Proton-Pump Inhibitors Suppress T Cell Response by Shifting Intracellular Zinc Distribution.

Proton-pump inhibitors (PPI), e.g., omeprazole or pantoprazole, are the most widely used drugs for various gastrointestinal diseases. However, more and more side effects, especially an increased risk of infections, have been reported in recent years. The underlying mechanism has still not yet been fully uncovered. Hence, in this study, we analyzed the T cell response after treatment with pantoprazole in vitro. Pantoprazole preincubation reduced the production and secretion of interferon (IFN)-γ and interleukin (IL)-2 after the T cells were activated with phytohemagglutinin (PHA)-L or toxic shock syndrome toxin-1 (TSST-1). Moreover, a lower zinc concentration in the cytoplasm and a higher concentration in the lysosomes were observed in the pantoprazole-treated group compared to the untreated group. We also tested the expression of the zinc transporter Zrt- and Irt-like protein (Zip)8, which is located in the lysosomal membrane and plays a key role in regulating intracellular zinc distribution after T cell activation. Pantoprazole reduced the expression of Zip8. Furthermore, we measured the expression of cAMP-responsive element modulator (CREM) α, which directly suppresses the expression of IL-2, and the expression of the phosphorylated cAMP response element-binding protein (pCREB), which can promote the expression of IFN-γ. The expression of CREMα was dramatically increased, and different isoforms appeared, whereas the expression of pCREB was downregulated after the T cells were treated with pantoprazole. In conclusion, pantoprazole downregulates IFN-γ and IL-2 expression by regulating the expression of Zip8 and pCREB or CREMα, respectively.

A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity.

BACKGROUND: Dopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans. METHODS: Using a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons. RESULTS: Nominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562-treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate. CONCLUSIONS: PF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period. CLINICALTRIALS.GOV IDENTIFIER: NCT02306876.

Effects of different light conditions on the retinal microstructure and ultrastructure of Dicentrarchus labrax larvae.

Light is a key environmental parameter known to influence fish throughout various stages of their life, from embryonic development to sexually mature adults. In a recent study, the effects of different light conditions on the growth of Dicentrarchus labrax larvae were investigated using light-emitting diodes (LEDs) as a light source. Here, pathological examinations were carried out to assess whether variations in light affected the visual system of the larvae, including any negative impacts on the retina or the growth rate. Although light did not affect the total thickness (TT) of the retina, the thickness of the retinal pigment epithelium layer (PRE), photoreceptor layer (PRos/is), outer nuclear layer (ONL), and inner nuclear layer (INL), and the PRE/TT and ONL/TT ratios were all significantly higher in larvae exposed to blue light than in larvae exposed to white light. Additionally, the thickness of PRE and the outer nuclear layer and the RPE/TT and ONL/TT ratios of larvae exposed to 2.0 W m-2 were significantly lower than in larvae exposed to 0.3 W m-2. By contrast, the INL/TT ratio in larvae exposed to 2.0 W m-2 was significantly higher than in larvae exposed to 0.3 W m-2. Additionally, the INL and ganglion cell layer nuclei density of larvae exposed to 2.0 W m-2 were significantly higher than in those exposed to 0.3 W m-2 (p < 0.05). Transmission electron microscopy revealed different levels of abnormalities in the photoreceptor layers in all treatment groups. Considering the growth of the larvae, the results of the study suggest that continuous LED exposure induced damage to photoreceptor cells but was not relevant to the growth performance of D. labrax larvae. Moreover, the results obtained here also support the high plasticity of retinal development in response to altered environmental light conditions.

Incremental Pose Map Optimization for Monocular Vision SLAM Based on Similarity Transformation.

