Aspidopterys obcordata vine inulin fructan affects urolithiasis by modifying calcium oxalate crystallization.

Aspidopterys obcordata vine is a Chinese Dai ethnic herb used to treat urolithiasis. However, the material basis and underlying mechanisms remain undefined. In this study, a 2.3 kD inulin-like A. obcordata fructan (AOFOS) was isolated by size exclusion column chromatography and characterized by ultrahigh-performance liquid chromatography-ion trap-time of flight mass spectrometry (UPLC-IT-TOF-MS), nuclear magnetic resonance (NMR) spectroscopy, gas chromatography mass spectrometry (GC-MS) and high-performance gel permeation chromatography (HGPC). In addition, AOFOS showed unique anti-urolithiasis activity in Drosophila kidney stone models. Mechanism study indicated that AOFOS reduced the size of calcium oxalate crystals by inhibiting the formation of large size crystals and the generation rate of calcium oxalate crystals as well as the crystal form conversion from calcium oxalate monohydrate (COM) to calcium oxalate dihydrate (COD).

Synthesis of Five-Membered Cyclic Guanidines via Cascade [3 + 2] Cycloaddition of α-Haloamides with Organo-cyanamides.

The convenient preparation of N2-unprotected five-membered cyclic guanidines was achieved through a cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides under mild conditions in good to excellent yields (up to 99%). The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.

Atypical ductal hyperplasia on core needle biopsy: Surgical outcomes of 200 consecutive cases from a high-volume breast program.

Atypical ductal hyperplasia (ADH) is an indication for excisional biopsy to rule out occult breast cancer. We analyzed pathological findings on excisional biopsy for ADH diagnosed in a high volume breast center equipped with digital tomosynthesis. Two hundred consecutive patients were diagnosed with ADH on core biopsy with radiographic concordance followed by excisional biopsy. On excisional biopsy, 33 patients (16.5%) were diagnosed with DCIS or invasive breast cancer. Patients with a concurrent diagnosis of papilloma had a higher risk of upstaging on both univariate and multivariate analysis (41.7% vs. 14.9%, p=0.015). No other statistically significant predictors of upgrading were identified (p>0.05).

[Correlation of Mycoplasma genitalium infection with semen parameters and sperm DNA integrity in male infertility patients].

OBJECTIVE: To analyze the relationship of Mycoplasma genitalium (MG) infection with routine semen parameters and sperm DNA integrity in male infertility patients. METHODS: Totally, 114 semen samples, 34 MG-positive and 80 MG-negative, were collected from male infertility patients and subjected to routine semen analysis with the computer-assisted sperm analysis system, Papanicolaou staining for observation of sperm morphology, and sperm chromatin diffusion (SCD) test for detection of sperm DNA integrity. Semen parameters and DNA integrity were compared between the MG-positive and MG-negative groups with SPSS 21.0 statistical software and the relationship between the semen parameters and DNA integrity analyzed by Pearson correlation analysis. RESULTS: The MG-positive samples, compared with the MG-negative ones, showed significantly decreased semen volume (ï¼»2.87 ± 0.37ï¼½ vs ï¼»3.86 ± 0.43ï¼½ ml, P < 0.01), sperm concentration (ï¼»29.05 ± 6.17ï¼½ vs ï¼»32.56 ± 5.97ï¼½ ×106/ml, P < 0.01), and percentages of progressively motile sperm (PMS) (ï¼»15.86 ± 2.79ï¼½% vs ï¼»23.65 ± 3.47ï¼½%, P < 0.01) and morphologically normal sperm (MNS) (ï¼»6.35 ± 2.06ï¼½% vs ï¼»7.14 ± 1.89ï¼½%, P < 0.05), increased proportions of non-halo sperm (ï¼»15.02 ± 3.52ï¼½% vs ï¼»9.72 ± 2.94ï¼½%, P <0.01) and small-halo sperm (ï¼»16.37 ± 5.26ï¼½% vs ï¼»11.07 ± 1.65ï¼½%, P < 0.01) and sperm DNA fragmentation index (DFI) (ï¼»31.39 ± 3.16ï¼½% vs ï¼»20.79 ± 3.59ï¼½%, P < 0.01), and reduced proportion of large-halo sperm (ï¼»54.75 ± 8.74ï¼½% vs ï¼»64.15 ± 9.76ï¼½%, P < 0.01). DFI was negatively correlated with the percentages of PMS (r = －0.516, P < 0.05) and MNS (r = －0.429, P < 0.05) in the MG-positive group, but not correlated with any of the routine semen parameters in the MG-negative patients (P > 0.05). CONCLUSIONS: MG infection may be an important factor affecting sperm quality in male infertility patients. Active prevention and treatment of MG infection can help prevent male infertility.

