Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1.

Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV+) and somatostatin-expressing (SST+), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV+ and SST+ interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV+ interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST+ interneurons has the opposite effect. Thus, DG and CA3 PV+ and SST+ interneurons bidirectionally modulate the flow of information through the hippocampal circuit.

Decreased T cell expression of H/ACA box small nucleolar RNA 12 promotes lupus pathogenesis in patients with systemic lupus erythematosus.

Objective To investigate whether the aberrant expression of non-coding RNAs (ncRNAs) in T cells from patients with systemic lupus erythematosus (SLE) could contribute to the pathogenesis of lupus. Methods Expression profiles of RNA transcripts in T cells from three patients with SLE and three controls were analyzed by microarray analysis. Potentially aberrant-expressed ncRNAs were validated using T cell samples from 23 patients with SLE and 17 controls. Transfection studies and microarray analyses were conducted to search for any gene expression that is regulated by specific ncRNAs. Results Initial analysis revealed differential expression of 18 ncRNAs in SLE T cells. After validation, decreased expression of H/ACA box small nucleolar RNA 12 (SNORA12) was confirmed in SLE T cells (0.69-fold, P = 0.007) compared with normal T cells, and its expression level was inversely associated with higher SLE disease activity scores. Jurkat cells transfected with a plasmid encoding SNORA12 showed increased expression of two genes and decreased expression of 15 genes in Jurkat cells. These changes of gene expression were significantly associated with the SLE pathway in the Kyoto Encyclopedia of Genes and Genomes map using microarray analysis. Overexpression of SNORA12 altered the expression of CD69, decreased the expression of histone cluster 1 H4 family member k (HIST1H4K), inhibited the secretion of interferon gamma and the expression of HIST1H4K was increased in SLE T cells. Conclusion Among the ncRNAs, we found that the expression level of SNORA12, which belongs to the family of small nucleolar RNAs, was lower in SLE T cells and affected T cell function. This novel finding suggests that aberrant-expressed snoRNAs lead to dysfunction of T cells and may be involved in the immunopathogenesis of SLE.

TGF-ß upregulates the translation of USP15 via the PI3K/AKT pathway to promote p53 stability.

Crosstalk between transforming growth factor beta (TGF-ß) signaling and p53 has a critical role in cancer progression. TGF-ß signals via Smad and non-Smad pathways. Under normal conditions, wild-type p53 forms a complex with Smad2/3 and co-activates transcription of a variety of tumor suppressor genes, resulting in tumor suppressive effects. Thus, p53 stability is essential in progression of tumor suppressive responses mediated by TGF-ß signaling. However, it remains unknown whether p53 stability is regulated by TGF-ß. In the current study, we identify that USP15 binds to and stabilizes p53 through deubiquitination in U2OS and HEK293 cells. TGF-ß promotes the translation of USP15 through activation of mammalian target of rapamycin by the phosphoinositide 3-kinase/AKT pathway. Upregulation of USP15 translation links the crosstalk between TGF-ß signaling and p53 stability, allowing this cytokine to have a critical role in cancer progression.

NKX6.1 functions as a metastatic suppressor through epigenetic regulation of the epithelial-mesenchymal transition.

The transcription factor NKX6.1 (NK6 homeobox 1) is important in the development of pancreatic ß-cells and neurons. Although recent publications show that NKX6.1 is hypermethylated and downregulated during tumorigenesis, the function of NKX6.1 in carcinogenesis remains elusive. Here, we address the metastasis suppressor function of human NKX6.1 using cell, animal and clinical analyses. Our data show that NKX6.1 represses tumor formation and metastatic ability both in vitro and in vivo. Mechanistically, NKX6.1 suppresses cell invasion by inhibiting the epithelial-to-mesenchymal transition (EMT). NKX6.1 directly enhances the mRNA level of E-cadherin by recruiting BAF155 coactivator and represses that of vimentin and N-cadherin by recruiting RBBP7 (retinoblastoma binding protein 7) corepressor. Clinical cancer tumors with metastasis show low NKX6.1 protein expression coinciding with low E-cadherin and high vimentin expression. Our results demonstrate that NKX6.1 functions as an EMT suppressor by interacting with different epigenetic modifiers, making it a potential novel therapeutic option.

Risk of cataract for people with tuberculosis: results from a population-based cohort study.

