Incidence of Ischemic Colitis and Serious Complications of Constipation Among Patients Using Alosetron: Systematic Review of Clinical Trials and Post-Marketing Surveillance Data

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75196/1/j.1572-0241.2006.00459.x.pd

Exhaled nitric oxide during infancy as a risk factor for asthma and airway hyperreactivity

Childhood asthma is often characterised by elevated exhaled nitric oxide (eNO), decreased lung function, increased airway reactivity and atopy; however, our understanding of when these phenotypic airway characteristics develop remains unclear. This study evaluated whether eNO, lung function, airway reactivity and immune characteristics during infancy are risk factors of asthma at age 5 years. Infants with eczema, enrolled prior to wheezy illness (n=116), had eNO, spirometry, airway reactivity and allergen sensitisation assessed at entry to the study and repeated at age 5 years (n=90). Increasing eNO at entry was associated with an increased risk of asthma (p=0.037) and increasing airway reactivity (p=0.015) at age 5 years. Children with asthma at 5 years of age had a greater increase in eNO between infancy and age 5 years compared with those without asthma (p=0.002). Egg sensitisation at entry was also associated with an increased risk of asthma (p=0.020), increasing eNO (p = 0.002) and lower forced expiratory flows (p=0.029) as a 5 year-old. Our findings suggest that, among infants at high risk for developing asthma, eNO early in life may provide important insights into the subsequent risk of asthma and its airway characteristics

Imaging of brain structural and functional effects in people with human immunodeficiency virus

Before the introduction of antiretroviral therapy, human immunodeficiency virus (HIV) infection was often accompanied by central nervous system (CNS) opportunistic infections and HIV encephalopathy marked by profound structural and functional alterations detectable with neuroimaging. Treatment with antiretroviral therapy nearly eliminated CNS opportunistic infections, while neuropsychiatric impairment and peripheral nerve and organ damage have persisted among virally suppressed people with HIV (PWH), suggesting ongoing brain injury. Neuroimaging research must use methods sensitive for detecting subtle HIV-associated brain structural and functional abnormalities, while allowing for adjustments for potential confounders, such as age, sex, substance use, hepatitis C coinfection, cardiovascular risk, and others. Here, we review existing and emerging neuroimaging tools that demonstrated promise in detecting markers of HIV-associated brain pathology and explore strategies to study the impact of potential confounding factors on these brain measures. We emphasize neuroimaging approaches that may be used in parallel to gather complementary information, allowing efficient detection and interpretation of altered brain structure and function associated with suboptimal clinical outcomes among virally suppressed PWH. We examine the advantages of each imaging modality and systematic approaches in study design and analysis. We also consider advantages of combining experimental and statistical control techniques to improve sensitivity and specificity of biotype identification and explore the costs and benefits of aggregating data from multiple studies to achieve larger sample sizes, enabling use of emerging methods for combining and analyzing large, multifaceted data sets. Many of the topics addressed in this article were discussed at the National Institute of Mental Health meeting Biotypes of CNS Complications in People Living with HIV, held in October 2021, and are part of ongoing research initiatives to define the role of neuroimaging in emerging alternative approaches to identifying biotypes of CNS complications in PWH. An outcome of these considerations may be the development of a common neuroimaging protocol available for researchers to use in future studies examining neurological changes in the brains of PWH

Identification of a Novel “Almost Neutral” Mu Opioid Receptor Antagonist in CHO Cells Expressing the Cloned Human Mu Opioid Receptor

The basal (constitutive) activity of G protein-coupled receptors allows for the measurement of inverse agonist activity. Some competitive antagonists turn into inverse agonists under conditions where receptors are constitutively active. In contrast, neutral antagonists have no inverse agonist activity, and they block both agonist and inverse agonist activity. The mu opioid receptor (MOR) demonstrates detectable constitutive activity only after a state of dependence is produced by chronic treatment with a MOR agonist. We therefore sought to identify novel MOR inverse agonists, and novel neutral MOR antagonists in both untreated and agonist-treated MOR cells. CHO cells expressing the cloned human mu receptor (hMOR-CHO cells) were incubated for 20 hr with medium (control) or 10 μM (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester (herkinorin, HERK). HERK-treatment generates a high degree of basal signaling and enhances the ability to detect inverse agonists. [35S]-GTP-γ-S assays were conducted using established methods. We screened 21 MOR “antagonists” using membranes prepared from HERK-treated hMOR-CHO cells. All antagonists, including CTAP and 6β-naltrexol, were inverse agonists. However, LTC-2 7 4 ( (-)-3-cyclopropylmethyl-2,3,4,4aα,5,6,7,7aα-octahydro-1H-benzofuro[3,2-e]isoquinolin-9-ol)) showed the lowest efficacy as an inverse agonist, and, at concentrations less than 5 nM, had minimal effects on basal [35S]-GTP-γ-S binding. Other efforts in this study identified KC-2-009 ((+)-3-((1R,5S)-2-((Z)-3-Phenylallyl)-2-azabicyclo[3.3.1]nonan-5-yl)phenol hydrochloride) as an inverse agonist at untreated MOR cells. In HERK-treated cells, KC-2-009 had the highest efficacy as an inverse agonist. In summary, we identified a novel and selective MOR inverse agonist (KC-2-009), and a novel MOR antagonist (LTC-274) that shows the least inverse agonist activity among 21 MOR antagonists. LTC-274 is a promising lead compound for developing a true MOR neutral antagonist

T2 FLAIR hyperintensity volume Is associated with cognitive function and quality of life in clinically stable patients with lower grade gliomas