Atypical lobular hyperplasia on core needle biopsy: contemporary results from a large community hospital breast program.

PURPOSE: The management of biopsy proven atypical lobular hyperplasia (ALH) is controversial. Although upgrade rates are low, excisional biopsy is often performed to rule out occult breast cancer. METHODS: In this study, we analyzed our experience with excisional biopsy for ALH diagnosed in the digital tomosynthesis era with radiographic concordance in the community hospital setting. This study included 93 consecutive patients diagnosed with pure ALH on core biopsy from January 2013-December 2017 who underwent subsequent excisional biopsy. Potential clinical, radiographic and pathologic predictors of upgrading were analyzed. RESULTS: At the time of excisional biopsy, five patients (5.4%) were upgraded to DCIS or invasive breast cancer. There was also a trend towards higher upgrade rates in patients with contralateral breast cancer (p = 0.06), biopsy performed by ultrasound or MRI (p = 0.07) and extensive ALH (p = 0.10). Other clinical, radiographic and pathologic variables were not predictive of upgrade rate (p > 0.1 for all). CONCLUSION: Patients with pure ALH with radiographic concordance have a low risk of pathologic upgrading on excisional biopsy. Potential predictors of upgrade rate warrant further analysis in a larger dataset.

Synthesis of Sulfamate-Fused 2-Aminopyrroles via an Isocyanide-Based Three Component [1+2+2] Annulation.

An efficient preparation of sulfamate-fused 2-aminopyrroles was achieved through an isocyanide-based three-component [1+2+2] annulation of isocyanides, dialkyl acetylenedicarboxylates, and sulfamate-derived cyclic imines in good to excellent yields (up to 99 %). This reaction proceeds smoothly without any activation or modification of substances under neutral and metal-free conditions. The reaction could also be conveniently performed on a gram scale.

Synthesis of spirobarbiturate-pyrrolidinones via a domino aza-Michael/SN2 cyclization of barbiturate-derived alkenes with N-alkoxy α-haloamides.

A highly efficient domino aza-MIRC (Michael Induced Ring Closure) reaction between barbiturate-derived alkenes and N-alkoxy α-haloamides has been achieved in moderate to excellent yields. This reaction proceeds smoothly under mild conditions via a domino aza-Michael addition/intramolecular SN2 sequence, providing a practical tool in the synthesis of bioactive molecules spirobarbiturate-3-pyrrolidinones.

Surgical management of large adrenal tumors: impact of different laparoscopic approaches and resection methods on perioperative and long-term outcomes.

