Use of Fmoc-N-(2-hydroxy-4-methoxybenzyl) amino acids in peptide synthesis

The use of N, O-bisFmoc-N-(2-hydroxy-4-methoxybenzyl) amino acid derivatives in the synthesis of peptides with difficult sequences has already been described. With these amino acid derivatives the reversible protecting group 2-hydroxy-4-methoxybenzyl (Hmb) for the backbone amide bonds of peptide chains is introduced, and thus the aggregation due to hydrogen-bond interchain association is inhibited. This paper describes the synthesis and use of Fmoc-N-(2-hydroxy-4-methoxybenzyl)amino acid derivatives as an alternative means of introducing Hmb backbone protection. These new monoFmoc derivatives were obtained in higher yield than the bisFmoc derivatives. Coupling yields to the amino peptide resin were the same as those obtained with bisFmoc derivatives, under the TBTU/HOBt/DIEA conditions. We also compared different syntheses of a difficult peptide with the Fmoc approach [triple coupling, capping, use of chaotropic agents, backbone protection using monoFmoc (Hmb)Ala] and with optimized Boc chemistry. Both the backbone protection and optimized Boc chemistry approaches gave the desired product in excellent yield and purity. © Munksgaard 1997.     

Body Fat Percentage of Children Varies According to Their Diet Composition

Objective To ascertain the association between diet composition and body fat percentage in 9- and 10-year-old children. Also, to examine the influence of gender, total energy intake, fitness, physical activity, and parental body mass on the relationship between diet composition and adiposity.Design Diet composition was assessed using the National Cancer Institute food frequency questionnaire, and adiposity was measured using the average of results determined using two skinfold equations. Fitness levels and physical activity were ascertained using the 1-mile run/walk test and a self-report 15-item scale, respectively.Subjects A sample of 262 children (162 boys and 100 girls, mean age=9.8±0.5 years) participated.Statistical analysis Regression analysis was used to determine the extent to which diet composition contributed to adiposity without statistical control for any potentially confounding variables. Partial correlations were calculated to assess the relationship between macronutrient intake and adiposity after potential confounders (gender, total energy intake, physical fitness, and parental body mass) were controlled statistically.Results Energy intake was positively related to adiposity. Fat intake, calculated as a percentage of total energy, was also positively related to adiposity, before and after control for potential confounding variables. Percentage of energy derived from carbohydrate was inversely related to adiposity, before and after controlling for potential confounders.Applications These findings indicate that the macronutrient intake of children, particularly dietary fat and carbohydrate intake, may play a role in adiposity, independent of the influence of total energy intake, gender, physical fitness, and parental body mass index.     

Do Electrode and Lead Design Differences for Permanent Cardiac Pacing Translate into Clinically Demonstrable Differences? (Comparison of Sintered Platinum and Activated Vitreous and Porous Carbon Electrodes)

A randomized prospective study was undertaken to compare the electrical performances of three permanent, endocardial, tined pacing leads with different electrode designs--sintered platinum, vitreous carbon, and porous carbon. Ninety-nine patients received one of the leads (S80 31; 423S 32; S100 36). Acute R wave amplitude and ST elevation of the native endocardial electrogram, voltage threshold, impedance, and current flow at four pulse durations (0.25-1.0 msec) were measured. Voltage thresholds were measured noninvasively at each of four pulse durations at 2 days and 1, 3, and 6 months after implantation. No significant differences were found in sensing properties, or current flow at threshold at 0.5 msec pulse duration. The 423S lead had a significantly higher impedance at threshold and both a higher impedance and lower current flow at 5 V. No significant differences in threshold voltages were found between the three leads at any pulse duration, at any of the assessed times after implantation. Six-month thresholds for the S80, 423S, and S100 leads were 1.18 +/- 0.35, 1.17 +/- 0.29, and 1.06 +/- 0.38 V respectively at 0.5 msec pulse duration. Differences between 'high performance' pacing leads need to be of a greater order of magnitude before they can be exploited to give any real clinical advantage to patients.     

Computer-Assisted Design of an Implantable, Intrathoracic Artificial Lung

Abstract: A semiempirical mathematical model of convective oxygen transport is used to design a new, low pressure loss, implantable artificial lung that could be used as a bridge to lung transplantation in patients with advanced respiratory failure. The mass transfer and flow friction relations pertinent to the design of a cross–flow hollow fiber membrane lung are described. The artificial lung is designed to transfer over 200 ml/min of oxygen at blood flow rates up to 5 L/min. A compact design and a blood-side pressure loss of <15 mm Hg allows the device to be implanted in the left chest without the need for a prosthetic blood pump. Surgical implantation of the artificial lung would require the creation of inflow and outflow anastomoses. Oxygen would be supplied via an external source. Blood properties, operating conditions, and empirically determined mass transfer and flow properties are all specified and input into a computer program that numerically solves the design equations. Computer–generated values for the device frontal area, blood path length, and fiber surface area are thereby obtained. The use of this computer–assisted design minimizes the need for extensive trial–and–error testing of prototype devices. Results from in vitro tests of a prototype implantable lung indicate that the mathematical model we describe is an accurate and useful tool in the design of hollow fiber artificial lungs.     

Routine hysteroscopy for patients with a high risk of uterine malignancy

Summary. Seventy patients with abnormal vaginal bleeding were examined with a Storz hysteroscope. The examination took an average of only 5 min. Sixty patients had the examination under general anaesthesia, five under paracervical block and five had no form of anaesthesia. All tolerated the procedure well. There were no complications directly related to the hysteroscopic examination. There was complete correlation between the histology of the endometrium obtained at subsequent curettage and the hysteroscopic findings.     

