Factors influencing the effects of murine cytomegalovirus on the pancreas.

Background: As human cytomegalovirus (HCMV) infections are implicated in insulin-dependent diabetes mellitus (IDDM), the effects of murine (M)CMV infection of inbred mice on the pancreas are of interest.

Results: Inflammation and periacinar oedema peaked on day 3 and were replaced by a focal inflammation, but infected cells were rare. The islets were spared in C57BL mice.

Imaging of intracranial aneurysms and subarachnoid hemorrhage.

Advances in CT, MR imaging, and catheter angiography provide the radiologist and neurosurgeon with a variety of imaging options for screening, diagnosis, presurgical evaluation, and postoperative monitoring of patients with intracranial aneurysms. Noninvasive imaging techniques have not replaced conventional angiography for the comprehensive evaluation o aneurysms but are effective in screening patients suspected to have an unruptured aneurysm or for preoperative planning in emergency situations that preclude catheter angiography. CT, CT angiography, MR imaging, and MR angiography can all complement the information obtained with catheter angiography in presurgical planning, and the choice of supplemental studies should be individualized.

Synthesis and antiviral activity of prodrugs of the nucleoside 1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-erythropentofuranosyl] cytosine.

The synthesis and antiviral evaluation of 21 prodrugs of 1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-erythropentofuranosyl ] cytosine 1 is reported. Cytosine N4-imine analogues were prepared by condensation of 1 with selected formamide dimethyl acetals. Amino acid substituted prodrugs were prepared from 1 or imine prodrug 2 by coupling with either N-tert-butoxycarbonyl (t-Boc)-L-valine or N-t-Boc-L- phenylalanine in the presence of dicyclohexycarbodiimide (DCC) and 4-dimethylaminopyridine (4-DMAP).

alpha/beta-T cell receptor (TCR)+CD4-CD8- (NKT) thymocytes prevent insulin-dependent diabetes mellitus in nonobese diabetic (NOD)/Lt mice by the influence of interleukin (IL)-4 and/or IL-10.

We have previously shown that nonobese diabetic (NOD) mice are selectively deficient in alpha/beta-T cell receptor (TCR)+CD4-CD8- NKT cells, a defect that may contribute to their susceptibility to the spontaneous development of insulin-dependent diabetes mellitus (IDDM). The role of NKT cells in protection from IDDM in NOD mice was studied by the infusion of thymocyte subsets into young female NOD mice. A single intravenous injection of 10(6) CD4-/lowCD8- or CD4-CD8- thymocytes from female (BALB/c x NOD)F1 donors protected intact NOD mice from the spontaneous onset of clinical IDDM.

A single sequence change destabilizes the influenza virus neuraminidase tetramer.

A single change (E119G) in the influenza A virus N9 neuraminidase (NA) results in resistance of the enzyme to the NA inhibitor 4-Guanidino-Neu5Ac2en (4-GuDANA). This change causes a salt link between Glu119, which sits in a pocket in the bottom of the active site of the enzyme, and the 4-guanidinium moiety of the inhibitor to be lost. NA "heads" of the resistant enzyme produced only a few small crystals under conditions in which the wild-type enzyme readily formed large crystals.

Serial MR in gene therapy for recurrent glioblastoma: initial experience and work in progress.

Purpose: To describe the MR imaging findings in a pilot study evaluating gene therapy for treatment of patients with recurrent glioblastoma.

Methods: Serial MR examinations were evaluated retrospectively in patients treated with gene therapy that included a retroviral vector containing the herpes simplex virus thymidine kinase gene and intravenous ganciclovir. Images were obtained after tumor resection and after each cycle of treatment, at approximately 40-day intervals.

The impact of heart health promotion on coronary heart disease lifestyle risk factors in schoolchildren: lessons learnt from a community-based project.

A community health promotion project called Action Heart was undertaken in two electoral wards in Rotherham to try to change lifestyles of people. Schools were included within the project. Coronary heart disease lifestyle risk factors were measured at baseline and after a three year period in the intervention area and a similar control area.

Synthesis utilizing insoluble polymers: new reactions and small molecules.

It can be argued that solid-phase organic chemistry is the preferred method of preparing screening libraries for lead compound discovery and lead optimization within the pharmaceutical industry. Solid-phase peptide chemistry is the most reliable and general of the synthetic methods available today; however, the purities of products are inadequate for the needs of the current market and the screening departments of pharmaceutical companies. Recent synthetic advances in solid-phase organic chemistry have started to increase the range of chemistry that can be used to prepare 'drug-like' small molecules in library format.

Flow cytometric study of T cell development in NOD mice reveals a deficiency in alphabetaTCR+CDR-CD8- thymocytes.

As a result of failed induction of T cell tolerance to pancreatic B cells, non-obese diabetic (NOD) mice develop spontaneous autoimmune insulin-dependent diabetes mellitus (IDDM). The thymic stroma, which plays a crucial role in thymic T cell maturation, undergoes extensive premature disorganization in NOD mice, so it is of interest to examine NOD T cell development. In this study, both major and minor developmental populations of thymocytes of NOD/Lt mice were studied and compared to those of BALB/c, C57BL/6 and CBA mice by multiparameter flow cytometry (FACS).

Low and minimal flow inhalational anaesthesia.

Purpose: To describe the pharmacokinetic behaviour and practical aspects of low (0.5-1 l.min-1) and minimal (0.

RadNotes: a novel software development tool for radiology education.