The novel contribution of this paper is to propose an incremental pose map optimization for monocular vision simultaneous localization and mapping (SLAM) based on similarity transformation, which can effectively solve the scale drift problem of SLAM for monocular vision and eliminate the cumulative error by global optimization. With the method of mixed inverse depth estimation based on a probability graph, the problem of the uncertainty of depth estimation is effectively solved and the robustness of depth estimation is improved. Firstly, this paper proposes a method combining the sparse direct method based on histogram equalization and the feature point method for front-end processing, and the mixed inverse depth estimation method based on a probability graph is used to estimate the depth information. Then, a bag-of-words model based on the mean initialization K-means is proposed for closed-loop feature detection. Finally, the incremental pose map optimization method based on similarity transformation is proposed to process the back end to optimize the pose and depth information of the camera. When the closed loop is detected, global optimization is carried out to effectively eliminate the cumulative error of the system. In this paper, indoor and outdoor environmental experiments are carried out using open data sets, such as TUM and KITTI, which fully proves the effectiveness of this method. Closed-loop detection experiments using hand-held cameras verify the importance of closed-loop detection. This method can effectively solve the scale drift problem of monocular vision SLAM and has strong robustness.

Modeling and Flight Experiments for Swarms of High Dynamic UAVs: A Stochastic Configuration Control System with Multiplicative Noises.

UAV Swarm with high dynamic configuration at a large scale requires a high-precision mathematical model to fully exploit its boundary performance. In order to instruct the engineering application with high confidence, uncertainties induced from either systematic measurement or the environment cannot be ignored. This paper investigates the I t o ^ stochastic model of the UAV Swarm system with multiplicative noises. By combining the cooperative kinematic model with a simplified individual dynamic model of fixed-wing-aircraft for the first time, the configuration control model is derived. Considering the uncertainties in actual flight, multiplicative noises are introduced to complete the I t o ^ stochastic model. Following that, the estimator and controller are designed to control the formation. The mean-square uniform boundedness condition of the proposed stochastic system is presented for the closed-loop system. In the simulation, the stochastic robustness analysis and design (SRAD) method is used to optimize the properties of the formation. More importantly, the effectiveness of the proposed model is also verified using real data of five unmanned aircrafts collected in outfield formation flight experiments.

Growth and survival of Takifugu rubripes larvae cultured under different light conditions.

We assessed the effects of light intensity and spectrum on the growth and survival of Takifugu rubripes larvae from 30 to 69 days after hatching. Five lighting regimes were applied using 0.5, 1.5, and 3.0 W m-2 full spectrum white (W0.5, W1.5, W3.0), 0.5 W m-2 yellow (Y0.5), and 0.5 W m-2 blue light (B0.5). At the end of the experiment, body length, wet weight, and specific growth rate from day 0 to day 39 were significantly greater in larvae reared under W3.0 than under B0.5 (P Ë‚ 0.05). No significant differences were observed among W0.5, W1.5, and W3.0, or among W0.5, Y0.5, and B0.5 (P > 0.05). Survival rate was significantly higher in larvae reared under W1.5 than W0.5 (P Ë‚ 0.05), but no significant differences were observed among W0.5, Y0.5, and B0.5 (P > 0.05). Additionally, light conditioning did not affect the total thickness of the retina. Although the ratio of the thickness of the retinal pigment epithelium layer/total thickness (TT) was significantly higher in larvae exposed to W3.0 compared with those exposed to other light conditions, and the thickness of the outer nuclear layer/TT was significantly lower in larvae exposed to W3.0 compared with those exposed to W0.5 (P < 0.05), no relationship was confirmed between the structure of the retina and the growth performance of the T. rubripes larvae. Expression patterns of two stress-related and seven growth-related genes were also compared with the biometric parameters investigated in the experimental groups. No significant differences in the aanat1a, crh, ss1, igf1, or igf2 expression were observed among the five treatments. Pomc expression was significantly lower in larvae exposed to W1.5 than the larvae exposed to W0.5, and it was significantly lower in larvae exposed to Y0.5 than in larvae exposed to W0.5 or B0.5 (P < 0.05). Significant differences were also found in the expression of gh, with the highest levels being observed under W3.0, while the lowest levels were observed in B0.5 (P < 0.05). Ghrh expression was significantly higher in W3.0 (P < 0.05). These results should be considered when designing rearing protocols for fugu larvae in aquaculture systems.

