SIGLEC1 (CD169): a marker of active neuroinflammation in the brain but not in the blood of multiple sclerosis patients

We aimed to evaluate SIGLEC1 (CD169) as a biomarker in multiple sclerosis (MS) and Neuromyelitis optica spectrum disorder (NMOSD) and to evaluate the presence of SIGLEC1(+) myeloid cells in demyelinating diseases. We performed flow cytometry-based measurements of SIGLEC1 expression on monocytes in 86 MS patients, 41 NMOSD patients and 31 healthy controls. Additionally, we histologically evaluated the presence of SIGLEC1(+) myeloid cells in acute and chronic MS brain lesions as well as other neurological diseases. We found elevated SIGLEC1 expression in 16/86 (18.6%) MS patients and 4/41 (9.8%) NMOSD patients. Almost all MS patients with high SIGLEC1 levels received exogenous interferon beta as an immunomodulatory treatment and only a small fraction of MS patients without interferon treatment had increased SIGLEC1 expression. In our cohort, SIGLEC1 expression on monocytes was—apart from those patients receiving interferon treatment - not significantly increased in patients with MS and NMOSD, nor were levels associated with more severe disease. SIGLEC1(+) myeloid cells were abundantly present in active MS lesions as well as in a range of acute infectious and malignant diseases of the central nervous system, but not chronic MS lesions. The presence of SIGLEC1(+) myeloid cells in brain lesions could be used to investigate the activity in an inflammatory CNS lesion

Application of the Loo-Riegelman absorption method

The Loo-Riegelman absorption method provides the correct A ∞ /V 1 value and the correct rate constant k a (if absorption is first order), whether metabolism occurs in compartment 1 only, compartment 2 only, or both compartments 1 and 2 of the two-compartment open model. In cases where there is metabolism in compartment 2, the disposition parameters estimated from intravenous data are only apparent and not the real values. The correct A ∞ /V 1 and k a values are obtained, however, only under conditions not hithertofore specified. These conditions are that there must be essentially no bias in the disposition parameters k 12 , k 21 , and k el . and in the C 0 value estimated from the intravenous data, and that in the oral study a large number of interpolated plasma concentrations, as well as the observed plasma concentrations, must be used, especially for drugs with long half-lives. It is shown that application of the Guggenheim method to the initial A 1 V 1 , t values frequently provides a better method of estimating A ∞ /V 1 and k a than the classical method. If biased disposition parameters are used in application of the Loo-Riegelman method to oral data, then essentially the correct value of k a will be estimated, but the estimate of A ∞ /V 1 will be approximately equal to the true value of A ∞ /V 1 multiplied by the ratio of the biased C 0 value (obtained in fitting the intravenous data) to the true C 0 value of the intravenous data. The above indicates that intravenous data should be fitted by computer until there are no systematic deviations or trends and as small a sum of squared deviations as possible is obtained. The oral data should be fitted by spline or Akima methods, or similar procedures, to produce a function which passes through each observed plasma concentration and at the same time provides a large number of interpolated concentration data .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45059/1/10928_2005_Article_BF01066595.pd

Inclusive e+^+e−^- production in collisions of pions with protons and nuclei in the second resonance region of baryons

Inclusive e$^+$e$^-$ production has been studied with HADES in $\pi^-$ + p, $\pi^-$ + C and $\pi^- + \mathrm{CH}_2$ reactions, using the GSI pion beam at $\sqrt{s_{\pi p}}$ = 1.49 GeV. Invariant mass and transverse momentum distributions have been measured and reveal contributions from Dalitz decays of $\pi^0$, $\eta$ mesons and baryon resonances. The transverse momentum distributions are very sensitive to the underlying kinematics of the various processes. The baryon contribution exhibits a deviation up to a factor seven from the QED reference expected for the dielectron decay of a hypothetical point-like baryon with the production cross section constrained from the inverse $\gamma$ n$\rightarrow \pi^-$ p reaction. The enhancement is attributed to a strong four-momentum squared dependence of the time-like electromagnetic transition form factors as suggested by Vector Meson Dominance (VMD). Two versions of the VMD, that differ in the photon-baryon coupling, have been applied in simulations and compared to data. VMD1 (or two-component VMD) assumes a coupling via the $\rho$ meson and a direct coupling of the photon, while in VMD2 (or strict VMD) the coupling is only mediated via the $\rho$ meson. The VMD2 model, frequently used in transport calculations for dilepton decays, is found to overestimate the measured dielectron yields, while a good description of the data can be obtained with the VMD1 model assuming no phase difference between the two amplitudes. Similar descriptions have also been obtained using a time-like baryon transition form factor model where the pion cloud plays the major role.Comment: (HADES collaboration

Pharmacokinetics of ibuprofen in man IV: Absorption and disposition

Fifteen normal male volunters received 400, 800, and 1200 mg doses of ibuprofen as 1, 2, or 3 tablets, respectively, in crossover fashion, then 420 mg in solution form during the fourth week. Plasma concentration of ibuprofen was measured by an HPLC method. Individual subject concentration-time (C,t) data following the solution were analyzed by two different methods, and results unequivocally indicated the open two compartment model with first order absorption. However, the computer fitting of both arithmetic and geometric mean concentrations led to a different model. A method was developed to obtain absorption data (fraction of drug absorbed , F a , versus time) for a multicompartmental system from oral data alone, without intravenous data. The method assumes that V p is constant intrasubject and that absorption is complete following administration of both the solution and tablets. The method was successfully applied to the ibuprofen tablet data. It was shown also that such a method is necessary to obtain ibuprofen absorption data since intrasubject variation of the microscopic rate constants k 12 , k a21 , and k el ( as reflected by the intrasubject variation of the hybrid rate parameters λ 1 and λ 2 or Β and a) is of the same order of magnitude as intersubject variation. Absorption of ibuprofen from tablets was shown not to be simple first order as for the solution. The absorption profiles following one tablet were S- shaped, while those following 2 or 3 tablets had partial linear segments indicating zero order absorption .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45032/1/10928_2005_Article_BF01062664.pd

Disposition of sulfadimethoxine in cattle: Inclusion of protein binding factors in a pharmacokinetic model

Sulfadimethoxine was administered intravenously and orally to four cattle, and plasma and urine samples were collected at various times postdose. Modeling these data with a linear pharmacokinetic model gave unsatisfactory fits, and the data were subsequently fitted to a one‐compartment model with saturable protein binding. The saturable protein binding model included the usual linear excretion and elimination processes as well as protein binding parameters. The values obtained in vivo for the binding constant, 5.01 × 10 M, and the total protein concentration, 7.89 × 10 M, compared favorably with previously reported in vitro values. These results indicate that protein binding can be successfully included in a pharmacokinetic model. Copyrigh