESEARCH DESIGN AND METHODS We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. RESULTS We observed a high genetic correlation between children/adolescents and adult T1D case subjects (rg = 0.87), as well as subgroups of autoantibody status (rg ≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 × 10−8) and rs3802604 in GATA3 (OR 1.24, P = 2.06 × 10−8), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 × 10−232) and rs705699 in SUOX (OR 1.46, P = 7.48 × 10−20). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 × 10−12), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85–0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 × 10−11) and lower fasting C-peptide levels (P = 7.19 × 10−3) in individuals newly diagnosed with T1D. CONCLUSIONS Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.

The neural substrates for predatory hunting, an evolutionarily conserved appetitive behavior, remain largely undefined. Photoactivation of zona incerta (ZI) GABAergic neurons strongly promotes hunting of both live and artificial prey. Conversely, photoinhibition of these neurons or deletion of their GABA function severely impairs hunting. Here electrophysiological recordings reveal that ZI neurons integrate prey-related multisensory signals and discriminate prey from non-prey targets. Visual or whisker sensory deprivation reduces calcium responses induced by prey introduction and attack and impair hunting. ZI photoactivation largely corrects the hunting impairment caused by sensory deprivations. Motivational and reinforcing assays reveal that ZI photoactivation is associated with a strong appetitive drive, causing repetitive self-stimulatory behaviors. These ZI neurons project to the periaqueductal gray matter to induce hunting and motivation. Thus, we have delineated the function of ZI GABAergic neurons in hunting, which integrates prey-related sensory signals into prey detection and attack and induces a strong appetitive motivational drive.

To evaluate the effect of Dexmedetomidine (Dex) on the inflammatory response and the integrity of blood-spinal cord barrier (BSCB) after spinal cord ischemia-reperfusion injury (SCIRI).To investigate the role of Dex in spinal cord I/R, particularly in the high mobility group box 1-toll-like receptor 4-nuclear factor κB (HMGB1-TLR4-NF-κB) pathway and the integrity of BSCB.High mobility group box 1 (HMGB1) has been identified as a key mediator for the inflammatory response after spinal cord injury. Toll-like receptor 4-nuclear factor κB (TLR4-NF-κB) signaling pathway is the downstream of HMGB1. Dex preconditioning could protect the spinal cord from I/R injury by inhibiting HMGB1 and stabilizing the integrity of BSCB. But its underlying mechanism is not fully understood.Forty-eight male Japanese white rabbits were randomly assigned to three groups (16 rabbits/group): sham, I/R, and Dex + I/R. The hind-limb motor function was assessed at 12 hours intervals for 48 hours after reperfusion using the modified Tarlov scale score. The expression of HMGB1, TLR4, NF-κB, and tumor necrosis factor α (TNF-α) was evaluated by real-time polymerase chain reaction (RT-PCR) and Western blot. The permeability of BSCB was examined via Evans blue (EB) extravasation.Compared with sham group, spinal cord I/R increased the expression of HMGB1, TLR4, NF-κB, and TNF-α as well as the permeability of BSCB (P 0.05). Spinal cord I/R induced the decline of the score of hind-limb motor function (P 0.01). Preconditioning with Dex attenuated the up-regulation of the express of HMGB1, TLR4, NF-κB, TNF-α, and stabilized the permeability of BSCB (P 0.05). Dex preconditioning also improved the hiatopathological outcome and the motor function (P 0.01).Dex preconditioning may inhibit the inflammatory response and stabilize the integrity of BSCB at least partially by inhibiting the HMGB1-TLR4-NF-κB signaling pathway to protect spinal cord from ischemia/reperfusion injury.2.

Methylglyoxal (MGO), an endogenous reactive carbonyl compound, plays a key role in the pathogenesis of diabetic neuropathy. The aim of this study is to investigate the role of MGO in diabetic itch and hypoalgesia, two common symptoms associated with diabetic neuropathy. Methods: Scratching behavior, mechanical itch (alloknesis), and thermal hypoalgesia were quantified after intradermal (i.d.) injection of MGO in naive mice or in diabetic mice induced by intraperitoneal (i.p.) injection of streptozotocin (STZ). Behavioral testing, patch-clamp recording, transgenic mice, and gene expression analysis were used to investigate the mechanisms underlying diabetic itch and hypoalgesia in mice. Results: I.d. injection of MGO evoked dose-dependent scratching in normal mice. Addition of MGO directly activated transient receptor potential ankyrin 1 (TRPA1) to induce inward currents and calcium influx in dorsal root ganglia (DRG) neurons or in TRPA1-expressing HEK293 cells. Mechanical itch, but not spontaneous itch was developed in STZ-induced diabetic mice. Genetic ablation of Trpa1 (Trpa1-/- ), pharmacological blockade of TRPA1 and Nav1.7, antioxidants, and mitogen-activated protein kinase kinase enzyme (MEK) inhibitor U0126 abrogated itch induced by MGO or in STZ-induced diabetic mice. Thermal hypoalgesia was induced by intrathecal (i.t.) injection of MGO or in STZ-induced diabetic mice, which was abolished by MGO scavengers, intrathecal injection of TRPA1 blockers, and in Trpa1-/- mice. Conclusion: This study revealed that Nav1.7 and MGO-mediated activation of TRPA1 play key roles in itch and hypoalgesia in a murine model of type 1 diabetes. Thereby, we provide a novel potential therapeutic strategy for the treatment of itch and hypoalgesia induced by diabetic neuropathy.

Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson’s disease by targeting the cellular copper efflux protein ATP7B (WLN). Interestingly, both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Herein, we show that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged Mo2S6O2 cluster. TM expels copper ions from Cu-WLN4 and forms a copper-free dimer. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. Reaction with multi-domain proteins indicates that TM can also connect two domains in the same molecule, forming Mo-bridged intramolecular crosslinks. These results provide structural and chemical insight into the mechanism of action of TM against ATPase, and reveal the molecular mechanism by which TM attenuates the cisplatin resistance mediated by copper efflux proteins., Tetrathiomolybdate (TM) and Cu-ATPases, e.g. Wilson (WLN) protein, affect the efficacy of common anticancer drug cisplatin. Here, the authors show that TM generates a protein dimer with a WLN domain by expelling copper and provide insight into the synergy of TM and cisplatin in cancer chemotherapy.

Carboazidation of alkenes and alkynes holds the promise to construct valuable molecules directly from chemical feedstock therefore is significantly important. Although a few examples have been developed, there are still some unsolved problems and lack of universal methods for carboazidation of both alkenes and alkynes. Here we describe an iron-catalyzed rapid carboazidation of alkenes and alkynes, enabled by the oxidative radical relay precursor t-butyl perbenzoate. This strategy enjoys success with a broad scope of alkenes under mild conditions, and it can also work with aryl alkynes which are challenging substrates for carboazidation. A large number of diverse structures, including many kinds of amino acid precursors, fluoroalkylated vinyl azides, other specific organoazides, and 2H-azirines can be easily produced., Carboazidation of alkenes and alkynes holds the promise to construct valuable, functionalized molecules. Here, the authors report a general and efficient iron-catalyzed carboazidation of both alkenes and alkynes enabled by t-butyl perbenzoate.

Preoperative anxiety is common and often comes with a higher probability of worse recovery. However, the neurological mechanism of the effect of preoperative anxiety on general anesthesia and subsequent awakening remains unknown. In this study, we report an anxious state results in delayed awakening in anxiety model mice from sevoflurane general anesthesia. More profound inhibition of DA neurons in the VTA contributes to delayed awakening. Optogenetic stimulation of VTA DA neurons can reverse the delay. The results indicate that VTA DA neurons may be involved in the delay in awakening from general anesthesia caused by anxiety.

OBJECTIVE This study aimed to evaluate the efficacy and safety of mulberry twig alkaloids (Sangzhi alkaloids [SZ-A]) in the treatment of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This was a multicenter, randomized, double-blind, double-dummy, and parallel controlled noninferiority clinical trial that was conducted for 24 weeks. A total of 600 patients were randomly allocated to the SZ-A group (n = 360) or acarbose group (n = 240). The primary efficacy end point was the change of glycosylated hemoglobin (HbA1c) compared with baseline. In addition, adverse events (AEs), severe AEs (SAEs), treatment-related AEs (TAEs), and gastrointestinal disorders (GDs) were monitored. RESULTS After treatment for 24 weeks, the change in HbA1c was –0.93% (95% CI –1.03 to –0.83) (–10.2 mmol/mol [–11.3 to –9.1]) and –0.87% (–0.99 to –0.76) (–9.5 mmol/mol [–10.8 to –8.3]) in the SZ-A and acarbose groups, respectively, and the least squares mean difference was –0.05% (95% CI –0.18 to 0.07) (–0.5 mmol/mol [–2.0 to 0.8]) between the two groups, with no significant difference on the basis of covariance analysis (P > 0.05). The incidence of TAEs and GDs was significantly lower in the SZ-A group than the acarbose group (P < 0.01), but no differences for AEs or SAEs between the two groups were observed (P > 0.05). CONCLUSIONS SZ-A exhibited equivalent hypoglycemic effects to acarbose in patients with T2D. Nevertheless, the incidence of TAEs and GDs was lower following SZ-A treatment than acarbose treatment, suggesting good safety.