Evaluation of D1/D5 Partial Agonist PF-06412562 in Parkinson's Disease following Oral Administration.

BACKGROUND: PF-06412562 is a moderately potent, highly selective oral D1/D5 dopamine receptor partial agonist. OBJECTIVE: To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson's disease. METHODS: Following overnight levodopa (L-dopa, Sinemet®) washout, subjects received a single dose of levodopa in open-label period 1. Periods 2 and 3 had a double-blinded, sponsor-open, randomized, 2-way cross-over, placebo-controlled design, during which subjects were randomized to PF-06412562 30 mg (+ 20 mg 4 h later) or placebo. Maximum percent improvement from baseline in finger-tapping speed (measure of bradykinesia) measured using KinesiaTM technology (as the primary end point) and change from baseline in the Movement Disorder Society's Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) motor section scores (the preferred exploratory end point) were evaluated. RESULTS: Nineteen subjects received levodopa; 13 met the period 2/3 entry criteria and received PF-06412562, 30 + 20 mg, or placebo. The prespecified primary efficacy criterion for significant improvement in finger-tapping was not met due to inconsistencies in the task leading to large between-period fluctuations of within-patient baseline values. Change from baseline in MDS-UPDRS-III score with PF-06412562 resulted in a placebo-adjusted point estimate of -10.59 with a one-sided 90% upper CI of PF-06412562 versus placebo model-based contrast of (-inf, -7.44) at 1.5-2.5 h after the dose (p < 0.0001). All adverse events were mild-to-moderate. CONCLUSIONS: We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D1/D5 partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D1 agonists.

Investigation on compression and mildew of mixed and separated maize.

This study explores the influence of different segregation configurations on the creep behaviors and mildew of maize. An inexpensive and easy-to-use system was designed, and three configurations of maize kernels distribution, i.e., uniform mixing (Mdm), alternating distribution (Mda), and segregated state distribution (Mds), with wet basis moisture content of 22.9%, were compressed under vertical pressure of 200 kPa through a one-dimensional oedometer. The compression and creep behaviors were investigated using the strain/settlement-time results, and aerobic plate counting (APC) was performed to study the effect of distribution configuration on the mildew effect. A finite-element model was established to simulate the temperature variation caused by physical environmental factors, and the heat production by fungi was quantified using the difference in temperature between simulation and test. The results indicate that the three-element Schiffman model can represent the creep behavior of the maize with different distribution configurations. The average temperature of Mdm, Mda, and Mds were 7.53%, 12.98%, and 14.76% higher than the average room temperature, respectively. The aerobic plate count of Mdm, Mda, and Mds were 1.0 × 105, 2.2 × 105, and 8.8 × 105 cfu g-1 stored for 150 h, respectively. In general, the temperature and APC in segregated maize bulk are higher than uniform grain. The effectiveness of the numerical model was verified, and the heat production by maize bulk fungi was quantified using the test and numerical temperature difference. The average heat was the least in Mdm with 2.8 × 106 J m-3, and Mda and Mds were 1.7 and 2 times more than Mdm. And the heat was related to the segregation configurations and agreed very well with the APC and temperature results.

Polyphenylene Sulfide Ultrafine Viscous Fibrous Membrane Modified by ZIF-8 for Highly Effective Oil/Water Separation under High Salt or Alkaline Conditions.

The oil/water separation in harsh environments has always been a challenging topic all over the world. In this study, the ZIF-8/PPS fiber membranes were fabricated via the combination of hot pressing and in situ growth. The distribution of ZIF-8 in the membranes was adjusted by changing the ZIF-8 in situ growth time, which could control the oil/water separation effect. Due to the hydrophilic nature of the ZIF-8/PPS fiber membranes, the water molecules in the oil-in-water emulsion could quickly penetrate into the fiber membrane under the drive of pressure, gravity, and capillary force, forming a water layer on the surface of the fiber membranes. The coupling of the water layer and the fiber structure prevented direct contact between the oil molecules and the fiber membrane, thereby realizing the separation of the emulsion. The results show that when the ZIF-8 in situ growth time was 10 h, the contact angle, the porosity, and the pure water flux of the ZIF-8/PPS fiber membranes were 72.5°, 52.3%, and 12,351 L/h·m2, respectively. More importantly, the separation efficiency of M10 was 97%, and the oil/water separation efficiency reached 95% after 14 cycles. This study provides a novel strategy for preparing MOFs/fiber materials for oil/water separation in harsh environments.

