Novel antitumor 2-cyanoaziridine-1-carboxamides

A set of 20 2-cyanoaziridine-1-carboxamides was synthesized from 2-cyanoaziridine and appropriate isocyanates. These compounds were active against a variety of solid and hematological tumor cells in culture, including strains resistant to doxorubicin and mitoxantrone. Their potencies in these assays correlated with the lipophilicity of substituents. The N-phenyl derivative was more potent and equally effective to imexon, a cyclized 2-cyanoaziridine-1-carboxamide of clinical interest, against cloned fresh human tumors.     

The material basis for reduced mechanical properties in oim mice bones

Osteogenesis imperfecta (OI), a heritable disease caused by molecular defects in type I collagen, is characterized by skeletal deformities and brittle bones. The heterozygous and homozygous oim mice (oim/+ and oim/oim) exhibit mild and severe OI phenotypes, respectively, serving as controlled animal models of this disease. In the current study, bone geometry, mechanics, and material properties of 1-year-old mice were evaluated to determine factors that influence the severity of phenotype in OI. The oim/oim mice exhibited significantly smaller body size, femur length, and moment of area compared with oim/+ and wild-type (+/+) controls. The oim/oim femur mechanical properties of failure torque and stiffness were 40% and 30%, respectively, of the +/+ values, and 53% and 36% of the oim/+ values. Collagen content was reduced by 20% in the oim/oim compared with +/+ bone and tended to be intermediate to these values for the oim/+. Mineral content was not significantly different between the oim/oim and +/+ bones. However, the oim/oim ash content was significantly reduced compared with that of the oim/+. Mineral carbonate content was reduced by 23% in the oim/oim bone compared with controls. Mineral crystallinity was reduced in the oim/oim and oim/+ bone compared with controls. Overall, for the majority of parameters examined (geometrical, mechanical, and material), the oim/+ values were intermediate to those of the oim/oim and +/+, a finding that parallels the phenotypes of the mice. This provides evidence that specific material properties, such as mineral crystallinity and collagen content, are indicative and possibly predictive of bone fragility in this mouse model, and by analogy in human OI.     

The effects of triethanolamine myristate, a fatty acid salt, on the bioavailability of riboflavin in dogs

A study in dogs was performed in which a physiologic approach to delaying gastric emptying was examined. Triethanolamine myristate (a fatty acid salt) was used to delay gastric emptying in hopes of increasing the bioavailability of riboflavin. A bilayer tablet consisting of triethanolamine myristate and riboflavin resulted in an absolute bioavailability of 2-3 times greater than the bioavailability of riboflavin alone. Increases in bioavailability although to a lesser extent, were also seen with the 30 min pretreatment with triethanolamine myristate. The results suggest that it was possible to delay gastric emptying.     

Micromechanical models for the Brownian motion of hair cell stereocilia

Brownian motion of the hairs (stereocilia) of amphibian hair cells has been shown in experiments to be in the range of some nm. Our models of the Brownian motion of coupled harmonic oscillators with mechanical properties of stereocilia lead to similar displacements. Computer simulation shows that stochastic fluctuations enhance the encoding of low level acoustic signals. Stochastic resonance lowers the detection threshold of auditory signals to amplitudes one order of magnitude lower than that of the Brownian motion.     

Laser temperature jump study of the helix<==>coil kinetics of an alanine peptide interpreted with a 'kinetic zipper' model

The kinetics of the helix<==>coil transition of an alanine-based peptide following a laser-induced temperature jump were monitored by the fluorescence of an N-terminal probe, 4-(methylamino)benzoic acid (MABA). This probe forms a peptide hydrogen bond to the helix backbone, which changes its fluorescence quantum yield. The MABA fluorescence intensity decreases in a single exponential relaxation, with relaxation times that are weakly temperature dependent, exhibiting a maximum value of approximately 20 ns near the midpoint of the melting transition. We have developed a new model, the kinetic version of the equilibrium 'zipper' model for helix<==>coil transitions to explain these results. In this 'kinetic zipper' model, an enormous reduction in the number of possible species results from the assumption that each molecule contains either no helical residues or a single contiguous region of helix (the single-sequence approximation). The decay of the fraction of N-terminal residues that are helical, calculated from numerical solutions of the kinetic equations which describe the model, can be approximately described by two exponential relaxations having comparable amplitudes. The shorter relaxation time results from rapid unzipping (and zipping) of the helix ends in response to the temperature jump, while the longer relaxation time results from equilibration of helix-containing and non-helix-containing structures by passage over the nucleation free energy barrier. The decay of the average helix content is dominated by the slower process. The model therefore explains the experimental observation that relaxation for the N-terminal fluorescent probe is approximately 8-fold faster than that for the infrared probe of Williams et al. [(1996) Biochemistry 35, 691-697], which measures the average helix content, but does not account for the absence of observable amplitude for the slow relaxation in the fluorescence experiments (<10% slow phase). If we assume that the activation barrier for the coil-->helix rate is purely entropic, the model can also explain the maximum in the temperature dependence of the relaxation time for the fluorescent probe. Parameters that best reproduce the melting curves and the ratio of relaxation times predict a value of the cooperativity parameter sigma which is approximately 3-fold larger than previously reported values obtained from fitting equilibrium data only. The helix growth rate of approximately 10(8) s-1 that reproduces the experimental relaxation times is approximately 100-fold slower than those observed in molecular dynamics simulations. These parameters can be used to simulate the kinetically cooperative formation of a helix from the all-coil state.     

