Neurovascular decoupling measured with quantitative susceptibility mapping is associated with cognitive decline in patients with type 2 diabetes.

Disturbance of neurovascular coupling (NVC) is suggested to be one potential mechanism in type 2 diabetes mellitus (T2DM) associated mild cognitive impairment (MCI). However, NVC evidence derived from functional magnetic resonance imaging ignores the relationship of neuronal activity with vascular injury. Twenty-seven T2DM patients without MCI and thirty healthy controls were prospectively enrolled. Brain regions with changed susceptibility detected by quantitative susceptibility mapping (QSM) were used as seeds for functional connectivity (FC) analysis. NVC coefficients were estimated using combined degree centrality (DC) with susceptibility or cerebral blood flow (CBF). Partial correlations between neuroimaging indicators and cognitive decline were investigated. In T2DM group, higher susceptibility values in right hippocampal gyrus (R.PHG) were found and were negatively correlated with Naming Ability of Montreal Cognitive Assessment. FC increased remarkably between R.PHG and right middle temporal gyrus (R.MTG), right calcarine gyrus (R.CAL). Both NVC coefficients (DC-QSM and DC-CBF) reduced in R.PHG and increased in R.MTG and R.CAL. Both NVC coefficients in R.PHG and R.MTG increased with the improvement of cognitive ability, especially for executive function. These demonstrated that QSM and DC-QSM coefficients can be promising biomarkers for early evaluation of cognitive decline in T2DM patients and help to better understand the mechanism of NVC.

Overexpressed HspB6 Underlines a Novel Inhibitory Role in Kainic Acid-Induced Epileptic Seizure in Rats by Activating the cAMP-PKA Pathway.

Epilepsy is a commonly occurring neurological disease that has a large impact on the patient's daily life. Phosphorylation of heat shock protein B6 (HspB6) has been reported to protect the central nervous system. In this investigation, we explored whether HspB6 played a positive effect on epilepsy with the involvement of the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) pathway. The epileptic seizure was induced in rats by intraperitoneal injection of kainic acid (KA). The extent of HspB6 phosphorylation and expressions of HspB6, PKA, and inflammatory factors TNF-α, IL-1ß, and IL-6 were quantified along with neuronal apoptosis. To further understand the regulatory mechanism of the HspB6 in the hippocampus, we altered the expression and the extent of HspB6 phosphorylation to see whether the cAMP-PKA pathway was inactivated or not in hippocampal neurons of rats post KA. Results showed that HspB6 was poorly expressed, resulting in the inactivation of the cAMP-PKA pathway in rats post KA, as well as an aggravated inflammatory response and hippocampal neuronal apoptosis. HspB6 overexpression and the cAMP-PKA pathway activation decreased the expression of inflammatory factors and inhibited hippocampal neuronal apoptosis. Additionally, HspB6 phosphorylation further augments the inhibitory effects of HspB6 on the inflammatory response and hippocampal neuronal apoptosis. The cAMP-PKA pathway activation was found to result in increased HspB6 phosphorylation. HspB6 decreased apoptosis signal-regulating kinase 1 (ASK1) expression to inhibit inflammatory response and hippocampal neuronal apoptosis. Collectively, our findings demonstrate that activation of the cAMP-PKA pathway induces overexpression and partial phosphorylation of HspB6 lead to the inhibition of ASK1 expression. This in turn protects rats against epilepsy and provides a potential approach to prevent the onset of epileptic seizure in a clinical setting.

Functional-structural decoupling in visual network is associated with cognitive decline in patients with type 2 diabetes mellitus: evidence from a multimodal MRI analysis.

Type 2 diabetes mellitus (T2DM) and cognitive dysfunction are highly prevalent disorders worldwide. Although visual network (VN) alteration and functional-structural coupling are potential warning factors for mild cognitive impairment (MCI) in T2DM patients, the relationship between the three in T2DM without MCI is unclear. Thirty T2DM patients without MCI and twenty-nine healthy controls (HC) were prospectively enrolled. Visual components (VC) were estimated by independent component analysis (ICA). Degree centrality (DC), amplitude of low frequency fluctuation (ALFF) and fractional anisotropy (FA) were established to reflect functional and structural characteristics in these VCs respectively. Functional-structural coupling coefficients were further evaluated using combined FA and DC or ALFF. Partial correlations were performed among neuroimaging indicators and neuropsychological scores and clinical variables. Three VCs were selected using group ICA. Deteriorated DC, ALFF and DC-FA coefficients in the VC1 were observed in the T2DM group compared with the HC group, while FA and ALFF-FA coefficients in these three VCs showed no significant differences. In the T2DM group, DC in the VC1 positively correlated with 2 dimensions in the California Verbal Learning Test, including Trial 4 and Total trial 1-5. The impaired DC-FA coefficients in the VC1 markedly affected the Total perseverative responses % of the Wisconsin Card Sorting Test. These findings indicate that DC and DC-FA coefficients in VN may be potential imaging biomarkers revealing early cognitive deficits in T2DM.