Application of Psyllium Husk as a Friendly Filtrate Reducer for High-Temperature Water-Based Drilling Fluids.

Aiming at the challenge that environmental protection and high-temperature fluid loss reduction performance of the traditional water-based drilling fluid treatment agent are difficult to balance, our studies added psyllium husk as a high-temperature-resistant and environmentally friendly filtrate reducer to a water-based drilling fluid. The composition, physical and chemical properties, and microstructure of psyllium husk are characterized. Then, the effects of psyllium husk after hot rolling at different temperatures on the rheological properties and fluid loss properties of bentonite-based slurry are evaluated. The results show that the psyllium husk added to the bentonite-based slurry can effectively improve the rheological properties and fluid loss properties of the bentonite-based slurry, and the temperature resistance can reach 160 °C. After hot rolling at 160 °C, adding 1 w/v % psyllium husk can reduce the API fluid loss and high-temperature and high-pressure fluid loss of the bentonite-based slurry by 76.04 and 56.91%, respectively, showing excellent fluid loss reduction performance at high temperatures. The branched structure and uronic acid of psyllium husk can inhibit the degradation of its own molecular structure to a certain extent, which is the fundamental reason why psyllium husk still has excellent fluid loss reduction performance at high temperatures. Psyllium husk is expected to replace some traditional synthetic polymers and be used in environmentally friendly high-temperature-resistant water-based drilling fluids.

Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells.

13-cis retinoic acid (13-cis RA; also known as isotretinoin) is the most potent agent available for treatment of acne. It is known that the drug induces apoptosis in cells cultured from human sebaceous glands, but its mechanism of action has not been determined. In this study, skin biopsies were taken from 7 patients with acne prior to and at 1 week of treatment with 13-cis RA. TUNEL staining confirmed that 13-cis RA induced apoptosis in sebaceous glands. Transcriptional profiling of patient skin and cultured human sebaceous gland cells (SEB-1 sebocytes) indicated that lipocalin 2 was among the genes most highly upregulated by 13-cis RA. Lipocalin 2 encodes neutrophil gelatinase-associated lipocalin (NGAL), which functions in innate immune defense and induces apoptosis of murine B lymphocytes. Increased immunolocalization of NGAL was noted in patients' sebaceous glands following treatment with 13-cis RA, and recombinant NGAL induced apoptosis in SEB-1 sebocytes. Furthermore, apoptosis in response to 13-cis RA was inhibited in the presence of siRNA to lipocalin 2. These data indicate that NGAL mediates the apoptotic effect of 13-cis RA and suggest that agents that selectively induce NGAL expression in sebaceous glands might represent therapeutic alternatives to the use of 13-cis RA to treat individuals with acne.

Transcriptomic analyses reveal novel genes with sexually dimorphic expression in Takifugu rubripes brain during gonadal sex differentiation.

BACKGROUND: Quantification of mRNAs in gonads and other tissues at the early critical development stage of sex differentiation may help to provide a global view of regulatory mechanisms underlying sex differentiation. We have recently reported the transcriptomic profiling of fugu gonad associated with sex differentiation. OBJECTIVES: This study attempted to identify the genes in the brain that are involved in gonadal differentiation and development. METHODS: In this study, a transcriptomic scan of potential candidate genes involved in sex differentiation was conducted in the brains of fugu larvae at 30 and 40 dah (morphological gonadal sex differentiation had not yet occurred). The dimorphic expression patterns of several candidate genes were verified using quantitative PCR. RESULTS: A total of 28.24 Gb of clean reads were obtained and 22,337 genes were identified in the brains of fugu larvae. These included 1008 novel genes that provide abundant data for functional analysis of sex differentiation. 229 genes were identified in the 30 dah larvae that were abundant in the XY brain and 21 that were abundant in the XX brain. In the 40 dah larvae, 325 genes were identified abundant in the XY brain and 174 were identified abundant in the XX brain. CONCLUSION: This is the first investigation into the transcriptome of the fugu larvae brain at the early sex differentiation stage. The results obtained here will enhance the understanding of molecular mechanisms that underly fugu sex differentiation.