Heart health inequalities in Canada: modules, theory and planning

It is well known that prevalence and incidence rates of cardiovasculardisease (CVD) and CVD risk factors are not equally distributedamong socioeconomic groups. Known risk factors account for part,but not all of unequally distributed CVD rates. Socioeconomicconditions and psychosocial dynamics may explain another pareof the increased CVD rates. Theoretically, it may be possibleto lower CVD rates and CVD risk factor prevalence among lowersocioeconomic status (SES) groups by using a community development(socio-environment) strategy directed towards changes in socioenvrronmentalrisk conditions and psychosocial risk factors, rather than CVDrisk factors per Se. This article describes a protocol for sucha strategy based upon the planning work of Canadian health professionals,loosely organized under a project titled ‘Heart HealthInequalities in Canada’ This protocol incorporates baselinedata on CVD and CVD risk factor prevalence, but is premisedon actions negotiated between community organizations and healthauthorities, rather than defined unilaterally by health authorities.As such, program design activities and evaluation will differfrom a more general population-based risk factor reduction strategy.     

Cross system agreement for substance use disorders: DSM-III-R, DSM-IV and ICD-10

This report presents results of a field trial of Substance Use Disorders as defined by DSM-III-R, DSM-IV (proposed) and ICD-10. Diagnoses based on the three systems were derived from interviews using the Composite International Diagnostic Interview (CIDI) in a heterogeneous sample of 521 adults drawn from clinical and community settings. Two issues are addressed: (1) cross system agreement; and (2) syndrome coherence of proposed criterion sets for Substance Dependence in each of the three systems. Findings were as follows: (1) Cross system agreement for Dependence was generally high, especially between DSM-III-R and DSM-IV. (2) Cross system agreement was lower for DSM-III-R and DSM-IV Abuse and very low for DSM-IV Abuse and ICD-10 Harmful Use. (3) Agreement varied across drug categories with lowest DSM-III-R/DSM-IV agreement for alcohol abuse and DSM-IV/ICD-10 agreement for marijuana use disorders. (4) Overall prevalence differed for the three systems with DSM-IV yielding highest rates followed by DSM-III-R and ICD-10 in that order. (5) Factor analysis of Dependence criteria showed high loadings of all items on a single factor across the three diagnostic systems and for all categories of drugs. Implications for validity of the dependence syndrome construct and for revisions in DSM-IV are discussed.     

Characterization of a soluble form of CD58 in synovial fluid of patients with rheumatoid arthritis (RA)

Reduced levels of a soluble form of the adhesion receptor and CD2 ligand CD58 (sCD58) were previously described in RA patients. In order to understand the biological significance of this finding we biochemically characterized sCD58 in RA and asked how well sCD58 binds to CD2. sCD58 concentrations were measured in serum and synovial fluid (SF) samples of RA patients by two ELISAs, one detecting domain 1 of CD58 (CD58-D1), and the other one the complete molecule (CD58-D1 + D2). Small amounts of split sCD58-D1 were found in most RA sera, but not SF. In addition, split sCD58-D2 was detected in SF by affinity chromatography, SDS–PAGE, and Western blotting. Gel filtration gave similar peaks at 95–125 kD for RA sera, SF, and normal serum. Binding of SF-sCD58 to the CD2⁺ Jurkat variant JBB1 or recombinant CD2 was stronger than urinary sCD58 and reached binding of oligomeric recombinant CD58 at low concentrations. In conclusion, sCD58-split products were found in RA sera and SF. At concentrations as they occur in vivo, SF-sCD58 binds to CD2 much more strongly than urinary sCD58. It is conceivable that locally released sCD58 blocks the CD2/CD58 interaction under physiological conditions. Insufficient release of sCD58, e.g. in synovitis, might result in T cell accumulation and perpetuation of inflammation.     

Anti-CD2 (OX34) MoAb treatment of adjuvant arthritic rats: attenuation of established arthritis, selective depletion of CD4+ T cells, and CD2 down-modulation

Anti-CD2 MoAbs have previously been shown to induce tolerance and to block B cell differentiation, T cell and monocyte activation. Since these immune functions are important in joint inflammation, we asked whether administration of the anti-CD2 MoAb OX34 has a beneficial effect on established rat adjuvant arthritis, a model of human rheumatoid arthritis, and how it affects CD2-bearing leucocyte subsets. Female Lewis rats with established adjuvant arthritis received a total of 5 mg OX34 or isotype-matched control MoAb starting on day 15 after adjuvant injection. Weight and arthritis score (AS) were measured in a blinded fashion. Peripheral blood cells were analysed for numbers of leucocyte subsets at various time points. Animals were killed on day 30 and lymphatic organs were processed for immunohistology. Clinically, OX34 treatment led to increased body weight and reduced AS. Although OX34 binds to CD4⁺ and CD8⁺ T cells in a comparable fashion, OX34 treatment reduced CD4⁺ T cells, but not CD8⁺ T cells. Among CD4⁺ T cells CD45RC⁺ (‘naive’) T cells virtually disappeared; CD45RC⁻ (‘recently activated’) T cells were slightly reduced. A reduction of CD4⁺ T cells was also found in the lung, liver, bone marrow, spleen and lymph nodes. Down-modulation of the CD2 molecule by OX34, again, affected CD4⁺ T cells, suggesting a specific signal for CD4⁺ but not CD8⁺ T cells. In conclusion, the anti-CD2 MoAb OX34 attenuates established rat adjuvant arthritis. In spite of similar binding to CD4⁺ and CD8⁺ T cells, OX34 depletes only CD4⁺ T cells and down-modulates the CD2 molecule on these cells. These results suggest a therapeutic benefit from CD2-directed therapy for chronic types of arthritis.