Insights into the dual activation mechanism involving bifunctional cinchona alkaloid thiourea organocatalysts: an NMR and DFT study.

In-depth understanding of the activation mechanism in asymmetric organocatalysis is of great importance for rational development of highly efficient catalytic systems. In this Article, the mechanism for the direct vinylogous Michael reaction of α,ß-unsaturated γ-butyrolactam (Nu) and chalcone (EI) catalyzed by the bifunctional cinchona alkaloid thiourea organocatalyst (Cat) was studied with a combination of experimental (NMR) and theoretical (DFT) approaches, through which a new dual activation pathway was found. The key feature of this new dual activation mechanism (Pathway C) is that one N-H(A) of the thiourea moiety and the N-H of the protonated amine in Cat simultaneously activate Nu, while the other N-H(B) of the thiourea moiety activates EI. Both the NMR measurement and the DFT calculation identified that the interaction of Cat with Nu is stronger than that with EI in the catalyst-substrate complexes. Kinetic studies via variable-temperature NMR measurements indicated that, with the experimental activation energy E(a) of 10.2 kcal/mol, the reaction is all first-order in Nu, EI, and Cat. The DFT calculation further revealed that the C-C bond formation is both the rate-determining and the stereoselectivity-controlling steps. In agreement with the experimental data, the energy barrier for the rate-determining step along Pathway C was calculated as 8.8 kcal/mol. The validity of Pathway C was further evidenced by the calculated enantioselectivity (100% ee) and diastereoselectivity (60:1 dr), which are in excellent match with the experimental data (98% ee and >30:1 dr, respectively). Mechanistic study on the Michael addition of nitromethane to chalcone catalyzed by the Catalyst I further identified the generality of this new dual activation mechanism in cinchona alkaloid thiourea organocatalysis.

[Effects of Bushen Shuji Granule on IL-6 in the culture fluid sample of fibroblast cells from the synovial liquid of the ankylosing spondylitis patients].

OBJECTIVE: To explore the effects of Bushen Shuji Granule (BSG) on inhibiting the interleukin 6 (IL-6) level in the synovial fluid sample of fibroblast cells from the ankylosing spondylitis (AS) patients. METHODS: Using serum pharmacologic method, the IL-6 level in the culture fluid sample of fibroblast cells was observed by ELISA method with different concentrations of medicated serum containing BSG. The IL-6 level at the mRNA level was detected using reverse transcriptase-polymerase chain reaction (RT-PCR). The vehicle serum and sulfasalazine (SSZ) serum were taken as controls. RESULTS: Results of ELISA showed the IL-6 level in the AS group was more than that in the vehicle serum group with obvious statistical difference. BSG could obviously inhibited the IL-6 level, showing statistical difference when compared with the vehicle serum group. Besides, obvious dose-dependent correlation existed between BSG and its inhibition on fibroblast proliferation. And the IL-6 level at the mRNA level in the AS group was higher than that in the vehicle serum group, showing statistical difference by semi-quantitative analysis. CONCLUSION: BSG could play its clinical role of anti-inflammation and anti-fibrosis through inhibiting the IL-6 level in the culture fluid sample of fibroblast cells.

Noise enhances subthreshold oscillations in injured primary sensory neurons.

Noise can play a constructive role in the detection of weak signals in various kinds of peripheral receptors and neurons. What the mechanism underlying the effect of noise is remains unclear. Here, the perforated patch-clamp technique was used on isolated cells from chronic compression of the dorsal root ganglion (DRG) model. Our data provided new insight indicating that, under conditions without external signals, noise can enhance subthreshold oscillations, which was observed in a certain type of neurons with high-frequency (20-100 Hz) intrinsic resonance from injured DRG neurons. The occurrence of subthreshold oscillation considerably decreased the threshold potential for generating repetitive firing. The above effects of noise can be abolished by blocking the persistent sodium current (I(Na, P)). Utilizing a mathematical neuron model we further simulated the effect of noise on subthreshold oscillation and firing, and also found that noise can enhance the electrical activity through autonomous stochastic resonance. Accordingly, we propose a new concept of the effects of noise on neural intrinsic activity, which suggests that noise may be an important factor for modulating the excitability of neurons and generation of chronic pain signals.

[Expression pattern of FAM135B and K (lysine) acetyltransferase 5 in esophageal squamous cell carcinoma in Uygur patients].

