Pharmacological Evaluation of the SCID T Cell Transfer Model of Colitis: As a Model of Crohn's Disease

Animal models are important tools in the development of new drug candidates against the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. In order to increase the translational value of these models, it is important to increase knowledge relating to standard drugs. Using the SCID adoptive transfer colitis model, we have evaluated the effect of currently used IBD drugs and IBD drug candidates, that is, anti-TNF-α, TNFR-Fc, anti-IL-12p40, anti-IL-6, CTLA4-Ig, anti-α4β7 integrin, enrofloxacin/metronidazole, and cyclosporine. We found that anti-TNF-α, antibiotics, anti-IL-12p40, anti-α4β7 integrin, CTLA4-Ig, and anti-IL-6 effectively prevented onset of colitis, whereas TNFR-Fc and cyclosporine did not. In intervention studies, antibiotics, anti-IL-12p40, and CTLA4-Ig induced remission, whereas the other compounds did not. The data suggest that the adoptive transfer model and the inflammatory bowel diseases have some main inflammatory pathways in common. The finding that some well-established IBD therapeutics do not have any effect in the model highlights important differences between the experimental model and the human disease

Norwegian ship-owners' adoption of alternative fuels

The shipping sector's rising greenhouse gas emissions are often considered “hard-to-abate”. Some ship-owners have recently adopted or started to consider the adoption of alternative fuels, but systematic studies of this are still lacking. We address this gap by studying how ship-owners differ in both actual and intended adoption of alternative fuels. We analyze data from a unique survey with 281 ship-owners in Norway, a major ship-owning country and center for maritime technology development, with descriptive statistics and analysis of variance. We find early adopters among large and established ship-owners in offshore, international cargo and domestic passenger shipping segments, which are often subjected to specific contractual demands for alternative fuel adoption. Laggards were typically small and young ship-owners operating in shipping segments where demands for alternative fuel adoption are weak. Our findings also suggest that firms' business strategy and financial and knowledge resources may have relevance for ship-owner's adoption of alternative fuels. Our study has implications for national and international policymaking, highlighting for example how contracting mechanisms can be an effective tool in incentivizing the adoption of alternative fuels.publishedVersio

Distinct transthyretin oxidation isoform profile in spinal fluid from patients with Alzheimer’s disease and mild cognitive impairment

BACKGROUND: Transthyretin (TTR), an abundant protein in cerebrospinal fluid (CSF), contains a free, oxidation-prone cysteine residue that gives rise to TTR isoforms. These isoforms may reflect conditions in vivo. Since increased oxidative stress has been linked to neurodegenerative disorders such as Alzheimer’s disease (AD) it is of interest to characterize CSF-TTR isoform distribution in AD patients and controls. Here, TTR isoforms are profiled directly from CSF by an optimized immunoaffinity-mass spectrometry method in 76 samples from patients with AD (n = 37), mild cognitive impairment (MCI, n = 17)), and normal pressure hydrocephalus (NPH, n = 15), as well as healthy controls (HC, n = 7). Fractions of three specific oxidative modifications (S-cysteinylation, S-cysteinylglycinylation, and S-glutathionylation) were quantitated relative to the total TTR protein. Results were correlated with diagnostic information and with levels of CSF AD biomarkers tau, phosphorylated tau, and amyloid β(1-42) peptide. RESULTS: Preliminary data highlighted the high risk of artifactual TTR modification due to ex vivo oxidation and thus the samples for this study were all collected using strict and uniform guidelines. The results show that TTR is significantly more modified on Cys(10) in the AD and MCI groups than in controls (NPH and HC) (p ≤ 0.0012). Furthermore, the NPH group, while having normal TTR isoform distribution, had significantly decreased amyloid β peptide but normal tau values. No obvious correlations between levels of routine CSF biomarkers for AD and the degree of TTR modification were found. CONCLUSIONS: AD and MCI patients display a significantly higher fraction of oxidatively modified TTR in CSF than the control groups of NPH patients and HC. Quantitation of CSF-TTR isoforms thus may provide diagnostic information in patients with dementia symptoms but this should be explored in larger studies including prospective studies of MCI patients. The development of methods for simple, robust, and reproducible inhibition of in vitro oxidation during CSF sampling and sample handling is highly warranted. In addition to the diagnostic information the possibility of using TTR as a CSF oxymeter is of potential value in studies monitoring disease activity and developing new drugs for neurodegenerative diseases

Exercise-Stress Echocardiography Reveals Systolic Anterior Motion of the Mitral Valve as a Cause of Syncopes in a Cardiac Amyloidosis Patient

Patients with cardiac amyloidosis are at increased AV-block and syncope risk. Therefore, a prophylactic pacemaker is often implanted. However, this case illustrates that other mechanisms should be ruled out prior to pacemaker implantation. The patient studied had mitral valve thickening without increased left ventricular outflow track (LVOT) velocity. However, bicycle exercise-stress test with simultaneous echocardiography revealed a stepwise decrease in blood pressure, a substantial increase in the LVOT velocity, and severe systolic anterior motion of the mitral valve. The patients’ symptoms were likely explained by these findings. Therefore, a comprehensive clinical evaluation is warranted prior to pacemaker implantation in cardiac amyloidosis patients

National Background is Associated with Disparities in Initiation and Persistence to Statin Treatment in Subjects with Diabetes in Denmark