BACKGROUND: The indication of retroperitoneal laparoscopic adrenalectomy (RLA) was extended with the retroperitoneal approach and has been wildly accepted and technologically matured. However, the management of large adrenal tumors via this approach still remains controversial. The aim of this study was to perform a comprehensive analysis on the minimally invasive surgical management of larger adrenal tumors. METHODS: A total of 78 patients with large adrenal tumors (> 5 cm) and 97 patients with smaller adrenal tumors (< 5 cm) were enrolled in this study. The patient characteristics were preferentially analyzed. The intra-operative and postoperative indicators were compared between those who underwent RLA and those who underwent transperitoneal laparoscopic adrenalectomy (TLA); the intra-operative and postoperative indicators were also compared between the large tumor group and smaller tumor group of those who underwent RLA. Furthermore, the analyses of partial RLA were focused on the perioperative indicators and follow-up results. RESULTS: RLA was superior to TLA in terms of operation time (98.71 ± 32.30 min vs. 124.36 ± 34.62 min, respectively, P = 0.001), hospitalization duration (7.43 ± 2.82 days vs. 8.91 ± 3.40 days, respectively, P = 0.04), duration of drain (4.83 ± 0.37 days vs. 3.94 ± 2.21 days, respectively, P = 0.02), first oral intake (2.82 ± 0.71 days vs. 1.90 ± 0.83 days, respectively, P < 0.001) and time to ambulation (3.89 ± 1.64 days vs. 2.61 ± 1.42 days, respectively, P < 0.001). Further analyses of the RLA patients demonstrated that the larger tumor (> 5 cm) group showed superior results for the intraoperative indicators than the smaller tumor (< 5 cm) group (P < 0.05), while the results for the postoperative indicators between the two tumor size groups were similar (P > 0.05). Data confirmed that the partial resection method was superior to the total resection method from the perspective of the hormone supplement (0% vs. 48.15%, P = 0.002). The 2-year recurrence-free rates were 92.60 and 92.86% for the total and partial RLA resection methods, respectively (P = 0.97). The partial RLA resection method had a similar complete remission rate as the total RLA resection method (96.30% vs. 100%, respectively, P = 0.47). CONCLUSION: Both RLA and TLA seem to provide similar effects for the surgical management of large adrenal tumors. However, partial RLA resection should be considered for the management of benign tumors to reduce the hormone supplement.

The Value of Mean Platelet Volume for Prognosis of Patients with Acute Cerebral Infarction.

BACKGROUND: The purpose of this study was to investigate the value of mean platelet volume (MPV) for prognosis of patients with acute cerebral infarction (ACI). METHODS: One hundred ACI patients and 80 healthy volunteers acting as healthy controls (HCs) were consecutively included in this study. Their baseline clinical and laboratory characteristics were extracted from an electroniccase system. ACI patients were followed for 90 days to collect the main study endpoints including poor prognosis, death due to cardiovascular causes, and the recurrence of stroke. ACI patients were evaluated after 7 days in the hospital using the National Institute of Health Stroke Scale (NIHSS) score to evaluate stroke severity on admission and using the modified Rankin Scale (mRS) to evaluate functional disorders. Receiver operating characteristic (ROC) curve analysis was used to estimate the predictive value of MPV on ACI. Kaplan-Meier survival analysis and Cox regression models were used to analyse the value of MPV as a predictor of ACI. RESULTS: This study suggested that MPV and rate of hypertension were higher in ACI patients than in the HC group. In the follow-up period, 32 ACI patients suffered study endpoints; they had higher average MPV, NIHSS scores, longer ACI onset times, and shorter event-free survival time compared to control patients. ROC curves showed that MPV was an index for prognosis of ACI patients with an AUC of MPV of 0.82 (95% confidence interval (CI): 0.74 - 0.90), and the best cutoff was 10.05 fL. MPV, NHISS scores, age, and TG were independent risk factors for endpoints of ACI patients. MPV with hazard ratio (HR) was 1.94 (95% CI, 1.37 - 2.72, p = 0.000), NIHSS score with HR was 1.22 (95% CI, 1.03 - 1.44, p = 0.021), age with HR was 1.06 (95% CI, 1.00 - 1.11, p = 0.038), and TG HR was 0.60 (95% CI, 0.36 - 1.00, p = 0.048) using Cox regression models. P  0.05 for all groups was considered statistically significant. CONCLUSIONS: Mean platelet volume was an independent risk factor and serves as a sensitive index for the prognosis of ACI patients.

Chitosan cross-linked with poly(ethylene glycol)dialdehyde via reductive amination as effective controlled release carriers for oral protein drug delivery.

The covalently cross-linked chitosan-poly(ethylene glycol)1540 derivatives have been developed as a controlled release system with potential for the delivery of protein drug. The swelling characteristics of the hydrogels based on these derivatives as the function of different PEG content and the release profiles of a model protein (bovine serum albumin, BSA) from the hydrogels were evaluated in simulated gastric fluid with or without enzyme in order to simulate the gastrointestinal tract conditions. The derivatives cross-linked with difunctional PEG1540-dialdehyde via reductive amination can swell in alkaline pH and remain insoluble in acidic medium. The cumulative release amount of BSA was relatively low in the initial 2h and increased significantly at pH 7.4 with intestinal lysozyme for additional 12h. The results proved that the release-and-hold behavior of the cross-linked CS-PEG1540H-CS hydrogel provided a swell and intestinal enzyme controlled release carrier system, which is suitable for oral protein drug delivery.