OBJECTIVE: To explore the expression of the family with sequence similarity 135 member B (FAM135B) and K(lysine) acetyltransferase 5 (KAT5) in esophageal squamous cell carcinoma (ESCC) in Uygur patients. METHODS: The expression of FAM135B and KAT5 in ESCC tissues and paired adjacent tissues from 40 Uygur patients were detected using Roche Benchmark XT. The correlation of FAM135B and KAT5 and their correlation with the clinicopathological characteristics of the patients were analyzed. RESULTS: The positivity rates of FAM135B and KAT5 in ESCC tissues were 92.50% (37/40) and 15.00%(6/40) in these patients, respectively. The ESCC tissues showed a significantly higher rate of strong FAM135B expression than the adjacent tissues [45.00% (18/40) vs 22.50% (9/40); Χ2=4.528, P=0.033], but the rates of negative KAT5 expression was similar between ESCC and adjacent tissues [85.00% (34/40) vs 87.50% (35/40); Χ2=0.105, P=0.745]. Strong expressions of FAM135B in ESCC tissues and the paired adjacent tissues were well correlated (Kendall's coefficient = 0.707, P<0.001). In ESCC tissues, a strong expression of FAM135B showed a significant negative correlation with KAT5 expression (Kendall's coefficient=-0.946, P<0.001). Neither FAM135B nor KAT5 expression was associated with the patients' gender, age, tumor site, tumor differentiation, invasion, lymph node metastasis and clinical stage (all P>0.05). CONCLUSION: A strong expression of FAM135B may be an important molecular basis for the occurrence of ESCC in Uygur patients and plays its role by negatively regulating the expression of KAT5.

Responsiveness of a neural pacemaker near the bifurcation point.

We compared the responsiveness of a neural firing pacemaker in different dynamic states during the process of period-adding bifurcation to excitatory and inhibitory electrical field stimulus. In the region far from the bifurcation point, with the increase of the intensity of excitatory stimulus, the firing rate increased in an approximately linear manner and no firing pattern transition was observed. While in the region near the bifurcation point, the firing rate increased markedly higher accompanied with the transition of firing pattern when the intensity of excitatory stimulus remained the same. The stimulus-response of the region near the bifurcation point shifted upward significantly compared to that of the region far from the bifurcation point. Inhibitory stimulus with the same intensity, however, decreased the firing rate slightly without the transition of firing pattern in the region near the bifurcation point. These results suggest that the responsiveness in the region near the bifurcation point is more sensitive than that in the region far from the bifurcation point, which we named "critical sensitivity", and this has directional selectivity.

High frequency stimulation of the STN restored the abnormal high-voltage spindles in the cortex and the globus pallidus of 6-OHDA lesioned rats.

Many studies showed that abnormal oscillations in the cortical-basal ganglia loop is involved in the pathophysiology of Parkinson's disease (PD). In contrast to the well-studied beta synchronization, high-voltage spindles (HVSs), another type of abnormal oscillation observed in PD, are neglected. To explore the role of subthalamic nucleus-deep brain stimulation (STN-DBS) in HVSs regulation, we simultaneously recorded the local field potential (LFP) in the globus pallidus (GP) and electrocorticogram (ECoG) in the primary motor cortex(M1) in freely moving 6-hydroxydopamine (6-OHDA) lesioned or control rats before, during, and after STN-DBS. Consistent with our previous study, HVSs occurrence, duration, and relative power and coherence between the M1 cortex and GP increased in 6-OHDA lesioned rats. We found that high but not low frequency stimulation restored the abnormal HVSs activity and motor deficit. These results suggest that the STN is involved in the abnormal oscillation between the M1 cortex and GP.

Decreased HCN2 expression in STN contributes to abnormal high-voltage spindles in the cortex and globus pallidus of freely moving rats.

Abnormal oscillation in the cortical-basal ganglia loop is involved in the pathophysiology of parkinsonism. High-voltage spindles (HVSs), one of the main type abnormal oscillations in Parkinson's disease, are regulated by dopamine D2-like receptors but not D1-like receptors. However, little is known about how dopamine D2-like receptors regulate HVSs and the role of hyperpolarization-activated cyclic nucleotide-gated2 (HCN2) in HVSs regulation. We simultaneously recorded the local field potential (LFP) in globus pallidus (GP) and electrocorticogram (ECoG) in primary motor cortex (M1) in freely moving 6-hydroxydopamine (6-OHDA) lesioned or control rats. The expression of HCN2 and dopamine D2 receptor in the subthalamic nucleus (STN) was examined by immunochemical staining and Western blotting. We also tested the role of HCN2 in HVSs regulation by using pharmacological and shRNA methodology. We found that dopamine D2-like receptor agonists suppressed the increased HVSs in 6-OHDA lesioned rats. HCN2 was co-expressed with dopamine D2 receptor in the STN, and dopamine depletion decreased the expression of HCN2 as well as dopamine D2 receptor which contribute to the regulation of HVSs. HCN2 was down regulated by HCN2 shRNA, which thereby led to an increase in the HVSs in naïve rats while HCN2 agonist reduced the HVSs in 6-OHDA lesioned rats. These results suggest that HCN2 in the STN is involved in abnormal oscillation regulation between M1 cortex and GP.

