The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis

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Beliefs about fetal alcohol spectrum disorder among men and women at alcohol serving establishments in South Africa

Background: South Africa has one of the highest rates of fetal alcohol spectrum disorder (FASD) in the world. However, little is known about what men and women who attend alcohol serving establishments believe about alcohol use during pregnancy and how these beliefs may be related to alcohol use. Objectives: To understand FASD beliefs and related behaviors among men and women attending alcohol-serving establishments. Methods: We surveyed 1047 men (n?=?565) and women (n?=?482) -including pregnant women and men with pregnant partners- attending alcohol serving establishments in a township located in Cape Town, South Africa. Results: Among both pregnant (n?=?53) and non-pregnant (n?=?429) women, 54% reported drinking alcohol at least 2–4 times per month, and 57% reported having at least 3–4 alcohol drinks during a typical drinking session. Pregnant women were less likely to believe that they should not drink alcohol and that alcohol can harm a fetus when compared to non-pregnant women. Similar findings were observed between men with pregnant partners compared to men without pregnant partners. Among women, beliefs about how much alcohol pregnant women can safely drink were associated with self-reported alcohol use. Conclusions: Efforts to address FASD need to focus on understanding how men and women perceive alcohol use during pregnancy and situational factors that contribute to alcohol consumption among pregnant women attending alcohol serving establishments. Structural and individual-level interventions targeting women at alcohol serving establishments should be prioritized to mitigate alcohol use during pregnancy.     

Comparison of self-report and objective measures of physical activity in US adults with osteoarthritis

To describe levels of daily physical activity and examine the extent of agreement between self-reported and objectively measured indices of physical activity, and characteristics associated with under or overestimated physical activity among persons with osteoarthritis (OA). Using cross-sectional data from the 2003–2006 National Health and Nutrition Examination Survey, we identified 533 adults ≥45 years of age with self-reported OA who completed physical activity questionnaires and had accelerometry data collected using Actigraph AM-7164. Average daily minutes of moderate to vigorous activity and 95 % confidence intervals (95 % CIs) using self-reported and objective measures were compared across sociodemographic and clinical subgroups and Spearman’s rank correlations were calculated. Differences between self-reported and objectively measured moderate to vigorous activity across various personal characteristics were also estimated. Most persons with OA were non-Hispanic white (87.9 %) and women (68.9 %) with an average age of 65 years old. Self-reported measure of daily moderate to vigorous activity was on average 7 min higher compared to objective measure (17.9 vs. 10.8 min/day). Correlations between self-reported and objective measures across sociodemographic groups were mostly weak to moderate ranging from 0.01 to 0.48. Participants with higher education and better self-reported health status were more likely to over-estimate their moderate to vigorous activity using self-reported measures. Measurement methods and sociodemographic and health factors are associated with differences in reporting physical activity among persons with OA. Future research examining relationships between physical activity and health outcomes in OA should be aware of measurement issues and differences of reporting in subgroups.     

The diagnostic value of the fibrinogen/fibrin fragment E antigen assay in clinically suspected deep vein thrombosis

We have evaluated the fibrinogen/fibrin fragment E antigen assay as a diagnostic test in patients with clinically suspected venous thrombosis by comparing the results of this assay with venography in 272 patients. The result of the fragment E antigen assay was elevated in 79 of 80 patients with positive venograms for recent venous thrombosis (sensitivity 99%) and within the normal range in 161 of 192 patients with normal venograms (specificity 84%). The fragment E assay was also evaluated in 130 medical and surgical controls without evidence of venous thrombosis by leg scanning and the test was found to be relatively nonspecific. However, in the patient group under study, a correct clinical diagnosis of no thrombosis, based on a normal fragment E result, was made in 161 of 162 cases (negative predictive value of 99%). Therefore, a normal test result effectively excludes a diagnosis of venous thrombosis in clinically symptomatic patients. The assay, as currently performed, is technically demanding and takes 24 hr to complete. Therefore, it will have to be simplified before it can be applied to clinical practice.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice [published erratum appears in Blood 1995 Apr 1;85(7):1983]

CD11b is the alpha chain of the Mac-1 integrin and is preferentially expressed in myeloid cells (neutrophils, monocytes, and macrophages). We have previously shown that the CD11b promoter directs cell-type- specific expression in myeloid lines using transient transfection assays. To confirm that these promoter sequences contain the proper regulatory elements for correct myeloid expression of CD11b in vivo, we have used the -1.7-kb human CD11b promoter to direct reporter gene expression in transgenic mice. Stable founder lines were generated with two different reporter genes, a Thy 1.1 surface marker and the Escherichia coli lacZ (beta-galactosidase) gene. Analysis of founders generated with each reporter demonstrated that the CD11b promoter was capable of driving high levels of transgene expression in murine macrophages for the lifetime of the animals. Similar to the endogenous gene, transgene expression was preferentially found in mature monocytes, macrophages, and neutrophils and not in myeloid precursors. These experiments indicate that the -1.7 CD11b promoter contains the regulatory elements sufficient for high-level macrophage expression. This promoter should be useful for targeting heterologous gene expression to mature myeloid cells.