Spatial training preserves associative memory capacity with augmentation of dendrite ramification and spine generation in Tg2576 mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and there is currently no efficient cure for this devastating disease. Cognitive stimulation can delay memory loss during aging and in patients with mild cognitive impairment. In 3 × Tg-AD mice, training decreased the neuropathologies with transient amelioration of memory decline. However, the neurobiological mechanisms underlying the learning-improved memory capacity are poorly understood. Here, we found in Tg2576 mice spatial training in Morris water maze (MWM) remarkably improved the subsequent associative memory acquisition detected by contextual fear conditioning. We also found that spatial training enhanced long term potentiation, dendrite ramification and spine generation in hippocampal dentate gyrus (DG) and CA1 neurons at 24 h after the training. In the molecular level, the MWM training remarkably activated calcium/calmodulin-dependent protein kinase II (CaMKII) with elevation of glutamate AMPA receptor GluA1 subunit (GluA1), postsynaptic density protein 93 (PSD93) and postsynaptic density protein 95 (PSD95) in the hippocampus. Finally, the training also significantly ameliorated AD-like tau and amyloid pathologies. We conclude that spatial training in MWM preserves associative memory capacity in Tg2576 mice, and the mechanisms involve augmentation of dendrite ramification and spine generation in hippocampus.

CaMKII-dependent dendrite ramification and spine generation promote spatial training-induced memory improvement in a rat model of sporadic Alzheimer's disease.

Participation in cognitively stimulating activities can preserve memory capacities in patients with Alzheimer's disease (AD), but the mechanism is not fully understood. Here, we used a rat model with hyperhomocysteinemia, an independent risk factor of AD, to study whether spatial training could remodel the synaptic and/or dendritic plasticity and the key molecular target(s) involved. We found that spatial training in water maze remarkably improved the subsequent short-term and long-term memory performance in contextual fear conditioning and Barnes maze. The trained rats showed an enhanced dendrite ramification, spine generation and plasticity in dentate gyrus (DG) neurons, and stimulation of long-term potentiation between perforant path and DG circuit. Spatial training also increased the levels of postsynaptic GluA1, GluN2A, GluN2B, and PSD93 with selective activation of calcium/calmodulin-dependent protein kinase II (CaMKII), although inhibition of CaMKII by stereotaxic injection of KN93 into hippocampal DG, abolished the training-induced cognitive improvement, dendrite ramification, and spine generation. We conclude that spatial training can preserve the cognitive function by CaMKII-dependent remodeling of dendritic plasticity in hyperhomocysteinemia-induced sporadic AD-like rats.

Impact of serum vitamin D level on risk of bladder cancer: a systemic review and meta-analysis.

Vitamin D has important biological functions including modulation of the immune system and anti-cancer effects. There was no conclusive finding of the impact of serum vitamin D level on bladder cancer risk. A systemic review and meta-analysis was performed to assess the impact of serum 25-hydroxyvitamin D level on bladder cancer risk. The pooled relative risk (RR) with 95% confidence interval (95%CI) was used to assess the impact of serum 25-hydroxyvitamin D level on bladder cancer risk. A total of 89,610 participants and 2238 bladder cancer cases were finally included into the meta-analysis. There was no obvious heterogeneity among those included studies (I(2) = 0%). Meta-analysis total included studies which showed that a high serum 25-hydroxyvitamin D level could obviously decrease risk of bladder cancer (RR = 0.75, 95%CI 0.65-0.87, P < 0.001). In addition, the pooled RRs were not significantly changed by excluding any single study. The findings from the meta-analysis suggest an obvious protective effect of vitamin D against bladder cancer. Individuals with higher serum 25-hydroxyvitamin D levels suffer from less risk of subsequent bladder cancer.