Background Despite the fundamental clinical significance of general anaesthesia, the cortical mechanism underlying anaesthetic-induced loss of consciousness (aLOC) remains elusive. Methods Here, we measured the dynamics of two major cortical neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate, through in vivo two-photon imaging and genetically encoded neurotransmitter sensors in a cell type-specific manner in the primary visual (V1) cortex. Findings We found a general decrease in cortical GABA transmission during aLOC. However, the glutamate transmission varies among different cortical cell types, where in it is almost preserved on pyramidal cells and is significantly reduced on inhibitory interneurons. Cortical interneurons expressing vasoactive intestinal peptide (VIP) and parvalbumin (PV) specialize in disinhibitory and inhibitory effects, respectively. During aLOC, VIP neuronal activity was delayed, and PV neuronal activity was dramatically inhibited and highly synchronized. Interpretation These data reveal that aLOC resembles a cortical state with a disrupted excitatory-inhibitory network and suggest that a functional inhibitory network is indispensable in the maintenance of consciousness. Funding This work was supported by the grants of the National Natural Science Foundation of China (grant nos. 81620108012 and 82030038 to H.D. and grant nos. 31922029, 61890951, and 61890950 to J.H.).

Summary Morphine is commonly used to relieve moderate to severe pain, but repeated doses cause opioid tolerance. Here, we used ATP sensor and fiber photometry to detect prefrontal ATP level. It showed that prefrontal ATP level decreased after morphine injection and the event amplitude tended to decrease with continuous morphine exposure. Morphine had little effect on prefrontal ATP due to its tolerance. Therefore, we hypothesized that the analgesic effect of morphine might be related to ATP in the medial prefrontal cortex (mPFC). Moreover, local infusion of ATP partially antagonized morphine analgesia. Then we found that inhibiting P2X7R in the mPFC mimicked morphine analgesia. In morphine-tolerant mice, pretreatment with P2X4R or P2X7R antagonists in the mPFC enhanced analgesic effect. Our findings suggest that reduction of prefrontal purinergic signaling is necessary for the morphine analgesia, which help elucidate the mechanism of morphine analgesia and may lead to the development of new clinical treatments for neuropathic pain., Graphical abstract, Highlights • Prefrontal ATP is involved in the analgesic effect of morphine • Blocking P2X7R in the mPFC mimics morphine's analgesic effect • Blocking P2X4R or P2X7R in the mPFC enhances morphine analgesia in tolerant mice, Neuroscience; Molecular Neuroscience; Clinical Neuroscience

Background The accumulation of α-synuclein (α-Syn) aggregates that leads to the onset of Parkinson's disease (PD) has been postulated to begin in the gastrointestinal tract. The normal human appendix contains pathogenic forms of α-Syn, and appendectomy has been reported to affect the incidence of PD. Objective This study investigated appendix abnormality in patients with PD. Methods We assessed appendix morphology in 100 patients with PD and 50 control subjects by multislice spiral computed tomography. We analyzed the clinical characteristics of patients with PD with diseased appendices, which was confirmed in seven patients by histopathological analysis. Results Chronic appendicitis-like lesions were detected in 53% of patients with PD, but these were not associated with the duration of motor symptoms. Appendicitis-like lesions, impaired olfaction, and rapid eye movement sleep behavior disorder were risk factors for PD. The following clinical symptoms could be used to identify patients with PD with appendicitis-like lesions: first motor symptoms were bradykinesia/rigidity, onset of motor symptoms in the central axis or left limb, prodromal constipation, high ratio of Unified Parkinson's Disease Rating Scale Part III score to symptom duration, low Montreal Cognitive Assessment score, and high Epworth Sleepiness Scale score. The seven patients with PD who were diagnosed with chronic appendicitis underwent appendectomy, and histopathological analysis revealed structural changes associated with chronic appendicitis and α-Syn aggregation. Conclusions These results indicate an association between chronic appendicitis-like lesions and PD, and suggest that α-Syn accumulation in the diseased appendix occurs in PD. © 2021 International Parkinson and Movement Disorder Society.

AimTo develop and validate a CpG-based classifier for preoperative discrimination of early and advanced-late stage colorectal cancer (CRC).MethodsWe identified an epigenetic signature based on methylation status of multiple CpG sites (CpGs) from 372 subjects in The Cancer Genome Atlas (TCGA) CRC cohort, and an external cohort (GSE48684) with 64 subjects by LASSO regression algorithm. A classifier derived from the methylation signature was used to establish a multivariable logistic regression model to predict the advanced-late stage of CRC. A nomogram was further developed by incorporating the classifier and some independent clinical risk factors, and its performance was evaluated by discrimination and calibration analysis. The prognostic value of the classifier was determined by survival analysis. Furthermore, the diagnostic performance of several CpGs in the methylation signature was evaluated.ResultsThe eight-CpG-based methylation signature discriminated early stage from advanced-late stage CRC, with a satisfactory AUC of more than 0.700 in both the training and validation sets. This methylation classifier was identified as an independent predictor for CRC staging. The nomogram showed favorable predictive power for preoperative staging, and the C-index reached 0.817 (95% CI: 0.753–0.881) and 0.817 (95% CI: 0.721–0.913) in another training set and validation set respectively, with good calibration. The patients stratified in the high-risk group by the methylation classifier had significantly worse survival outcome than those in the low-risk group. Combination diagnosis utilizing only four of the eight specific CpGs performed well, even in CRC patients with low CEA level or at early stage.ConclusionsOur classifier is a valuable predictive indicator that can supplement established methods for more accurate preoperative staging and also provides prognostic information for CRC patients. Besides, the combination of multiple CpGs has a high value in the diagnosis of CRC.