Systemic blockade of dopamine D2-like receptors increases high-voltage spindles in the globus pallidus and motor cortex of freely moving rats.

High-voltage spindles (HVSs) have been reported to appear spontaneously and widely in the cortical-basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP) and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D1-like receptors or D2-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1) in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D2-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D2-like receptor antagonists. On the contrary, the selective dopamine D1-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D2-like receptors, but not D1-like receptors, were involved in HVS regulation. This supports the important role of dopamine D2-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.

SK- and h-current contribute to the generation of theta-like resonance of rat substantia nigra pars compacta dopaminergic neurons at hyperpolarized membrane potentials.

Oscillation activities are the feature of neural network and correlated to different physiological states. The theta (θ) oscillation (2-7 Hz) has been reported in the basal ganglia, and the intrinsic resonance properties of individual neurons have provided a basis for this network oscillation. The basal ganglia neurons receive comprehensive modulation arising from dopaminergic (DA) neurons located in the substantia nigra pars compacta (SNc), but how the oscillation is regulated in SNc DA neurons remains poorly understood. In this paper, whole-cell patch-clamp recordings were performed on SNc DA neurons in rat brain slices to reveal the resonance properties and underlying mechanisms. After swept-sine-wave (ZAP protocol) current was injected into SNc DA neurons, θ resonance was induced, whose peak impedance went up with the rising of temperature, demonstrating the dependency of resonance on temperature. Voltage dependency of resonance was also observed at hyperpolarized membrane potentials. Further investigation demonstrated two individual components: (1) SK-current generated resonance at around -65 mV, which could be blocked by apamin (300 nM), a specific antagonist of the small-conductance calcium-dependent potassium channel; (2) h-current (I (h)) generated resonance at around -75 mV, which could be abolished by ZD7288 (10 µM), a selective blocker of HCN channels. We concluded that in SNc DA neurons, θ resonance was mediated by two distinct ionic channels at hyperpolarized potentials. Our results imply that θ frequency resonance of individual SNc DA neurons may participate in coordinating rhythmic firing activity and contribute to the physiological or pathophysiological behaviors of Parkinson's disease.

Membrane resonance and its ionic mechanisms in rat subthalamic nucleus neurons.

The oscillatory activity in the basal ganglia is believed to have an important function, but little is known about its actual mechanisms. We studied the resonance characteristics of subthalamic nucleus (STN) neurons and their ionic mechanisms using whole-cell patch-clamp recordings in rat brain slices. A swept-sine-wave current with constant amplitude and linearly increasing frequency was applied to measure the resonance frequency (f(res)) of STN neurons. We also used single-frequency sine wave current to evoke firing. We found that the resonance of STN neurons was temperature- and voltage-dependent. The f(res) of STN neurons was about 4Hz when the temperature was maintained at 38°C and holding potential was at -70mV. The f(res) increased with more negative holding potentials and decreased with lower temperature. Action potentials fired most readily when the input frequency was near f(res). After application of drug ZD7288 (20µM), the resonance of STN neurons was blocked and the spikes evoked by both impedance amplitude profile (ZAP) current and single-frequency sine wave current arose readily at the lowest frequencies, indicating that hyperpolarization-activated cation current (I(h)) generated the resonance and mediated a preferential coupling at frequencies near f(res) between inputs and firing. In conclusion, there is a θ-frequency resonance mediated by I(h) in STN neurons. The resonance characteristics are temperature- and voltage-dependent. The resonance mediates a frequency-selective coupling between inputs and firing.

[The median survival and the effect of antiretroviral therapy among HIV-positive former blood donors in Anhui province].

OBJECTIVE: To estimate the median survival and the effect of antiretroviral therapy (ART) among HIV-positive former blood donors of Fuyang in Anhui province, China. METHODS: A retrospective survey was conducted among HIV-positive former blood donors, and data was collected on survivors who had received ART. Weibull function was used to calculate median survival of HIV-positive former blood donors. The effect of ART was estimated through comparing the actual number of deaths after ART with the expected number of deaths in those who did not receive ART. RESULTS: The median period of HIV infection was at the end of 1994, with the median survival of HIV-positive former blood donors in Fuyang as 10.8 years. By the end of September 2008, among 159 former blood donors, 74 received ART, with their mean CD(4)(+) T-cell count increased from 247.8/microl to 475.1/microl (P < 0.0001). 76 of the 159 former blood donors died. When comparing the expected number of deaths calculated by Weibull function, 31.7% of the total number of deaths was reduced. CONCLUSION: Result from this study was in consistent to the UNAIDS' figures that in the absence of treatment, the net median survival time after infection with HIV was estimated to be 11 years and ART has reduced about one third of the expected deaths.