A randomized controlled trial of povidone-iodine/dexamethasone ophthalmic suspension for acute viral conjunctivitis.

PURPOSE: To evaluate the clinical safety and efficacy of povidone-iodine (PVP-I) 0.6%/dexamethasone (DEX) 0.1% ophthalmic suspension vs vehicle in patients with clinically suspected acute viral conjunctivitis. PATIENTS AND METHODS: This was a randomized, double-masked, parallel-group, vehicle-controlled study. Adults with a clinical diagnosis of suspected acute viral conjunctivitis were randomized 1:1 to PVP-I/DEX ophthalmic suspension or vehicle bilaterally four times daily for 5 days (Days 1-5). Evaluation was on Days 1, 3 (+1-day window), and 6 (+1). Patients with signs of acute viral conjunctivitis at the Day 6 visit received open-label PVP-I/DEX for five additional days and were evaluated on Day 11-14. The primary efficacy endpoint was clinical resolution of acute viral conjunctivitis in the study eye at the Day 6 visit. RESULTS: Overall, 132 patients were randomized and received treatment (PVP-I/DEX, n=66; vehicle, n=66); 38 patients continued into the open-label portion of the study. Not enough patients with confirmed adenoviral conjunctivitis (n=32/132) were enrolled to assess the primary endpoint, although there were some efficacy trends in the PVP-I/DEX group for global clinical score (sum of watery conjunctival discharge and bulbar conjunctival redness). There were no serious treatment-emergent adverse events (TEAEs) and no patients discontinued due to a TEAE. In the masked phase, 56.1% of patients receiving PVP-I/DEX experienced at least one TEAE vs 43.9% in the vehicle group; 78.9% of patients in the open-label phase experienced at least one TEAE. Most TEAEs were mild in severity. CONCLUSION: PVP-I/DEX ophthalmic suspension administered for ≤14 days had a favorable safety profile and was generally well tolerated.

Randomized, Controlled, Phase 2 Trial of Povidone-Iodine/Dexamethasone Ophthalmic Suspension for Treatment of Adenoviral Conjunctivitis.

PURPOSE: To evaluate the efficacy/safety of an ophthalmic suspension of povidone-iodine (PVP-I) 0.6% and dexamethasone 0.1% in patients with acute adenoviral conjunctivitis. DESIGN: Multicenter, randomized, vehicle-controlled, double-masked trial. METHODS: Adults with a positive Rapid Pathogen Screening Adeno-Detector Plus test were randomized 1:1:1 to PVP-I 0.6%/dexamethasone 0.1%, PVP-I 0.6%, or vehicle, bilaterally 4 times daily for 5 days (days 1-5). Patients were evaluated on days 3, 6, and 12 (+1-day window). Efficacy measures included clinical resolution and adenoviral eradication. RESULTS: Overall, 144 patients were included in the efficacy analysis (PVP-I/dexamethasone, n = 48; PVP-I, n = 50; vehicle, n = 46). The proportion of patients with clinical resolution (primary study eye with last observation carried forward [LOCF]) at the day 6 visit was higher with PVP-I/dexamethasone (31.3%) than with vehicle (10.9%; P = .0158) and PVP-I (18.0%; P = nonsignificant). The proportion with adenoviral eradication (primary study eye with LOCF) was higher with PVP-I/dexamethasone than with vehicle at the day 3 (35.4% vs 8.7%; P = .0019) and day 6 (79.2% vs 56.5%; P = .0186) visits and vs PVP-I (day 3 visit, 32.0%; day 6 visit, 62.0%; each P = nonsignificant). Treatment-emergent adverse events (AEs) occurred in 69.0% (vehicle), 62.7% (PVP-I), and 53.4% (PVP-I/dexamethasone) of patients in the safety dataset. Discontinuation owing to AEs occurred in 37 patients (vehicle, n = 16; PVP-I, n = 12; PVP-I/dexamethasone, n = 9). CONCLUSION: PVP-I/dexamethasone appeared safe and well tolerated, and significantly improved clinical resolution and adenoviral eradication in patients with acute adenoviral conjunctivitis.