In-depth profiling of transmembrane proteins in the brain leads to the identification of GPCR regulators in a disease model., Transmembrane proteins play vital roles in mediating synaptic transmission, plasticity, and homeostasis in the brain. However, these proteins, especially the G protein–coupled receptors (GPCRs), are underrepresented in most large-scale proteomic surveys. Here, we present a new proteomic approach aided by deep learning models for comprehensive profiling of transmembrane protein families in multiple mouse brain regions. Our multiregional proteome profiling highlights the considerable discrepancy between messenger RNA and protein distribution, especially for region-enriched GPCRs, and predicts an endogenous GPCR interaction network in the brain. Furthermore, our new approach reveals the transmembrane proteome remodeling landscape in the brain of a mouse depression model, which led to the identification of two previously unknown GPCR regulators of depressive-like behaviors. Our study provides an enabling technology and rich data resource to expand the understanding of transmembrane proteome organization and dynamics in the brain and accelerate the discovery of potential therapeutic targets for depression treatment.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.

Simple Summary Butterflies provide numerous ecological and socio-economic services and are important indicator species. China is home to over 2000 species of butterflies and in recent years has elevated biodiversity conservation on the national agenda. This manuscript reviews China’s butterfly conservation efforts and its legal and policy frameworks. We note some of the current limitations in butterfly conservation (inappropriate listing of protected species; over-reliance on inventories, rather than holistic research) and offer numerous recommendations to improve conservation efforts. Our recommendations include those related to integration of scientific data into policy (designation of scientifically-based protected areas; development of appropriate criteria for classifying protected species; use of umbrella species for conservation purposes), adoption of butterfly-friendly land use policies in rural and urban areas, butterfly ranching and farming, use of citizen science to improve data collection, and enhanced public outreach and environmental education campaigns. Our recommendations will help further the goals of China’s National Biodiversity Conservation Strategy and Action Plan (2011–2030). Abstract About 10% of the Earth’s butterfly species inhabit the highly diverse ecosystems of China. Important for the ecological, economic, and cultural services they provide, many butterfly species experience threats from land use shifts and climate change. China has recently adopted policies to protect the nation’s biodiversity resources. This essay examines the current management of butterflies in China and suggests various easily implementable actions that could improve these conservation efforts. Our recommendations are based on the observations of a transdisciplinary group of entomologists and environmental policy specialists. Our analysis draws on other successful examples around the world that China may wish to consider. China needs to modify its scientific methodologies behind butterfly conservation management: revising the criteria for listing protected species, focusing on umbrella species for broader protection, identifying high priority areas and refugia for conservation, among others. Rural and urban land uses that provide heterogeneous habitats, as well as butterfly host and nectar plants, must be promoted. Butterfly ranching and farming may also provide opportunities for sustainable community development. Many possibilities exist for incorporating observations of citizen scientists into butterfly data collection at broad spatial and temporal scales. Our recommendations further the ten Priority Areas of China’s National Biodiversity Conservation Strategy and Action Plan (2011–2030).

Purpose This essay aims to propose suggestions on what we can learn from previous investigations to conduct further studies on the potential mechanisms underlying the effect of diabetes mellitus on COVID-19. Methods We reviewed some literature on diabetes and other types of coronavirus infection such as Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) and made some summaries and comparisons. Results Diabetes affect the occurrence and progression of COVID-19. Conclusions In-depth and comprehensive exploration of the mechanism of diabetes affecting COVID-19 should be carried out.