Resting metabolic rate in subjects with paraplegia: the effect of pressure sores

OBJECTIVE: To determine the overall effect of paraplegia and pressure sores on resting metabolic rate. DESIGN: Unblinded, case-control study using a convenience sample. SETTING: Hospital primary care setting. PATIENTS: Fourteen individuals with paraplegia and pressure sores (PS-Para), 24 with paraplegia in good health (NPS-Para), and 23 non-spinal cord injury (SCI) controls. MAIN OUTCOME MEASURES: The planned outcome measures consisted of resting metabolic rate, percent of predicted resting metabolic rate, resting metabolic rate per kilogram body weight, and resting metabolic rate per meter squared body surface area. Post hoc analyses were used to identify the effect of completeness of lesion, smoking, and pressure sores on percent of predicted resting metabolic rate and resting metabolic rate per kilogram body weight. RESULTS: Percent of predicted resting metabolic rate and resting metabolic rate per kilogram body weight were significantly higher in the PS-Para group than in the NPS-Para or control groups (115% +/- 4% vs 100% +/- 2% or 107% +/- 2%, p < .05) and (25.9 +/- 1.2 vs 21.4 +/- 0.6 or 22.5 +/- 0.4 kcal/kg, p < .05, respectively). The resting metabolic rate per meter squared body surface area was significantly higher in the PS-Para group than in NPS-Para group (973 +/- 39 vs 874 +/- 20kcal/m2, p < .05). In the PS-Para group, current smokers had significantly higher resting metabolic rate per kilogram body weight than nonsmokers (27.3 +/- 1.7 vs 24.0 +/- 1.4kcal/kg, p < .01). Controlling for the effects of smoking in a multiple regression model, those in the PS-Para group had significantly (p < .001) greater percent of predicted resting metabolic rate and resting metabolic rate per kilogram body weight than those in the NPS-Para group. CONCLUSIONS: These findings indicate that individuals with SCI may have a decreased percent of predicted resting metabolic rate and those with pressure sores may have a hypermetabolic state. This hypermetabolic state is significantly higher than that resulting from smoking. Because ordinary prediction equations for energy expenditure may not be accurate when applied to subjects with paraplegia and pressure sores, quantification of energy needs by indirect calorimetry is recommended.     

Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium

OBJECTIVE: To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. DATA SOURCES: Forty research teams contributed data on APOE genotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. MAIN OUTCOME MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed for APOE genotypes epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon4, and epsilon4/epsilon4 relative to the epsilon3/epsilon3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. RESULTS: Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes epsilon2/epsilon4 (OR=2.6, 95% CI=1.6-4.0), epsilon3/epsilon4 (OR=3.2, 95% CI=2.8-3.8), and epsilon4/epsilon4 (OR=14.9, 95% CI= 10.8-20.6); whereas, the ORs were decreased for people with genotypes epsilon2/epsilon2 (OR=0.6, 95% CI=0.2-2.0) and epsilon2/epsilon3 (OR=0.6, 95% CI=0.5-0.8). The APOE epsilon4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03). The APOE epsilon4-AD association in Japanese subjects was stronger than in Caucasian subjects (epsilon3/epsilon4: OR=5.6, 95% CI=3.9-8.0; epsilon4/epsilon4: OR=33.1, 95% CI=13.6-80.5). The epsilon2/epsilon3 genotype appears equally protective across ethnic groups. We also found that among Caucasians, APOE genotype distributions are similar in groups of patients with AD whose diagnoses were determined clinically or by autopsy. In addition, we found that the APOE epsilon4 effect is evident at all ages between 40 and 90 years but diminishes after age 70 years and that the risk of AD associated with a given genotype varies with sex. CONCLUSIONS: The APOE epsilon4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association between APOE epsilon4 and AD in African Americans requires clarification, and the attenuated effect of APOE epsilon4 in Hispanics should be investigated further.