BACKGROUND: Tuberculosis (TB) is an infectious disease involving multiple organs, including the eyes. We examined the risk of cataract among patients with TB using population data. METHOD: Using data from the National Health Insurance (NHI) system of Taiwan, we established a TB cohort with 6994 patients newly diagnosed between 2000 and 2010. For each TB patient, four subjects without TB were randomly selected for the non-TB cohort, frequency matched by age, sex and diagnosis years. The incidence of cataract was measured by the end of 2011. The hazard ratio (HR) of cataract was estimated using Cox proportional hazards regression analysis. RESULTS: The overall incidence rate of cataract was 21% greater in the TB cohort than in the non-TB cohort (22.9 vs. 18.8/1000 person-years, P < 0.001), with an adjusted HR (aHR) of 1.26 (95%CI 1.16-1.37). Cataract incidence increased with age, and was higher in men than women and much higher for those with comorbidity. The hazard of cataract was higher in the first 6 months after TB diagnosis. CONCLUSION: TB patients are at elevated risk of developing cataract. Although the incidence decreased with time, the aHR remains statistically significant through the follow-up years.

Increased prevalence of JC polyomavirus viruria was associated with arthritis/arthralgia in patients with systemic lupus erythematosus.

OBJECTIVE: The objective of this paper is to investigate the prevalence of reactivation of the human polyomavirus John Cunningham virus (JCV) in patients with systemic lupus erythematosus (SLE) and its associated clinical manifestations. METHODS: Sixty-one patients with SLE and 22 controls were enrolled. Urine JCV viral load was quantified by real-time polymerase chain reaction (PCR). Length variants of the VP1 gene were analyzed using capillary electrophoresis. RESULTS: The prevalence of JCV viruria (63.9% vs. 18.2%, p < 0.001) and urine JCV viral load (2.92 ± 2.76 vs. 0.81 ± 1.85 copies/ml by log10 scale, p < 0.001) were significantly higher in patients with SLE compared with controls. JCV viruria (+) SLE patients had a higher occurrence of arthritis/arthralgia compared with JCV viruria (-) SLE patients (64.1% vs. 22.7%, p = 0.003). In SLE patients, the urine JCV viral load was significantly associated with the occurrence of arthritis/arthralgia. SLE patients with urine JCV viral load >10,000 copies/ml exhibited a 12.75-fold (95% confidence interval 2.88-56.40) risk in clinical arthritis/arthralgia, 18.90-fold (95% confidence interval 2.10-170.39) risk in persistent arthritis, and significantly greater number of length variants in the VP1 gene of JCV compared with JCV viruria (-) SLE patients. CONCLUSION: Reactivation of JCV in the urinary tract of SLE patients was very common. Both JCV viruria and urine JCV viral load were associated with the occurrence of arthritis/arthralgia in patients with SLE. High urine JCV viral load also was associated with the genetic variant in the VP1 gene.

The risk of chronic kidney disease in tuberculosis: a population-based cohort study.

BACKGROUND: The relationship between tuberculosis (TB) and subsequent chronic kidney disease (CKD) remains unclear. Therefore, we examined the risk of CKD among patients with TB in a nationwide study. METHODS: We conducted a retrospective cohort study using data from the National Health Insurance system of Taiwan. The cohort included 8735 patients who were newly diagnosed with TB. Patients were recruited between 1998 and 2002, and the date of diagnosis was defined as the index date. Each patient was randomly matched with four people from the general population without TB, according to age, gender and the index year. The occurrence of CKD was followed up until the end of 2011. The relative risks of CKD were estimated using the Cox proportional hazard model after adjusting for age, gender, index year and comorbidities. RESULTS: The overall incidence of CKD was 1.27-fold greater in the TB cohort than in the non-TB cohort. The adjusted hazard ratio (HR) of CKD associated with TB was higher in women (1.72; 95% confidence interval [CI]: 1.33-2.22), those aged <50 years (1.67; 95% CI: 1.15-2.41) and those without comorbidities (1.39; 95% CI: 1.06-1.83). In addition, patients with more comorbidities among hypertension, diabetes and hyperlipidemia have a greater risk of developing CKD in both cohorts, and the adjusted HRs were higher in the TB cohort than in the non-TB cohort. CONCLUSION: TB patients had a significantly higher risk of developing CKD than the general population. The detailed mechanisms need further investigation.

High-speed atomic force microscope based on an astigmatic detection system.

High-speed atomic force microscopy (HS-AFM) enables visualizing dynamic behaviors of biological molecules under physiological conditions at a temporal resolution of 1s or shorter. A small cantilever with a high resonance frequency is crucial in increasing the scan speed. However, detecting mechanical resonances of small cantilevers is technically challenging. In this study, we constructed an atomic force microscope using a digital versatile disc (DVD) pickup head to detect cantilever deflections. In addition, a flexure-guided scanner and a sinusoidal scan method were implemented. In this work, we imaged a grating sample in air by using a regular cantilever and a small cantilever with a resonance frequency of 5.5 MHz. Poor tracking was seen at the scan rate of 50 line/s when a cantilever for regular AFM imaging was used. Using a small cantilever at the scan rate of 100 line/s revealed no significant degradation in the topographic images. The results indicate that a smaller cantilever can achieve a higher scan rate and superior force sensitivity. This work shows the potential for using a DVD pickup head in future HS-AFM technology.