Cone-beam x-ray luminescence computed tomography based on x-ray absorption dosage.

With the advances of x-ray excitable nanophosphors, x-ray luminescence computed tomography (XLCT) has become a promising hybrid imaging modality. In particular, a cone-beam XLCT (CB-XLCT) system has demonstrated its potential in in vivo imaging with the advantage of fast imaging speed over other XLCT systems. Currently, the imaging models of most XLCT systems assume that nanophosphors emit light based on the intensity distribution of x-ray within the object, not completely reflecting the nature of the x-ray excitation process. To improve the imaging quality of CB-XLCT, an imaging model that adopts an excitation model of nanophosphors based on x-ray absorption dosage is proposed in this study. To solve the ill-posed inverse problem, a reconstruction algorithm that combines the adaptive Tikhonov regularization method with the imaging model is implemented for CB-XLCT reconstruction. Numerical simulations and phantom experiments indicate that compared with the traditional forward model based on x-ray intensity, the proposed dose-based model could improve the image quality of CB-XLCT significantly in terms of target shape, localization accuracy, and image contrast. In addition, the proposed model behaves better in distinguishing closer targets, demonstrating its advantage in improving spatial resolution.

Resolving adjacent nanophosphors of different concentrations by excitation-based cone-beam X-ray luminescence tomography.

Cone-beam X-ray luminescence computed tomography (CB-XLCT) has been proposed as a new molecular imaging modality recently. It can obtain both anatomical and functional tomographic images of an object efficiently, with the excitation of nanophosphors in vivo or in vitro by cone-beam X-rays. However, the ill-posedness of the CB-XLCT inverse problem degrades the image quality and makes it difficult to resolve adjacent luminescent targets with different concentrations, which is essential in the monitoring of nanoparticle metabolism and drug delivery. To address this problem, a multi-voltage excitation imaging scheme combined with principal component analysis is proposed in this study. Imaging experiments performed on physical phantoms by a custom-made CB-XLCT system demonstrate that two adjacent targets, with different concentrations and an edge-to-edge distance of 0 mm, can be effectively resolved.

Decreased middle temporal gyrus connectivity in the language network in schizophrenia patients with auditory verbal hallucinations.

As the most common symptoms of schizophrenia, the long-term persistence of obstinate auditory verbal hallucinations (AVHs) brings about great mental pain to patients. Neuroimaging studies of schizophrenia have indicated that AVHs were associated with altered functional and structural connectivity within the language network. However, effective connectivity that could reflect directed information flow within this network and is of great importance to understand the neural mechanisms of the disorder remains largely unknown. In this study, we utilized stochastic dynamic causal modeling (DCM) to investigate directed connections within the language network in schizophrenia patients with and without AVHs. Thirty-six patients with schizophrenia (18 with AVHs and 18 without AVHs), and 37 healthy controls participated in the current resting-state functional magnetic resonance imaging (fMRI) study. The results showed that the connection from the left inferior frontal gyrus (LIFG) to left middle temporal gyrus (LMTG) was significantly decreased in patients with AVHs compared to those without AVHs. Meanwhile, the effective connection from the left inferior parietal lobule (LIPL) to LMTG was significantly decreased compared to the healthy controls. Our findings suggest aberrant pattern of causal interactions within the language network in patients with AVHs, indicating that the hypoconnectivity or disrupted connection from frontal to temporal speech areas might be critical for the pathological basis of AVHs.

Abnormal resting state effective connectivity within the default mode network in major depressive disorder: A spectral dynamic causal modeling study.