Survival outcomes for patients with lower grade gliomas (LrGG) continue to improve. However, damage caused both by tumor growth and by the consequences of treatment often leads to significantly impaired cognitive function and quality of life (QoL). While neuropsychological testing is not routine, serial clinical MRIs are standard of care for patients with LrGG. Thus, having a greater understanding of MRI indicators of cognitive and QoL impairment risk could be beneficial to patients and clinicians. In this work we sought to test the hypothesis that in clinically stable LrGG patients, T2 FLAIR hyperintensity volumes at the time of cognitive assessment are associated with impairments of cognitive function and QoL and could be used to help identify patients for cognitive and QoL assessments and interventions. We performed anatomical MR imaging, cognitive testing and QoL assessments cross-sectionally in 30 clinically stable grade 2 and 3 glioma patients with subjective cognitive concerns who were 6 or more months post-treatment. Larger post-surgical T2 FLAIR volume at testing was significantly associated with lower cognitive performance, while pre-surgical tumor volume was not. Older patients had lower cognitive performance than younger patients, even after accounting for normal age-related declines in performance. Patients with Astrocytoma, IDH mutant LrGGs were more likely to show lower cognitive performance than patients with Oligodendroglioma, IDH mutant 1p19q co-deleted LrGGs. Previous treatment with combined radiation and chemotherapy was associated with poorer self-reported QoL, including self-reported cognitive function. This study demonstrates the importance of appreciating that LrGG patients may experience impairments in cognitive function and QoL over their disease course, including during periods of otherwise sustained clinical stability. Imaging factors can be helpful in identifying vulnerable patients who would benefit from cognitive assessment and rehabilitation

An Overview of Regional Experiments on Biomass Burning Aerosols and Related Pollutants in Southeast Asia: From BASE-ASIA and the Dongsha Experiment to 7-SEAS

By modulating the Earth-atmosphere energy, hydrological and biogeochemical cycles, and affecting regional-to-global weather and climate, biomass burning is recognized as one of the major factors affecting the global carbon cycle. However, few comprehensive and wide-ranging experiments have been conducted to characterize biomass-burning pollutants in Southeast Asia (SEA) or assess their regional impact on meteorology, the hydrological cycle, the radiative budget, or climate change. Recently, BASEASIA (Biomass-burning Aerosols in South-East Asia: Smoke Impact Assessment) and the 7-SEAS (7- South-East Asian Studies) Dongsha Experiment were conducted during the spring seasons of 2006 and 2010 in northern SEA, respectively, to characterize the chemical, physical, and radiative properties of biomass-burning emissions near the source regions, and assess their effects. This paper provides an overview of results from these two campaigns and related studies collected in this special issue, entitled Observation, modeling and impact studies of biomass burning and pollution in the SE Asian Environment. This volume includes 28 papers, which provide a synopsis of the experiments, regional weatherclimate, chemical characterization of biomass-burning aerosols and related pollutants in source and sink regions, the spatial distribution of air toxics (atmospheric mercury and dioxins) in source and remote areas, a characterization of aerosol physical, optical, and radiative properties, as well as modeling and impact studies. These studies, taken together, provide the first relatively complete dataset of aerosol chemistry and physical observations conducted in the sourcesink region in the northern SEA, with particular emphasis on the marine boundary layer and lower free troposphere (LFT). The data, analysis and modeling included in these papers advance our present knowledge of source characterization of biomass-burning pollutants near the source regions as well as the physical and chemical processes along transport pathways. In addition, we raise key questions to be addressed by a coming deployment during springtime 2013 in northern SEA, named 7-SEASBASELInE (Biomass-burning Aerosols Stratocumulus Environment: Lifecycles and Interactions Experiment). This campaign will include a synergistic approach for further exploring many key atmospheric processes (e.g., complex aerosol-cloud interactions) and impacts of biomass burning on the surface-atmosphere energy budgets during the lifecycles of biomass burning emissions

High Resolution Models of Transcription Factor-DNA Affinities Improve In Vitro and In Vivo Binding Predictions

Accurately modeling the DNA sequence preferences of transcription factors (TFs), and using these models to predict in vivo genomic binding sites for TFs, are key pieces in deciphering the regulatory code. These efforts have been frustrated by the limited availability and accuracy of TF binding site motifs, usually represented as position-specific scoring matrices (PSSMs), which may match large numbers of sites and produce an unreliable list of target genes. Recently, protein binding microarray (PBM) experiments have emerged as a new source of high resolution data on in vitro TF binding specificities. PBM data has been analyzed either by estimating PSSMs or via rank statistics on probe intensities, so that individual sequence patterns are assigned enrichment scores (E-scores). This representation is informative but unwieldy because every TF is assigned a list of thousands of scored sequence patterns. Meanwhile, high-resolution in vivo TF occupancy data from ChIP-seq experiments is also increasingly available. We have developed a flexible discriminative framework for learning TF binding preferences from high resolution in vitro and in vivo data. We first trained support vector regression (SVR) models on PBM data to learn the mapping from probe sequences to binding intensities. We used a novel -mer based string kernel called the di-mismatch kernel to represent probe sequence similarities. The SVR models are more compact than E-scores, more expressive than PSSMs, and can be readily used to scan genomics regions to predict in vivo occupancy. Using a large data set of yeast and mouse TFs, we found that our SVR models can better predict probe intensity than the E-score method or PBM-derived PSSMs. Moreover, by using SVRs to score yeast, mouse, and human genomic regions, we were better able to predict genomic occupancy as measured by ChIP-chip and ChIP-seq experiments. Finally, we found that by training kernel-based models directly on ChIP-seq data, we greatly improved in vivo occupancy prediction, and by comparing a TF's in vitro and in vivo models, we could identify cofactors and disambiguate direct and indirect binding