In recent years, as living standards have continued to improve, the number of diabetes patients in China, along with the incidence of complications associated with the disease, has been increasing. Among these complications, diabetic foot disease is one of the main causes of disability and death in diabetic patients. Due to the differences in economy, culture, religion and level of medical care available across different regions, preventive and treatment methods and curative results for diabetic foot vary greatly. In multidisciplinary models built around diabetic foot, the timely assessment and diagnosis of wounds and appropriate methods of prevention and treatment with internal and external surgery are key to clinical practice for this pathology. In 2019, under the leadership of the Jiangsu Medical Association and Chinese Diabetes Society, the writing group for the Guidelines on multidisciplinary approaches for the prevention and management of diabetic foot disease (2020 edition) was established with the participation of scholars from the specialist areas of endocrinology, burn injury, vascular surgery, orthopedics, foot and ankle surgery and cardiology. Drawing lessons from diabetic foot guidelines from other countries, this guide analyses clinical practices for diabetic foot, queries the theoretical basis and grades and gives recommendations based on the characteristics of the pathology in China. This paper begins with assessments and diagnoses of diabetic foot, then describes treatments for diabetic foot in detail, and ends with protections for high-risk feet and the prevention of ulcers. This manuscript covers the disciplines of internal medicine, surgical, nursing and rehabilitation and describes a total of 50 recommendations that we hope will provide procedures and protocols for clinicians dealing with diabetic foot.Registry number: IPGRP-2020cn124

Inflammation has been believed to contribute to coronavirus disease 2019 (COVID-19). Risk factors for death of COVID-19 pneumonia have not yet been well established.In this retrospective cohort study, we included the deceased patients in COVID-19 specialized ICU with laboratory-confirmed COVID-19 from Guanggu hospital area of Tongji Hospital from February 8th to March 30th. Demographic, clinical, laboratory, and outcome data were extracted from electronic medical records using a standard data collection form. We used Spearman rank correlation and Cox regression analysis to explore the risk factors associated with in-hospital death, especially the association between inflammatory cytokines and death.A total of 205 severe/critical COVID-19 pneumonia patients were admitted in the COVID-19 specialized ICU and 75 deceased patients were included in the final analysis. The median age of the deceasing patients was 70 years (IQR 65-79). The common symptoms were fever (78.9%), cough (70.4%), and expectoration (39.4%). The BNP and CRP levels were far beyond the normal reference range. In the Spearman rank correlation analysis, IL-8 was found to be significantly associated with the time from onset to death (rs= -0.30, P = .034) and that from admission to death (rs= -0.32, P = .019). Cox regression showed after adjusting age and sex, IL-8 levels were still significantly associated with the time from onset to death (P = .003) and that from admission to death (P  = .01).IL-8 levels were associated with in-hospital death in severe/critical COVID-19 patients, which could help clinicians to identify patients with high risk of death at an early stage.

Major depressive disorder (MDD) is a severe mental disorder with a high disability rate worldwide. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are the most common agents for antidepressant use. SSRIs and SNRIs are believed to achieve antidepressant effects through the activation of serotonergic or noradrenergic systems. However, whether the dopaminergic system is involved remains unclear. In our study, a genetically encoded dopamine sensor and in vivo fiber photometry recordings were used to measure the dopamine concentrations in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute intraperitoneal injection of SSRIs or SNRIs. Combined with the behavioral tests, we found that SNRIs increased dopamine concentrations in both the mPFC and the NAc and showed faster antidepressant effects than SSRIs. To verify the enhanced dopamine levels induce the faster antidepressant effects of SNRIs, we employed dopamine receptor antagonists to specifically block the dopaminergic function. The results showed that the faster antidepressant effects of SNRIs were weakened by the dopamine receptor antagonists. Altogether, our study reveals that SNRIs achieve faster antidepressant effects than SSRIs by elevating the dopamine concentrations in the mPFC and the NAc. Our work proposes further mechanisms for the first-line antidepressants, which provides more basis for clinical treatments. This article is part of the special issue on Stress, Addiction and Plasticity.

Depression is a common affective disorder characterized by significant and persistent low mood. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, is reported to have a rapid and durable antidepressant effect, but the mechanisms are unclear. Protein phosphorylation is a post-translational modification that plays a crucial role in cell signaling. Thus, we present a phosphoproteomics approach to investigate the mechanisms underlying stress-induced depression and the rapid antidepressant effect of ketamine in mice. We analyzed the phosphoprotein changes induced by chronic unpredictable mild stress (CUMS) and ketamine treatment in two known mood control centers, the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). We initially obtained >8,000 phosphorylation sites. Quantitation revealed 3,988 sites from the mPFC and 3,196 sites from the NAc. Further analysis revealed that changes in synaptic transmission-related signaling are a common feature. Notably, CUMS-induced changes were reversed by ketamine treatment, as shown by the analysis of commonly altered sites. Ketamine also induced specific changes, such as alterations in synapse organization, synaptic transmission, and enzyme binding. Collectively, our findings establish a signaling framework for stress-induced depression and the rapid antidepressant effect of ketamine.