Adenosine deaminase activity in pleural effusions of lymphoma patients.

BACKGROUND AND AIM: The purpose of this study was to assess the relationship of pleural adenosine deaminase (P-ADA) and non-Hodgkin's lymphoma (NHL). DESIGN AND METHODS: We retrospectively analysed 63 NHL patients with pleural effusions who accepted a diagnostic thoracentesis and who had P-ADA available at the China Medical University Hospital (Taichung, Taiwan) between January 2003 and April 2012. RESULTS: There were 46 exudates [40 malignant pleural effusions (MPE), 5 complicated para-pneumonic effusions and 1 undiagnosed effusion] and 17 transudates. The P-ADA activity was significantly different between the two groups (P < 0.005). Among 40 MPE cases, 29 were due to B-cell and 11 due to T-cell NHL. There was no pleural transudative effusion with P-ADA value higher than 26 U/l in our study, but simultaneously 48% (22/46) of exudative pleural effusions showed a P-ADA value under that cut-off point. The P-ADA level reached the diagnostic cut-off for tuberculosis (40 IU/l) in 11 cases of MPE (11/40 = 27.5%): 9 B-cell NHL (9/29 = 31%) and 2 T-cell NHL (2/11 = 18%). The median levels (25th, 75th percentiles) of P-ADA were 28 IU/l (14-50) in the MPE of B-cell NHL and 26 IU/l (14-28) in the T-cell NHL (P = 0.693). CONCLUSIONS: The use of P-ADA in NHL effusion could aid the separation of transudates from exudates. Around one-quarter MPE of NHL had abnormal P-ADA ( > 40 IU/l). There was no difference in the P-ADA activity in T-cell and B-cell NHL.

Operation of astigmatic-detection atomic force microscopy in liquid environments.

The astigmatic detection system (ADS) based on commercial optical pickup head was demonstrated to achieve a sub-nanometer sensitivity in detecting the vertical movement of an object surface in air. The detection laser spot of the ADS was sub-µm and the detection bandwidth was over 80 MHz. These advantages allow detection of high-frequency mechanical resonance of very small objects, which would have many important applications in nanotechnology. In this work, we optimized the operation conditions of ADS to achieve good sensitivity in aqueous solutions. We demonstrated good contrast and good spatial resolution of cancer cells in water with the optical profilometry mode. We also built an ADS-AFM (atomic force microscopy) for imaging in water. A novel cantilever holder was designed, and the spurious peaks were suppressed down to 26.0% of the real resonance peak. Most importantly, we demonstrated that the ADS-AFM could resolve single atomic steps on a graphite substrate and image soft DNA molecules on mica in water.

Efficacy of alcohols and alcohol-based hand disinfectants against human enterovirus 71.

BACKGROUND: Human enterovirus 71 (HEV71) infections are a significant public health threat in the Asia-Pacific region and occasionally cause severe neurological complications and even death in children. Although good hand hygiene is important for controlling infection, relevant data regarding the efficacy of widely used hand disinfectants against HEV71 are still lacking. AIM: To investigate the virucidal activity of alcohols and alcohol-based hand disinfectants against HEV71. METHODS: A common alcohol-based hand disinfectant (0.5% chlorhexidine gluconate + 70% isopropanol) as well as different concentrations of isopropanol and ethanol were tested for virucidal activity against HEV71 using the suspension and the fingerpad tests. FINDINGS: In suspension tests, 85% and 95% ethanol achieved a mean log10 reduction factor in HEV71 titre of >3 and nearly 6, respectively, within 10 min. By contrast, 70% and 75% ethanol and any concentration of isopropanol (70-95%) produced a factor of <1 in this test after the same exposure time. In fingerpad tests, only 95% ethanol showed a mean log10 reduction factor of >4, while both 75% ethanol and a chlorhexidine gluconate-containing formula were ineffective against HEV71 with a mean log10 reduction factor of <1 after a 30 s exposure time. CONCLUSIONS: Widely used alcohol-based hand disinfectants based on 70% ethanol or isopropanol have poor effectiveness against HEV71. Ninety-five percent ethanol is the most effective concentration, but still cannot fully inactivate HEV71 and may be impractical for use in many instances. Hand hygiene with alcohol-based hand disinfectants alone is not recommended for preventing HEV71 transmission.