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid ß-peptide in rats.

Amyloid ß-peptide (Aß) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). Humanin (HN) is a secretory peptide that inhibits the neurotoxicity of Aß. However, the mechanism(s) by which HN exerts its neuroprotection against Aß-induced AD-like pathological changes and memory deficits are yet to be completely defined. In the present study, we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre- and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aß(1-42). HN also attenuated Aß(1-42)-induced tau hyperphosphorylation, apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A (PP2A) catalytic subunit and thereby activating PP2A. HN also inhibited apoptosis and reduced the oxidative stress induced by Aß(1-42). These findings provide novel mechanisms of action for the ability of HN to protect against Aß(1-42)-induced AD-like pathological changes and memory deficits.

Highly enantioselective Michael addition promoted by a new diterpene-derived bifunctional thiourea catalyst: a doubly stereocontrolled approach to chiral succinimide derivatives.

A doubly stereocontrolled organocatalytic asymmetric Michael addition to the synthesis of substituted succinimides is described. Starting from aldehydes and maleimides, both enantiomers of the succinimides could be obtained in high to excellent yields (up to 98%) and enantioselectivities (up to 99%) when one of the two special chiral diterpene-derived bifunctional thioureas was individually used as a catalyst. Moreover, these catalysts can be efficiently used in large-scale catalytic synthesis with the same level of yield and enantioselectivity.

Activation of sirtuin 1 attenuates cerebral ventricular streptozotocin-induced tau hyperphosphorylation and cognitive injuries in rat hippocampi.

Patients with diabetes in the aging population are at high risk of Alzheimer's disease (AD), and reduction of sirtuin 1 (SIRT1) activity occurs simultaneously with the accumulation of hyperphosphorylated tau in the AD-affected brain. It is not clear, however, whether SIRT1 is a suitable molecular target for the treatment of AD. Here, we employed a rat model of brain insulin resistance with intracerebroventricular injection of streptozotocin (ICV-STZ; 3 mg/kg, twice with an interval of 48 h). The ICV-STZ-treated rats were administrated with resveratrol (RSV; SIRT1-specific activator) or a vehicle via intraperitoneal injection for 8 weeks (30 mg/kg, once per day). In ICV-STZ-treated rats, the levels of phosphorylated tau and phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) at the hippocampi were increased significantly, whereas SIRT1 activity was decreased without change of its expression level. The capacity of spatial memory was also significantly lower in ICV-STZ-treated rats compared with age-matched control. RSV, a specific activator of SIRT1, which reversed the ICV-STZ-induced decrease in SIRT1 activity, increases in ERK1/2 phosphorylation, tau phosphorylation, and impairment of cognitive capability in rats. In conclusion, SIRT1 protects hippocampus neurons from tau hyperphosphorylation and prevents cognitive impairment induced by ICV-STZ brain insulin resistance with decreased hippocampus ERK1/2 activity.

First-principles study on stability and magnetism of Ni m Al n (m = 1-3, n = 1-9) clusters.

The investigation on the structures, stabilities, and magnetism of Ni(m) Al(n) (m = 1-3, n = 1-9) clusters has been made by using first principles. We found some new ground-state structures which had not been found before. These mixed species prefer to adopt three-dimensional (3D) structures starting from four atoms. All the ground-state structures for the Ni-Al clusters are different from those of the corresponding pure Al clusters with the same number of atoms except for three atoms. The Mulliken population analysis shows that some charges transfer from the Al atoms to the Ni atoms. NiAl n (n = odd number) cations, Ni(2)Al(6) neutral, Ni(2)Al(1) and Ni(3)Al cations and anions, and Ni(3)Al(5) anion have the magnetic moments of 2 µ B. The magnetic moments of NiAl(4) and NiAl(6) cluster neutrals and cations are 2 µ B and 3 µ B, respectively. All the other cluster neutrals and ions do not have any nontrivial magnetic moments. The 3d electrons in Ni atoms are mainly responsible for the magnetism of the mixed Ni-Al clusters.

Nmnat2 attenuates Tau phosphorylation through activation of PP2A.