Aim: To study the expression pattern of circular RNAs in diabetic peripheral neuropathy. Materials & methods: Transmission electron microscopy was used to observe the ultrastructure of sciatic nerves and dorsal root ganglion (DRGs). circRNAs in DRGs were identified with high-throughput RNA sequencing. Whole-genome mRNAs were detected by a chip scan. Results: The ultrastructure of sciatic nerves and DRGs in diabetes mellitus mice changed significantly. A total of 11,004 circRNAs and 15 differentially expressed circRNAs, as well as 35,368 mRNAs and 133 differentially expressed mRNAs were identified in DRGs between wild-type and diabetes mellitus mice. 11 circRNAs and 14 mRNAs have a significant correlation using strict coexpression analysis. The expression of circRNA.4614 was validated to be upregulated significantly. Conclusion: Our study suggested that circRNAs might be involved in the regulation of mRNA expressions in diabetic peripheral neuropathy.

Losaria coon (Fabricius, 1793) is currently comprised of ten subspecies, which were originally described under two names, Papilio coon and P. doubledayi before 1909, when they were combined as one species. The main difference between them is the colour of abdomen and hindwing subterminal spots&mdash, yellow in coon and red in doubledayi. Wing morphology, male and female genitalia, and molecular evidence (DNA barcodes) were analysed for multiple subspecies of L. coon and three other Losaria species&mdash, rhodifer, neptunus, and palu. Our molecular data support the separation of L. coon and L. doubledayi stat. rev. as two distinct species, with L. rhodifer positioned between them in phylogenetic analyses. Wing morphology and genitalic structures also confirm the molecular conclusions. Our findings divide L. coon into two species occupying different geographic ranges: with L. coon restricted to southern Sumatra, Java, and Bawean Island, while L. doubledayi occurs widely in regions from North India to northern Sumatra, including Hainan and Nicobar Islands. Hence, future conservation efforts must reassess the status and threat factors of the two species to form updated strategies.

AIM To investigate the diagnostic value of abnormal serum carbohydrate antigen 199 (CA199) level in acute cholangitis secondary to choledocholithiasis. METHODS In this retrospective cohort study, the clinical data of 727 patients with choledocholithiasis admitted to the Third Affiliated Hospital of Zunyi Medical College from June 2011 to June 2017 were collected. Among these patients, 258 patients had secondary acute cholangitis and served as observation group, and the remaining 569 choledocholithiasis patients served as the control group. Serum liver function indexes and tumor markers were detected in both groups, and the receiver operating characteristic (ROC) curves were constructed for markers showing statistical significances. The cutoff value, sensitivity, and specificity of each marker were calculated according to the ROC curves. RESULTS The results of liver function tests showed no significant differences between the two groups (P > 0.05). Tumor markers including serum CA125, CA153, carcinoembryonic antigen, and alpha fetoprotein levels were also not significantly different (P > 0.05); however, the serum CA199 level was significantly higher in the observation group than in the control group (P < 0.05). The ROC curve analysis showed that the area under the curve was 0.885 (95%CI: 0.841-0.929) for CA199, and the cutoff value of 52.5 kU/L had the highest diagnostic accuracy, with a sensitivity of 86.8% and a specificity of 81.6%. CONCLUSION Abnormally elevated serum CA199 level has an important value in the diagnosis of acute cholangitis secondary to choledocholithiasis. It may be a specific inflammatory marker for acute cholangitis.

Objective To explore the predictive value of prepregnancy body mass index (pBMI) and early gestational fasting blood glucose (eFBG) in gestational diabetes mellitus (GDM). Methods This case–control study enrolled pregnant women at 6 to 16 weeks of gestation. The pBMI, eFBG and glycosylated haemoglobin (HbA1c) was recorded in the first trimester of pregnancy. Receiver-operating characteristic (ROC) curve analysis was used to measure the efficacy of factors that predict GDM. Results A total of 2119 pregnant women were enrolled in this study. Of these, 386 were diagnosed with GDM and 1733 did not have GDM. The age (odds ratio [OR] 1.16; 95% confidence interval [CI] 1.13, 1.20), pBMI (OR 1.12; 95% CI 1.07, 1.17) and eFBG (OR 5.37; 95% CI 3.93, 7.34) were independent risk factors for GDM occurrence. The areas under the ROC curve of eFBG, pBMI and eFBG + pBMI were 0.68 (95% credibility interval 0.65, 0.71), 0.66 (95% credibility interval 0.63, 0.69) and 0.71 (95% credibility interval 0.69, 0.74), respectively. The area under the curve of eFBG + pBMI was significantly higher than that of eFBG or pBMI alone. Conclusion The combination of eFBG and pBMI had a high predictive value for GDM.