Decreased microRNA(miR)-145 and increased miR-224 expression in T cells from patients with systemic lupus erythematosus involved in lupus immunopathogenesis.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with abnormal T cell immune responses. We hypothesized that aberrant expression of microRNAs (miRNAs) in T cells may contribute to the pathogenesis of SLE. First, we analysed the expression profiles of 270 human miRNAs in T cells from five SLE patients and five healthy controls and then validated those potentially aberrant-expressed miRNAs using real-time polymerase chain reaction (PCR). Then, the expression of mRNAs regulated by these aberrant-expressed miRNAs was detected using real-time PCR. Finally, miRNA transfection into Jurkat T cells was conducted for confirming further the biological functions of these miRNAs. The initial analysis indicated that seven miRNAs, including miR-145, miR-224, miR-513-5p, miR-150, miR-516a-5p, miR-483-5p and miR-629, were found to be potentially abnormally expressed in SLE T cells. After validation, under-expressed miR-145 and over-expressed miR-224 were noted. We further found that STAT1 mRNA targeted by miR-145 was over-expressed and apoptosis inhibitory protein 5 (API5) mRNA targeted by miR-224 was under-expressed in SLE T cells. Transfection of Jurkat cells with miR-145 suppressed STAT1 and miR-224 transfection suppressed API5 protein expression. Over-expression of miR-224 facilitates activation-induced cell death in Jurkat cells. In the clinical setting, the increased transcript levels of STAT1 were associated significantly with lupus nephritis. In conclusion, we first demonstrated that miR-145 and miR-224 were expressed aberrantly in SLE T cells that modulated the protein expression of their target genes, STAT1 and API5, respectively. These miRNA aberrations accelerated T cell activation-induced cell death by suppressing API5 expression and associated with lupus nephritis by enhancing signal transducer and activator of transcription-1 (STAT)-1 expression in patients with SLE.

Rotational positioning system adapted to atomic force microscope for measuring anisotropic surface properties.

The diverse atomic configurations induce the anisotropic surface properties. For investigating anisotropic phenomena, we developed a rotational positioning system adapted to atomic force microscope (AFM). This rotational positioning system is applied to revolve the measured sample to defined angular direction, and it composed of an inertial rotational stepper and a visual angular measurement. The inertial rotational stepper with diameter 30 mm and height 7.6 mm can be easily attached to the AFM-system built in any general optical microscope. Based on a clearance less bearing and the inertial driving method, its bidirectional angular resolution reaches 0.005° per step. For realizing a close-loop controlled angular positioning function, the visual measurement method is utilized. Through the feedback control, the angular positioning error is less than 0.01°. For verifying the system performance, we used it to investigate the anisotropic surface properties of graphite. Through a modified cantilever tip, the atomic-scale stick-slip, and the anisotropic friction phenomena can be distinctly detected.

Simultaneous osteonecrosis and osteomyelitis in a patient with cancer of the breast.

Breast cancer is generally managed surgically with adjuvant agents which include hormone therapy, chemotherapy, radiotherapy and bisphosphonate therapy. However, some of these adjuvant therapies may cause adverse events, including wound infection, neutropenia, bone marrow suppression and fever. The simultaneous presentation of osteonecrosis and osteomyelitis has not previously been described in patients with breast cancer undergoing hormone therapy and chemotherapy. We report a patient with breast cancer who developed bone infarcts in both legs as well as osteomyelitis in the right distal tibia after treatment which included a modified radical mastectomy, hormone therapy and chemotherapy. Simultaneous osteonecrosis and osteomyelitis should be considered in patients with breast cancer who are receiving chemotherapy and hormone therapy who present with severe bone pain, especially if there have been infective episodes during treatment.

Rare coexistence of gouty and septic arthritis: a report of 14 cases.

OBJECTIVES: To analyse the characteristic features of patients with coexistence of gouty arthritis and pyarthrosis at our university hospital in southern Taiwan, an area with high prevalence of hyperuricemia and gout. METHODS: A retrospective chart review was performed for patients who had concomitant gouty and septic arthritis from July 1998 to June 2008. Clinical and laboratory data of these patients were analysed. Furthermore, a comparison was made with published cases in English literature. RESULTS: Fourteen cases with coexistence of gouty arthritis and pyarthrosis have been identified during the past 10 years. There were 13 male and 1 female, all of Han Chinese in ethnicity, with ages ranging from 45 to 85 and an average of 63.7 years. At disease presentation, there were 11 oligoarticular cases (78.6%), 2 monoarticular cases (14.3%) and 1 polyarticular case (7.1%). Ankle and knee joints were most commonly involved. Bacteriological analyses demonstrated gram-positive cocci in 12 cases, of these 10 were oxacillin-sensitive Staphylococcus aureus (71.4%). Multiple tophi deposition was noted in 13 patients (92.9%) and among them 11 patients (84.6%) had associated chronic kidney disease. CONCLUSION: Different clinical presentations and bacteriological characteristics have been identified in the present series. While the mechanisms responsible for such a coexistence remain to be elucidated, these cases underline the importance of thorough evaluation of the aspirated synovial fluid. Our report adds a novel insight into the understanding of the clinical and microbiological manifestations of such a rare concurrence of gouty and septic arthritis.