The activity of protein phosptase-2A (PP2A) is significantly decreased in the brains of Alzheimer's disease (AD) patients, but the upstream effectors for regulating PP2A activity are not fully understood. Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) is a key enzyme involved in energy metabolism and its gene expression level is reduced in AD brain specimens. Whether Nmnat2 can activate PP2A deserves to be explored. Here, we first measured the level of Nmnat2, Tyr307-phosphorylation of PP2A, and tau phosphorylation in Tg2576 mice. We observed that the mRNA and protein levels of Nmnat2 were significantly decreased with a simultaneous elevation of p-Tyr307-PP2A and tau phosphorylation in Tg2576 mice. Further studies in HEK293 cells with stable expression of human tau441 (HEK293/tau) demonstrated that simultaneous inhibition of PP2A by okadaic acid abolished the Nmnat2-induced tau dephosphorylation. Moreover, we further demonstrated that overexpression of Nmnat2 could activate PP2A with attenuation of tau phosphorylation, whereas downregulation of Nmnat2 by shRNA inhibited PP2A with tau hyperphosphorylation at multiple AD-associated sites. Our data provide the first evidence that Nmnat2 affects tau phosphorylation by regulating PP2A activity, suggesting that Nmnat2 may serve as a potential target in arresting AD-like tau pathologies.

Capsaicin ameliorates stress-induced Alzheimer's disease-like pathological and cognitive impairments in rats.

Hyperphosphorylated tau aggregated into neurofibrillary tangles is a hallmark lesion of Alzheimer's disease (AD) and is linked to synaptic and cognitive impairments. In animal models, cold water stress (CWS) can cause cognitive disorder and tau hyperphosphorylation. Capsaicin (CAP), a specific TRPV1 agonist, is neuroprotective against stress-induced impairment, but the detailed mechanisms are still elusive. Here, we investigated whether CAP mitigates CWS-induced cognitive and AD-like pathological alterations in rats. The animals were administered CAP (10 mg/kg in 0.2 ml, 0.1% ethanol) or a control (0.2 ml normal saline, 0.1% ethanol) by intragastric infusion 1 h before CWS treatment. Our results showed that CAP significantly attenuated CWS-induced spatial memory impairment and suppression of PP-DG long-term potentiation; CAP abolished CWS-induced dendritic regression and enhanced several memory-associated proteins decreased by CWS, such as synapsin I and PSD93; CAP also prevented CWS-induced tau hyperphosphorylation by abolishing inhibition of protein phosphatase 2A. Taken together, this study demonstrated that activation of TRPV1 can mitigate CWS-induced AD-like neuropathological alterations and cognitive impairment and may be a promising target for therapeutic intervention in AD.

Betaine attenuates Alzheimer-like pathological changes and memory deficits induced by homocysteine.

Hyperhomocysteinemia (Hhcy) may induce memory deficits with ß-amyloid (Aß) accumulation and tau hyperphosphorylation. Simultaneous supplement of folate and vitamin B12 partially restored the plasma homocysteine level and attenuated tau hyperphosphorylation, Aß accumulation and memory impairments induced by Hhcy. However, folate and vitamin B12 treatment have no effects on Hhcy which has the methylenetetrahydrofolate reductase genotype mutation. In this study, we investigated the effects of simultaneous supplement of betaine on Alzheimer-like pathological changes and memory deficits in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine (Hcy). We found that supplementation of betaine could ameliorate the Hcy-induced memory deficits, enhance long-term potentiation (LTP) and increase dendritic branches numbers and the density of the dendritic spines, with up-regulation of NR1, NR2A, synaptotagmin, synaptophysin, and phosphorylated synapsin I protein levels. Supplementation of betaine also attenuated the Hcy-induced tau hyperphosphorylation at multiple AD-related sites through activation protein phosphatase-2A (PP2A) with decreased inhibitory demethylated PP2A(C) at Leu309 and phosphorylated PP2A(C) at Tyr307. In addition, supplementation of betaine also decreased Aß production with decreased presenilin-1 protein levels. Our data suggest that betaine could be a promising candidate for arresting Hcy-induced AD-like pathological changes and memory deficits.