RadNotes is a novel software development tool that enables physicians to develop teaching materials incorporating text and images in an intelligent, highly usable format. Projects undertaken in the RadNotes environment require neither programming expertise nor the assistance of a software engineer. The first of these projects, Thoracic Imaging, integrates image teaching files, concise disease and topic summaries, references, and flash card quizzes into a single program designed to provide an overview of chest radiology.

Association between alphabetaTCR+CD4-CD8- T-cell deficiency and IDDM in NOD/Lt mice.

NOD mice develop spontaneous IDDM as a result of T-cell-mediated autoimmune destruction of pancreatic beta-cells. It is not known why these T-cells become autoreactive, nor is it clear whether the breakdown in self-tolerance reflects a general problem in T-cell development or a selective defect in an as yet undefined regulatory cell population. In this study, we showed that NOD mice, although relatively normal with regard to most thymocyte subsets, exhibit a marked deficiency in alphabetaTCR+CD4-CD8- (alphabeta+DN) T-cells in the thymus and, to a lesser extent, in the periphery.

Multiple solid-phase synthesis of hydantoins and thiohydantoins.

A novel general protocol for the construction of hydantoins and thiohydantoins on a solid support has been developed. Using this novel methodology, the synthesis of a diverse 96-compound library has been achieved. Resin-bound dipeptides are cyclised via the formation of an intermediate isocyanate or isothiocyanate on resin as the key step in the strategy.

Solid phase synthesis of functionalized biaryl ethers: versatile scaffolds for combinatorial chemistry.

4-Fluoro-3-nitrobenzoic acid attached to a solid support was shown to react under mild conditions with a wide range of functionalized phenols to yield, after cleavage, the corresponding biaryl ethers in excellent purity. In a similar fashion, biaryl thioethers could be obtained. Further elaboration of immobilized biaryl ethers demonstrates the potential for combinatorial library generation.

Immunogenetics and the cause of autoimmune disease.

Autoimmune disease results from the action of environmental factors on a predisposed genotype. In this review, the role of genetic susceptibility in the aetiology of autoimmune disease is examined. As the genetics of autoimmune diabetes has been studied more intensively than that of other autoimmune diseases, supporting evidence is drawn principally from that example.

Differential effects of the incorporation of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) on the binding of the transcription factors, AP-1 and TFIID, to their cognate target DNA sequences.

The thymidine analog, 1-(2-deoxy-2-fluoro-beta-D-arabino-furanosyl)-5-iodouracil (FIAU), is incorporated into DNA in cell culture and in vivo. To investigate the effect of incorporation of FIAU into DNA on the binding of transcription factors, oligonucleotide duplexes which bind specifically to activator protein 1 (AP-1) or to TFIID were synthesized and binding of these oligonucleotides to their respective proteins was studied using gel-shift analysis. When thymidine at position -3, -1, 1 or 7 (relative to the first thymidine of the core binding sequence) was replaced with FIAU, binding to AP-1 was approximately 82, 28, 86 and 51%, respectively, of the binding to the non-substituted oligonucleotide to AP-1.

A study to assess the immunogenicity, reactogenicity and safety of hepatitis A vaccine administered subcutaneously to patients with congenital coagulation disorders.

The objective was to compare the immunogenicity, reactogenicity and safety of an inactivated hepatitis A vaccine administered subcutaneously to patients with congenital coagulation disorders. Subjects, 97 patients with congenital coagulation disorders (67 men aged > 16 and 30 children aged ≤ 16 years), received hepatitis A vaccine administered at 1440 ELISA (enzyme linked immunosorbent assay) units (ELU) to the adult group and at 720 ELU to the child group at 0 and 6 months by the subcutaneous route. The vaccine was well tolerated, with the incidence of adverse events decreasing with subsequent administration of vaccine.

Regulation of autoimmune diabetes: characteristics of non-islet-antigen specific therapies.

Non-islet-antigen specific treatments have been shown to alter the natural history of insulin dependent diabetes in both the non-obese diabetic (NOD) mouse and in recently diagnosed patients. However concerns have been raised regarding the possibility that non-islet-antigen specific therapy may trade cell mediated autoimmunity for antibody dependent autoimmunity. Female NOD mice at approximately 70 days of age were treated with the non-islet-antigen specific agents complete Freund's adjuvant (CFA) and Bacillus Calmette-Guerin (BCG) and assayed for the development of antibody mediated autoimmunity at 300 days of age.

Potent human immunodeficiency virus type 1 protease inhibitors that utilize noncoded D-amino acids as P2/P3 ligands.

Noncoded D-amino acids have been designed to replace the quinaldic amide-asparaginyl moiety (P2/P3 ligand) found in several potent human immunodeficiency virus (HIV) protease inhibitors such as LY289612. The substituted nitrogen, optimally an N-methanesulfonyl moiety, served as a CH2CONH2 (asparagine side chain mimic), while the amino acid side chain became the backbone and P3 ligand of these novel inhibitors. Compounds derived from S-aryl-D-cysteine proved to be potent HIV protease inhibitors which also exhibited potent whole cell antiviral activity.

Molecular basis for the resistance of influenza viruses to 4-guanidino-Neu5Ac2en.

We report the selection and characterization of influenza A/NWS-G70c and B/HK/8/73 (HG) viruses which are resistant to the potent influenza neuraminidase inhibitor, 4-guanidino-Neu5Ac2en. Viruses were selected which replicated in MDCK cells in the presence of 20 micrograms/ml inhibitor. The neuraminidase of resistant viruses was > 200-fold more resistant to 4-guanidino-Neu5Ac2en than was the neuraminidase of the parent viruses.