To explore the surgical methods and clinical effect of endoscopic endonasal approaches for the treatment of invasive pituitary adenomas (IPAs).A retrospective analysis was made of the clinical data of 74 patients (75 procedures) with IPAs treated by different endoscopic endonasal approaches at the Department of Neurosurgery, The First Affiliated Hospital of Shenzhen University from May 2014 to August 2017. The data include clinical manifestation, imaging features, surgical methods and complications, resection rate, cure rate, prognosis, and complications in different Knosp classifications and Hardy stages. The transcavernous approach was used in 47 patients, the lateral-cavernous approach was used in 14 patients, the tuberculum sella planum approach was used in 8 patients, and the diaphragma sellae open or dorsum sellae cut approach was used in 6 patients.The gross total resection (GTR) rate was 70.7% (53 patients) and tumor residue rate was 29.3% (22 patients). GTR rate for pituitary adenoma according to Knosp classification was 89.3% in grade 3 and 28.6% in grade 4. The biology cure rate was 75.0% and 23.8%, respectively. There was significance between them (P 0.05). In addition, the GTR rate of Hardy stage was 90.5% in stage C, 90.0% in stage D, 26.1% in stage E, and the biology cure rate was 80.1%, 75.0%, and 13.0%, respectively. There was significance among them (P 0.05) Postoperative severe complications included 9 patients (12.0%) with cerebrospinal fluid leaks, 26 patients (34.7%)with electrolyte imbalance, 36 patients (48.0%) with transient diabetes insipidus, 22 patients (29.3%) with hypopituitarism, 2 patients (2.7%) with permanent hypopituitarism, and 2 patients (2.7%)with epistaxis. The follow-up lasted 2-41 months (average, 19.3 months). No patient experienced recurrence after GTR, 1 patient undergoing subtotal experienced recurrence and underwent reoperation, 3 patients underwent postoperative Gamma Knife treatment, and 2 patients with refractory IPA were given temozolomide and metformin chemotherapy.According to the invasiveness of IPA, choosing the appropriate endoscopic surgical approach is helpful in removing tumors and reducing complications.

Screening high-risk individuals for gestational diabetes mellitus (GDM) in early pregnancy conventionally relies on established maternal risk factors; however, the sensitivity and specificity of these factors are not satisfactory. The present study aimed to determine whether the concentration of angiopoietin-like protein 8 (ANGPTL8), either alone or combined with other risk factors in early pregnancy, could be used to predict subsequent GDM. From August 2015 to January 2016, 474 women receiving prenatal care at around 12–16 weeks of gestation were recruited into the study. ANGPTL8 levels were measured at the first prenatal visit. All the participants received a 75 g OGTT during weeks 24–28 of gestation. ANGPTL8 levels in early pregnancy were considerably higher in women who developed GDM than those who maintained normal glucose tolerance (2822 ± 938 vs 2120 ± 1118 pg/ml, respectively; p

Yan Sun,1,* Pan-Pan Yang,1,* Zhen-Yuan Song,2 Yu Feng,1 Duan-Min Hu,1 Ji Hu,1 Guang-Yin Xu,3 Hong-Hong Zhang1,3 1Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Endocrinology, The East District of Suzhou Municipal Hospital, Suzhou, People’s Republic of China; 3Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, People’s Republic of China *These authors contributed equally to this work Aim: Patients with long-standing diabetes often demonstrate intestinal dysfunction, characterized as constipation or colonic hypersensitivity. Our previous studies have demonstrated the roles of voltage-gated sodium channels NaV1.7 and NaV1.8 in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. This study was designed to determine roles of antioxidant α-lipoic acid (ALA) on sodium channel activities and colonic hypersensitivity of rats with diabetes. Methods: Streptozotocin was used to induce diabetes in adult female rats. Colonic sensitivity was measured by behavioral responses to colorectal distention in rats. The excitability and sodium channel currents of colon projection DRG neurons labeled with DiI were measured by whole-cell patch-clamp recordings. The expressions of NaV1.7 and NaV1.8 of colon DRGs were measured by western blot analysis. Results: ALA treatment significantly increased distention threshold in responding to colorectal distension in diabetic rats compared with normal saline treatment. ALA treatment also hyperpolarized the resting membrane potentials, depolarized action potential threshold, increased rheobase, and decreased frequency of action potentials evoked by ramp current stimulation. Furthermore, ALA treatment also reduced neuronal sodium current densities of DRG neurons innervating the colon from rats with diabetes. In addition, ALA treatment significantly downregulated NaV1.7 and NaV1.8 expression in colon DRGs from rats with diabetes. Conclusion: Our results suggest that ALA plays an analgesic role, which was likely mediated by downregulation of NaV1.7 and NaV1.8 expressions and functions, thus providing experimental evidence for using ALA to treat colonic hypersensitivity in patients with diabetic visceral pain. Keywords: diabetes, colonic hypersensitivity, dorsal root ganglion, voltage-gated sodium channels, α-lipoic acid

