Increase in brain stem cytokine mRNA levels as an early response to chemical-induced myelin edema

This study examined the early response of pro-inflammatory and regulatory cytokines in the mouse brain following triethyltin (TET)-induced myelin injury characterized by edematous vacuolation. Following an acute intraperitoneal injection of triethyltin (TET) sulfate (3 mg/kg) to 17-day old CD1 mice, significant increases in brain stem TNF-alpha and IL-1alpha mRNA levels occurred at 6 and 24 h, respectively with elevations in TGF-beta1 and MIP-1alpha at 1 h. In the cortex, responses were limited to elevations at 6 h in TNF-alpha, TGF-beta1 and MIP-1alpha. These data suggest that a chemokine/cytokine response can occur with minimal alterations to the integrity of the myelin sheath and may contribute to the initial signaling mechanisms associated with demyelinating disorders.     

Vav regulates peptide-specific apoptosis in thymocytes

Homologies between vertebrate forebrain subdivisions are still uncertain. In particular the identification of homologs of the mammalian neocortex or the dorsal ventricular ridge (DVR) of birds and reptiles is still a matter of dispute. To get insight about the organization of the primordia of the main telencephalic subdivisions along the anteroposterior axis of the neural tube, a fate map of the dorsal prosencephalon was obtained in avian chimeras at the 8- to 9-somite stage. At this stage, the primordia of the pallium, DVR and striatum were located on the dorsal aspect of the prosencephalon and ordered caudorostrally along the longitudinal axis of the brain. Expression of homeobox-containing genes of the Emx, Dlx and Pax families were used as markers of anteroposterior developmental subdivisions of the forebrain in mouse, chick, turtle and frog. Their expression domains delineated three main telencephalic subdivisions in all species at the onset of neurogenesis: the pallial, intermediate and striatal neuroepithelial domains. The fate of the intermediate subdivisions diverged, however, between species at later stages of development. Homologies between forebrain subdivisions are proposed based on the conservation and divergence of these gene expression patterns.     

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent

3-?4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl?-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-?4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl?propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-?4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl? ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.     

Multicomponent water proton transverse relaxation and T2-discriminated water diffusion in myelinated and nonmyelinated nerve

The influence of compartmental boundaries on water proton transverse relaxation and diffusion measurements was investigated in three distinct excised nerves, namely, the non-myelinated olfactory nerve, the Schwann cell myelinated trigeminal nerve, and the oligodendrocyte myelinated optic nerve of the garfish. The transverse relaxation decay curves were multiexponential and their decomposition yielded three primary components with T2 values approximately 30-50, 150, and 500 ms, which were subsequently assigned to water protons in the myelin, axoplasm, and interaxonal compartments. The short T2 component was absent in the non-myelinated olfactory nerve, but present in both myelinated nerves and thus provides supporting evidence for the use of quantitative T2 measurements to measure the degree of myelination. The signal contribution of each T2 component to the apparent diffusion coefficient measurements was varied by incrementing the spin-echo time with a preparatory CPMG train of radiofrequency pulses. The apparent diffusion coefficient and its anisotropy were shown to be independent of the spin-echo time over the range of 70 to 450 ms.     

Rapid ganciclovir susceptibility assay using flow cytometry for human cytomegalovirus clinical isolates

Rapid, quantitative, and objective determination of the susceptibilities of human cytomegalovirus (HCMV) clinical isolates to ganciclovir has been assessed by an assay that uses a fluorochrome-labeled monoclonal antibody to an HCMV immediate-early antigen and flow cytometry. Analysis of the ganciclovir susceptibilities of 25 phenotypically characterized clinical isolates by flow cytometry demonstrated that the 50% inhibitory concentrations (IC50s) of ganciclovir for 19 of the isolates were between 1.14 and 6.66 microM, with a mean of 4.32 microM (+/-1.93) (sensitive; IC50 less than 7 microM), the IC50s for 2 isolates were 8.48 and 9.79 microM (partially resistant), and the IC50s for 4 isolates were greater than 96 microM (resistant). Comparative analysis of the drug susceptibilities of these clinical isolates by the plaque reduction assay gave IC50s of less than 6 microM, with a mean of 2.88 microM (+/-1.40) for the 19 drug-sensitive isolates, IC50s of 6 to 8 microM for the partially resistant isolates, and IC50s of greater than 12 microM for the four resistant clinical isolates. Comparison of the IC50s for the drug-susceptible and partially resistant clinical isolates obtained by the flow cytometry assay with the IC50s obtained by the plaque reduction assay showed an acceptable correlation (r2 = 0.473; P = 0.001), suggesting that the flow cytometry assay could substitute for the more labor-intensive, subjective, and time-consuming plaque reduction assay.     

Occupational injuries among older workers with visual, auditory, and other impairments. A validation study

This study aims to validate a previously defined model of the risk of occupational injuries among older workers with visual, auditory, or other impairments. That model was based upon the Health and Retirement Study (HRS). The previous logistic regression model was recalculated using data from the 1994 National Health Interview Survey (NHIS). The parameter estimates for impaired hearing (.181 in NHIS, 1.55 in HRS), impaired vision (2.42 in NHIS, 1.48 in HRS), and self-employment (0.22 in NHIS, 0.49 in HRS) were in same direction and of roughly the same magnitude. The previously defined model was confirmed using NHIS data. The data suggest that as the workforce ages, more attention must be paid to the accommodation of disabilities in the workplace, especially sensory impairments-poor vision and hearing.     

Nuclear architecture and the induction of chromosomal aberrations

Progress in fluorescence in situ hybridization, three dimensional microscopy and image analysis has provided the means to study the three-dimensional structure and distribution of chromosome territories within the cell nucleus. In this contribution, we summarize the present state of knowledge of the territorial organization of interphase chromosomes and their topological relationships with other macromolecular domains in the human cell nucleus, and present data from computer simulations of chromosome territory distributions. On this basis, we discuss models of chromosome territory and nuclear architecture and topological consequences for the formation of chromosome exchanges.     

Functional characterization of the Haemophilus influenzae 4.5S RNA

General registration of congenital malformations was established in Denmark in the early 1960s as a consequence of the thalidomide tragedy. The aims of the present paper are to describe the registration of congenital malformations in Denmark since the thalidomide tragedy, to discuss the limitations of these data and to point towards possibilities for improving the registration of congenital malformations in the future. Important components in a surveillance system are compulsory detailed reporting of malformations shortly after the diagnoses have been made and continuous expert evaluation of all reports. However, since 1995 the registration of congenital malformations in Denmark is based mainly on routine discharge diagnoses from hospitals. A high quality registration of congenital malformations in Denmark would be particularly valuable, because such a register together with existing health related registers and an ongoing large scale cohort study of pregnant women would provide a unique resource for etiological research in congenital malformations. Considering the consequences of congenital malformations for the affected children, their families and society, the establishment of a high quality registration of congenital malformations seems justifiable--and the Swedish experience shows that it is feasible.