Background: To investigate the effects of statin use over the last 10 years among diabetic patients who initiated glucose-lowering medications (GLMs) in Denmark. Methods: we identified all Danish citizens 30 years and older who claimed their first GLM between 1997 and 2006, with follow-up until 2007. Use of medications, national background, income, and hospitalizations were obtained by cross-linkage of national registries in Denmark. We analyzed factors related to initiation and interruption of statin treatment. The analyses included country of birth, citizenship and, as proxy for ethnic origin, we constructed variables based on both the subjects and on their parent's country of birth. Countries were grouped as Denmark, Western countries, Eastern countries, and Africa. Results: the cohort included 143,625 subjects. Compared with persons of Danish origin, the initiation of a statin medication during follow-up was significantly lower among patients of non-Danish origin: Odds ratio for subjects of Eastern origin 0.61 [CI 0.49–0.76] and 0.37 for subjects of African origin, [CI 0.24–0.59], both p < 0.001. The risk of interrupting statin treatment once it had been initiated was also higher in these groups (hazard ratio 2.03, [CI 1.91–2.17] for Eastern subjects and 1.94, [CI 1.63–2.32] for African subjects, both p < 0.0001). Combination of ethnic parameters to refine identification of the cohort led to the same conclusions as the analysis based only on country of birth or citizenship respectively. Conclusion: diabetes patients of African and Eastern origin in Denmark have less chance of being treated with a statin than those of western and Danish origin despite similar access to the Danish health care system

Functional Importance of L- and P/Q-Type Voltage-Gated Calcium Channels in Human Renal Vasculature

Calcium channel blockers are widely used for treatment of hypertension, because they decrease peripheral vascular resistance through inhibition of voltage-gated calcium channels. Animal studies of renal vasculature have shown expression of several types of calcium channels that are involved in kidney function. It was hypothesized that human renal vascular excitation-contraction coupling involves different subtypes of channels. In human renal artery and dissected intrarenal blood vessels from nephrectomies, PCR analysis showed expression of L-type (Ca v 1.2), P/Q-type (Ca v 2.1), and T-type subtype (Ca v 3.1 and Ca v 3.2) voltage-gated calcium channels (Ca v s), and quantitative PCR showed highest expression of L-type channels in renal arteries and variable expression between patients of subtypes of calcium channels in intrarenal vessels. Immunohistochemical labeling of kidney sections revealed signals for Ca v 2.1 and Ca v 3.1 associated with smooth muscle cells of preglomerular and postglomerular vessels. In human intrarenal arteries, depolarization with potassium induced a contraction inhibited by the L-type antagonist nifedipine, EC 50 1.2×10 −8 mol/L. The T-type antagonist mibefradil inhibited the potassium-induced constriction with large variations between patients. Interestingly, the P/Q-type antagonist, ω-agatoxin IVA, inhibited significantly the contraction with 24% at 10 −9 mol/L. In conclusion L-, P/Q, and T-type channels are expressed in human renal blood vessels, and L- and P/Q-type channels are of functional importance for the depolarization-induced vasoconstriction. The contribution of P/Q-type channels to contraction in the human vasculature is a novel mechanism for the regulation of renal blood flow and suggests that clinical treatment with calcium blockers might affect vascular reactivity also through P/Q-type channel inhibition. </jats:p

Evaluation of Maximum a Posteriori Estimation as Data Assimilation Method for Forecasting Infiltration-Inflow Affected Urban Runoff with Radar Rainfall Input

High quality on-line flow forecasts are useful for real-time operation of urban drainage systems and wastewater treatment plants. This requires computationally efficient models, which are continuously updated with observed data to provide good initial conditions for the forecasts. This paper presents a way of updating conceptual rainfall-runoff models using Maximum a Posteriori estimation to determine the most likely parameter constellation at the current point in time. This is done by combining information from prior parameter distributions and the model goodness of fit over a predefined period of time that precedes the forecast. The method is illustrated for an urban catchment, where flow forecasts of 0–4 h are generated by applying a lumped linear reservoir model with three cascading reservoirs. Radar rainfall observations are used as input to the model. The effects of different prior standard deviations and lengths of the auto-calibration period on the resulting flow forecast performance are evaluated. We were able to demonstrate that, if properly tuned, the method leads to a significant increase in forecasting performance compared to a model without continuous auto-calibration. Delayed responses and erratic behaviour in the parameter variations are, however, observed and the choice of prior distributions and length of auto-calibration period is not straightforward

Lung Damage in Mice after Inhalation of Nanofilm Spray Products: The Role of Perfluorination and Free Hydroxyl Groups

Exposures to two commercial nanofilm spray products (NFPs), a floor sealant (NFP 1) and a coating product for tiles (NFP 2), were investigated for airway irritation, airway inflammation, and lung damage in a mouse inhalation model. The particle exposure was characterized by particle number, particle size distribution, and gravimetric analysis. BALB/cJ mice were exposed for 60 min to the aerosolized products at 3.3–60 mg/m3 (105–106 fine particles/cm3) measured in the breathing zone of the mice. Lung inflammation and lung damage were assessed by study of bronchoalveolar lavage fluid (BALF) cytology, protein in BALF, and histology. Mass spectral analysis showed that NFP 1 and NFP 2 contained hydrolysates and condensates of a perfluorosilane and alkylsilane, respectively. NFP 1 induced a concentration-dependent decrease of the tidal volume lasting for at least 1 day. Exposure concentrations above 16.1 mg/m3 (2.1 × 106 fine particles/cm3) gave rise to significant increases of protein level in BALF and reduced body weight, and histological examination showed atelectasis, emphysema, and hemorrhages. A narrow interval between the no-effect level (16.1 mg/m3) and the lethal concentrations (18.4 mg/m3) was observed. The alkylsilane-based product (NFP 2) had no effect at the concentrations studied. Experiments with different types of perfluorinated silanes and alkylsiloxanes showed that the toxic effects did not arise solely from the perfluorination. The number of free hydroxyl groups in the silanes/alkylsiloxanes was also critical for the toxicity