INTRODUCTION: Understanding the neural basis underlying major depressive disorder (MDD) is essential for the diagnosis and treatment of this mental disorder. Aberrant activation and functional connectivity of the default mode network (DMN) have been consistently found in patients with MDD. It is not known whether effective connectivity within the DMN is altered in MDD. OBJECTS: The primary object of this study is to investigate the effective connectivity within the DMN during resting state in MDD patients before and after eight weeks of antidepressant treatment. METHODS: We defined four regions of the DMN (medial frontal cortex, posterior cingulate cortex, left parietal cortex, and right parietal cortex) for each participant using a group independent component analysis. The coupling parameters reflecting the causal interactions among the DMN regions were estimated using spectral dynamic causal modeling (DCM). RESULTS: Twenty-seven MDD patients and 27 healthy controls were included in the statistical analysis. Our results showed declined influences from the left parietal cortex to other DMN regions in the pre-treatment patients as compared with healthy controls. After eight weeks of treatment, the influence from the right parietal cortex to the posterior cingulate cortex significantly decreased. CONCLUSION: These findings suggest that the reduced excitatory causal influence of the left parietal cortex is the key alteration of the DMN in patients with MDD, and the disrupted causal influences that parietal cortex exerts on the posterior cingulate cortex is responsive to antidepressant treatment.

Gene array expression profiling in acne lesions reveals marked upregulation of genes involved in inflammation and matrix remodeling.

The pathogenesis of acne has been linked to multiple factors such as increased sebum production, inflammation, follicular hyperkeratinization, and the action of Propionibacterium acnes within the follicle. In an attempt to understand the specific genes involved in inflammatory acne, we performed gene expression profiling in acne patients. Skin biopsies were obtained from an inflammatory papule and from normal skin in six patients with acne. Biopsies were also taken from normal skin of six subjects without acne. Gene array expression profiling was conducted using Affymetrix HG-U133A 2.0 arrays comparing lesional to nonlesional skin in acne patients and comparing nonlesional skin from acne patients to skin from normal subjects. Within the acne patients, 211 genes are upregulated in lesional skin compared to nonlesional skin. A significant proportion of these genes are involved in pathways that regulate inflammation and extracellular matrix remodeling, and they include matrix metalloproteinases 1 and 3, IL-8, human beta-defensin 4, and granzyme B. These data indicate a prominent role of matrix metalloproteinases, inflammatory cytokines, and antimicrobial peptides in acne lesions. These studies are the first describing the comprehensive changes in gene expression in inflammatory acne lesions and are valuable in identifying potential therapeutic targets in inflammatory acne.

Peroxisome proliferator-activated receptors increase human sebum production.

Sebum production is key in the pathophysiology of acne, an extremely common condition, which when severe, may require treatment with isotretinoin, a known teratogen. Apart from isotretinoin and hormonal therapy, no agents are available to reduce sebum. Increasing our understanding of the regulation of sebum production is a milestone in identifying alternative therapeutic targets. Studies in sebocytes and human sebaceous glands indicate that agonists of peroxisome proliferator-activated receptors (PPARs) alter sebaceous lipid production. The goal of this study is to verify the expression and activity of PPARs in human skin and SEB-1 sebocytes and to assess the effects of PPAR ligands on sebum production in patients. To investigate the contribution of each receptor subtype to sebum production, lipogenesis assays were performed in SEB-1 sebocytes that were treated with PPAR ligands and isotretinoin. Isotretinoin significantly decreased lipogenesis, while the PPARalpha agonist-GW7647, PPARdelta agonist-GW0742, PPARalpha/delta agonist-GW2433, PPARgamma agonist rosiglitazone, and the pan-agonist-GW4148, increased lipogenesis. Patients treated with thiazolidinediones or fibrates had significant increases in sebum production (37 and 77%, respectively) when compared to age-, disease-, and sex-matched controls. These data indicate that PPARs play a role in regulating sebum production and that selective modulation of their activity may represent a novel therapeutic strategy for the treatment of acne.