Structure-based design of cathepsin K inhibitors containing a benzyloxy-substituted benzoyl peptidomimetic

Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid-based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors.     

Evidence-based dental care--a concept review

PURPOSE: Our purpose was to examine the benefits of assisted hatching in our program and to determine whether the procedure increases the implantation of nonviable embryos or monozygotic twinning. METHODS: Consecutive in vitro fertilization cycles using assisted hatching were compared with historical controls. The impact of assisted hatching was analyzed according to the woman's age. Outcome measures were clinical pregnancy, implantation rate, delivery rate, multiple pregnancy, spontaneous abortion, and incidence of monozygotic twins. RESULTS: The implantation rate was increased in women aged 35-39 and markedly increased in women aged 40-42. There was no change in spontaneous abortions and no increase in monozygotic twins. CONCLUSIONS: Assisted hatching is a safe and highly effective adjunct to in vitro fertilization for women aged 35-42 and did not increase spontaneous abortion or monozygotic twinning.     

Compliance with primary prevention in private practice: creating a tobacco-free environment

A sample of private orthodontic practices (n = 40) from a controlled trial for clinician-initiated tobacco-use prevention was used to test the effectiveness of preventive medicine representative (PMR) visits in creating and maintaining an anti-tobacco office environment. Clinical staff of 20 offices, randomly assigned to the experimental group, were trained by a PMR on the use of anti-tobacco materials (no-smoking signs, posters, and print materials). Twenty control-group offices did not receive any training or special treatment. Subsequently, experimental-group offices were visited by a PMR once every three months and were telephoned six weeks after each visit over a 12-month period. During visits and phone calls, PMRs prompted offices to order anti-tobacco materials. Visits served to introduce offices to new materials and to encourage their continued use. Data from direct observations and self-report measures showed significant differences between experimental and control offices for display of anti-tobacco materials at 1.5 months and 12 months (P < .001). Results suggest that PMR visits may serve as an effective method of introducing and maintaining preventive medicine procedures in clinical environments.     

The response of gamma delta T cells to Plasmodium falciparum is dependent on activated CD4+ T cells and the recognition of MHC class I molecules

Peripheral blood gamma delta T cells from non-exposed individuals respond to antigens of the malaria parasite, Plasmodium falciparum, in vitro. This response, largely caused by T cells bearing the V gamma 9+ chain of the T-cell receptor, is stimulated by components of the parasite expressed on the schizont stage and released at schizont rupture. The response of V gamma 9+ T cells to parasite components is inhibited by antibodies to major histocompatibility complex (MHC) class I and class II. However, the inhibition by anti-MHC class II antibodies can be overcome by the addition of interleukin-2 (IL-2) to the cultures, suggesting that gamma delta T cells themselves do not recognize MHC class II molecules but require an MHC class II-dependent response taking place in the culture. In contrast, the inhibition by anti-class I antibodies cannot be reversed by addition of IL-2. Since an accompanying CD4+ T-cell response occurred in peripheral blood mononuclear cells cultured with P falciparum antigens, it was considered that these cells provide the cytokines necessary for the subsequent activation and expansion of V gamma 9+ T cells recognizing components of the parasite and MHC class I molecules. This was confirmed by reconstituting the response of enriched gamma delta T cells to P falciparum schizont extract by addition of purified CD4+ T cells.     

Elevation of plasma leptin levels during pregnancy in normal and diabetic women

The impact of pregnancy and food intake on plasma leptin levels was investigated in insulin-dependent diabetes mellitus (IDDM) patients and healthy normal-weight women. Fourteen women with IDDM and 11 women with no diabetes or family history of diabetes were served a 707-kcal lunch in gestational weeks 34 to 38. Six breast-feeding women from each group were examined a second time within 1 month after delivery. Leptin levels were not different in the two groups either during pregnancy or postpartum. In addition to a positive correlation to body mass index (BMI), leptin levels tended to correlate with gestational weight gain. The leptin concentration during pregnancy was higher than the postpartum level, which was within the range of previously reported levels in non-obese nonpregnant women. Ingestion of the test meal did not affect leptin levels and there were no relationships between leptin and insulin or glucose, for either basal or postprandial (60-minute) levels. Only the insulin dose taken by the diabetic women correlated to leptin level. During pregnancy, there is an augmented energy expenditure and maternal metabolism is altered to increase fat stores. The present observation that leptin levels were elevated in pregnant women suggests an additional role for leptin in the accumulation of body fat.     

Monitoring for intraoperative awareness

Despite advances in anesthetic technique and technology, intraoperative awareness continues to occur with alarming regularity. The psychological effects on patients and the medicolegal consequences to providers have created the need for a reliable monitor of the hypnotic component of anesthesia. A new technology known as bispectral analysis (BIS) has the potential to put an end to the devastating occurrence of intraoperative awareness, as well as improve the overall effectiveness of anesthetic delivery and the surgical experience. Applicable to almost any situation requiring sedation or general anesthesia, BIS's reliability is a real-time measure of hypnosis levels.     

Haemonchus contortus glycoproteins contain N-linked oligosaccharides with novel highly fucosylated core structures

Structural studies on the N-linked oligosaccharides of Haemonchus contortus, an economically important nematode that parasitizes domestic ruminants, have revealed core fucosylation of a type not previously observed in any eukaryotic glycoprotein. Mass spectrometric analyses were performed on detergent extracts of homogenized adult H. contortus and on purified H11, a glycoprotein isolated from intestinal brush borders which has been previously shown to be an effective vaccine antigen. The major N-linked glycans identified in the present study have up to three fucose residues attached to their chitobiose cores. The fucoses are found at the 3- and/or 6-positions of the proximal GlcNAc and at the 3-position of the distal GlcNAc. The latter substitution is unique in N-glycans. Most anti-H11 monoclonal antibodies are known to recognize carbohydrate epitopes, and it is possible that the newly discovered multifucosylated core structures are highly immunogenic in this glycoprotein.     

Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice

When administered intracerebroventricularly to mice performing various learning tasks involving either short-term or long-term memory, secreted forms of the beta-amyloid precursor protein (APPs751 and APPs695) have potent memory-enhancing effects and block learning deficits induced by scopolamine. The memory-enhancing effects of APPs were observed over a wide range of extremely low doses (0.05-5,000 pg intracerebroventricularly), blocked by anti-APPs antisera, and observed when APPs was administered either after the first training session in a visual discrimination or a lever-press learning task or before the acquisition trial in an object recognition task. APPs had no effect on motor performance or exploratory activity. APPs695 and APPs751 were equally effective in the object recognition task, suggesting that the memory-enhancing effect of APPs does not require the Kunitz protease inhibitor domain. These data suggest an important role for APPss on memory processes.