Independent effects of food intake and insulin status on insulin-like growth factor-I in young pigs

The successful use of proteins in pharmaceutical and other commercial applications requires close examination of their relative fragility. Because of the resultant enhanced stability, proteins are often formulated in the solid state, even though dehydration tends to alter their structure. Even in the solid form, however, proteins may become inactivated due to various deleterious processes, e.g., aggregation. This review focuses on such mechanisms, with an emphasis on case studies conducted in our laboratory. Proteins which have both disulfide bonds and free thiols may aggregate via thiol-disulfide exchange, and this process may be facilitated by lyophilization-induced structural perturbations. For proteins possessing disulfides but not free thiols, aggregation also may occur when native disulfides are beta-eliminated, thus giving rise to thiol species which can catalyze disulfide scrambling. Other deleterious processes have also been uncovered, including a formaldehyde-mediated aggregation of formalinized vaccines. It is illustrated how knowledge of such deterioration pathways makes possible the rational development of stable solid protein formulations.     

MRI screening for acoustic neuroma without gadolinium: value of 3DFT-CISS sequence

To evaluate the efficacy of a gradient-echo sequence (3DFT-CISS) in the diagnosis of acoustic neuromas, two independent observers twice reviewed the images of the temporal bones of 83 patients. Contrast-enhanced T1-weighted spin echo images were used as the reference, showing 18 acoustic neuromas, including 5 purely intracanalicular and one intralabyrinthine tumours. High sensitivity (89-94%), specificity (94-97%) and accuracy (94-95%) were found. Intraobserver (kappa 0.93-1) and interobserver (kappa 0.83-0.84) reproducibility were very good. The smallest intracanalicular tumour was overlooked twice by both observers; the intralabyrinthine tumour once by one observer. All tumours were detected with a less stringent decision criterion, at the expense of lower specificity.     

C-reactive protein concentration in dogs with inflammatory leukograms

Serum C-reactive protein (CRP) concentration was measured, using an automated immunoturbidimetric assay, in 44 clinically normal dogs and 67 dogs with band neutrophil count > or = 10(9) cells/L, and values were found to be significantly (P < or = 0.05) different. Correlation of serum CRP concentration and band neutrophil count in the 67 dogs with > or = 10(9) band neutrophils/L resulted in a statistically significant (P < or = 0.05), but low correlation coefficient of 0.34. Serum CRP concentration and CBC values were determined for 6 clinically normal dogs undergoing anesthesia (controls) and 6 clinically normal dogs undergoing anesthesia and ovariohysterectomy. Significant alterations in CBC results and serum CRP concentration, compared with baseline values, were lacking in dogs of the control group. Serum CRP concentration was significantly (P < or = 0.05) increased above baseline values in dogs undergoing surgery and was significantly (P < or = 0.05) increased, compared with values in control dogs by 12 hours after surgery. In dogs undergoing surgery, serum CRP concentration was also significantly (P < or = 0.05) different from values in control dogs at 28 and 36 hours, but not at the 76- and 124-hour sample collection times. Alterations in CBC values compatible with possible or convincing inflammation were detected in 83% of the dogs undergoing surgery at the 8- and 12-hour postsurgery sample collection times, 100% of dogs at 16, 22, 28, and 36 hours after surgery, 83% of dogs at 52 and 76 hours after surgery, 67% of dogs at 100 hours after surgery, and 0% of dogs at 124 hours after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nurses' perceptions of factors influencing the use of a pain program

Factors that, according to nurse participants, influenced the application of what was learned in a pain program were explored by means of qualitative interviews. Participants indicated that the correspondence between the program and their personal view on pain management, attitudes toward the program and innovations in general, self-efficacy perceptions, and (un)familiarity and taboos with respect to program items influenced what they put into practice. In addition, participants indicated that interactions with colleagues, nursing managers, patients, and physicians affected their application of the program. Furthermore, organizational factors, such as limited time and lack of formal program implementation, were mentioned as influential.     

Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as new conformationally restricted ligands for melatonin receptors

Tetrahydroanthracene, tetrahydrophenanthrene, and tetrahydrophenalene moieties were used to design novel constrained melatoninergic agents. Compounds 1 and 2 were synthesized from the cyclization of the aryl succinic acids 6a,b followed by catalytic reduction, Curtius degradation to the amino derivatives, and acetylation. The phenalene derivatives 3 were prepared by cyclization of the aza lactones of the corresponding alpha-N-acetyl amino acids. The ketone derivatives were reduced directly by catalytic hydrogenation to produce the compounds 3. The different compounds were evaluated in vitro in binding assays using 2-[125I] iodomelatonin and chicken brain membranes. Melatonin and 2-acetamido-8-methoxytetralin were used as the reference compounds. The results showed the superiority of the dihydrophenalene framework 3 over those of tetrahydroanthracene and tetrahydrophenanthrene. 3a had relatively good affinity for melatonin receptors (Ki = 28.7 nM). Introduction of an additional methoxy group gave a derivative (3c) with nanomolar affinity (Ki = 0.7 nM), confirming the existence of a secondary binding site in the receptor which has been described previously. An increase in the affinity was also observed with the propionamido derivative 3e (Ki = 6.0 nM). The potential agonist properties of the compound 3e were evaluated on the dermal melanocytes of Xenopus laevis tadpoles. At the concentration of 2.3 nM (5 x Ki), melatonin gave a melanophore index value of 1. Similarly to melatonin, 3e was shown to be a potent agonist of the melanosome aggregation.     

Effects of cyclosporin A on bone turnover and on resorption of demineralized bone matrix

The effects of the immunosuppressive drug Cyclosporin A on orthotopic bone turnover and on the resorption of demineralized bone matrix were studied. In the first experiment, rats were labeled with 3H-proline and 45Calcium and treated with Cyclosporin A 2 mg/kg/day or placebo for 2 weeks. Cyclosporin A treatment resulted in an early transient increase in matrix and mineral turnover in the metaphyseal region of the tibia. Furthermore, Cyclosporin A increased mineral turnover in the diaphyseal part of the tibia, but the matrix turnover was unaffected. No osteopenia was seen after 2 weeks. In the second experiment, prelabeled (3H-proline) demineralized bone matrix from rats and rabbits was implanted in the abdominal walls of growing rats that were treated with Cyclosporin A or placebo. After 4 weeks there was no difference in the remaining activity in the implants from Cyclosporin A or placebo treated rats. Cyclosporin A treatment increased mineral content in demineralized allogenic bone matrix implants by 1/3. In the demineralized xenogenic bone matrix implants, mineral content was 4 times higher in the cyclosporin A treated implants.     

Differential regulation of vitamin D receptors in clonal populations of a chronic myelogenous leukemia cell line

BACKGROUND: Both crystalloid and blood cardioplegia result in cardiac dysfunction associated with myocardial edema. This edema is partially due to the lack of myocardial contraction during cardioplegia, which stops myocardial lymph flow. As an alternative, acceptable surgical conditions have been created in patients undergoing coronary artery bypass operations with esmolol-induced minimal myocardial contraction. We hypothesized that minimal myocardial contraction during circulatory support using either standard cardiopulmonary bypass (CPB) or a biventricular assist device would prevent myocardial edema by maintaining cardiac lymphatic function and thus prevent cardiac dysfunction. METHODS: We placed 6 dogs on CPB and 6 dogs on a biventricular assist device and serially measured myocardial lymph flow rate and myocardial water content in both groups and preload recruitable stroke work only in the CPB dogs. In all dogs we minimized heart rate with esmolol for 1 hour during total circulatory support. RESULTS: Although myocardial lymph flow remained at baseline level during CPB and increased during biventricular assistance, myocardial water accumulation still occurred during circulatory support. However, as edema resolved rapidly after separation from circulatory support, myocardial water content was only slightly increased after CPB and biventricular assistance, and preload recruitable stroke work was normal. CONCLUSIONS: Our data suggest that minimal myocardial contraction during both CPB and biventricular assistance supports myocardial lymphatic function, resulting in minimal myocardial edema formation associated with normal left ventricular performance after circulatory support. The concept of minimal myocardial contraction may be a useful alternative for myocardial protection, especially in high-risk patients with compromised left ventricular function.