This study was performed to evaluate the effectiveness of sublobar resection for the treatment of pulmonary aspergilloma compared with lobectomy.Patients with pulmonary aspergilloma who underwent lobectomy or sublobar resection in our department between March 2007 and December 2015 were retrospectively reviewed. Data were collected for patient demographic characteristics, medical history, preoperative investigations, perioperative findings, postoperative conditions, and recurrence status. Propensity-matched comparative analyses were performed to adjust for potential differences of patients' baseline characteristics between the groups.A total of 96 patients underwent lobectomy, 46 patients underwent attempted sublobar resection. The median follow-up time is 53 months. No recurrence was found in either group. Three patients (3.1%) in the lobectomy group required reoperation for bleeding. The patients who underwent sublobar resection had less underlying lung disease (p = 0.031), smaller lesions (p = 0.033), and were more likely to have been treated with video-assisted thoracic surgery (p0.001). These differences were eliminated by propensity score matching (46 pairs were successfully matched). Comparative analyses in matched groups demonstrate that there was no marked difference in the volume and duration of chest drainage or the length of postoperative hospital stay. However, the patients with sublobar resection had shorter operation time (p = 0.004), less blood loss (p = 0.042), and less postoperative complication (p = 0.048).Sublobar resection performed for small simple pulmonary aspergilloma and selected complex pulmonary aspergilloma has a low recurrence rate and confers perioperative advantages compared with lobectomy.

Background/Aims The relationship between C-peptide levels and gastrointestinal (GI) symptoms in type 2 diabetic patients is not clear. The purpose of this study is to examine the association between fasting C-peptide and GI symptoms of gastroparesis in type 2 diabetic patients. Methods We recruited 333 type 2 diabetic patients into the present study. All patients filled out questionnaires of gastroparesis cardinal symptom index (GCSI) to evaluate GI symptoms. Hospital anxiety and depression scale were adopted to define anxiety and depression. Patients with GCSI scores ≥ 1.9 were regarded as having symptoms of gastroparesis. Results In our study, 71 (21.3%) type 2 diabetic patients had GCSI scores ≥ 1.9. In comparison to patients with scores < 1.9, those with scores ≥ 1.9 had significantly lower fasting c-peptide levels (1.49 ng/mL vs 1.94 ng/mL, P < 0.001), higher prevalence of depression (40.9% vs 18.3%, P < 0.001) and anxiety (28.2% vs 13.0%, P = 0.002). Multivariate logistic regression revealed that fasting C-peptide was still significantly associated with symptoms of gastroparesis (odds ratio, 0.67; 95% confidence intervals, 0.48–0.94; P = 0.021), even after adjustments for age, sex, body mass index, HbA1c, current smoking and drinking status, anxiety, and depression. Furthermore, linear regressions showed that fasting C-peptide was independently and negatively related to GCSI scores (standardized regression coefficient, −0.29; P < 0.001) in patients with at least one GI symptom. Conclusion GI symptoms of diabetic gastroparesis affect approximately 20% of type 2 diabetes patients and are associated with lower fasting C-peptide levels independent of depression and anxiety status.

Propofol has been shown to exert neuroprotective effects on the injured spinal cord. However, the effect of propofol on the blood-spinal cord barrier (BSCB) after ischemia/reperfusion injury (IRI) is poorly understood. Therefore, we investigated whether propofol could maintain the integrity of the BSCB. Spinal cord IRI (SCIRI) was induced in rabbits by infrarenal aortic occlusion for 30 minutes. Propofol, 30 mg/kg, was intravenously infused 10 minutes before aortic clamping as well as at the onset of reperfusion. Then, 48 hours later, we performed histological and mRNA/protein analyses of the spinal cord. Propofol decreased histological damage to the spinal cord, attenuated the reduction in BSCB permeability, downregulated the mRNA and protein expression levels of matrix metalloprotease-9 (MMP-9) and nuclear factor-κB (NF-κB), and upregulated the protein expression levels of occludin and claudin-5. Our findings suggest that propofol helps maintain BSCB integrity after SCIRI by reducing MMP-9 expression, by inhibiting the NF-κB signaling pathway, and by maintaining expression of tight junction proteins.

The subalpine swordtail butterfly Graphium (Pazala) parus (Niceville, 1900) is endemic to the Hengduan Mountains centered in West China, its biological and ecological characters still remain poorly...

The long-armed scarab Cheirotonus gestroi is an endangered large insect in southwestern China and neighboring countries. Herein, we present the first complete mitochondrial genome of C. gestroi. The 16,899 bp long circular genome consists of 2 ribosomal RNA genes, 22 transfer RNA genes, 13 protein-coding genes, and a non-coding control region. Phylogenetic analysis showed that C. gestroi shared the closest evolutionary relationship with C. jansoni and that Scarabaeidae and Lucanidae were correctly identified within superfamily Scarabaeoidea. The complete mitogenome sequence will provide a basis for further phylogenetic studies and conservation genetics of the genus Cheirotonus.