Work-related traumatic spinal cord lesions in Chile, a 20-year epidemiological analysis.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To describe the characteristics of patients with work-related traumatic spinal cord injuries (TSCI) in Chile. SETTING: Hospital del Trabajador in Santiago, Santiago, Chile. METHODS: Patients suffering from TSCI incurred at the workplace from 1986 to 2005 were identified through records of the Asociación Chilena de Seguridad (ACHS, Chilean Safety Association). RESULTS: The medical records of 173 patients, 172 men and 1 woman, were analyzed. The yearly average incidence was 7.8 per million workers. Age at TSCI onset was 38.2 ± 12.1 years. The principal external causes for TSCI incurred at the workplace were falls from a height in 86 cases (49.7%) and trauma blows to the vertebral spine in 61 cases (35.3 %). More falls occurred in the field construction, and other traumas occurred as a result of traumatic blows caused by tree trunks and stones in forestry and mining sectors. Mortality in this series was 8.7%, and the worst prognosis was for older patients with complete tetraplegia. The paraplegia:tetraplegia ratio was 3.2:1. CONCLUSIONS: The characteristics of workplace TSCI are specific to this population. It is important therefore to develop prevention programs for specific work-related TSCI.

A synthetic library of cell-permeable molecules.

Small molecules that induce or stabilize the association of macromolecules have proven to be useful effectors of a wide variety of biological processes. To date, all examples of such chemical inducers of dimerization have involved known ligands to well-characterized proteins. The generality of this approach could be broadened by enabling the discovery of heterodimerizers that target known macromolecules having no established ligand, or heterodimerizers that produce a novel biologic response in screens having no predetermined macromolecular target. Toward this end, we report the construction of a diversified library of synthetic heterodimerizers consisting of an invariant ligand that targets the FK506-binding protein (AP1867) attached to 320 substituted tetrahydrooxazepines (THOXs). The THOX components were generated by a combination of liquid- and solid-phase procedures employing sequential Mitsonobu displacements to join two structurally diversified olefin-containing monomers, followed by ruthenium-mediated olefin metathesis to effect closure of the seven-membered ring. The 320 resin-bound THOX ligands were coupled in parallel to AP1867, and the products were released from the resin to yield candidate heterodimerizers in sufficient yield and purity to be used directly in biologic testing. A representative panel of 25 candidate heterodimerizers were tested for their ability to pass through the membrane of human fibrosarcoma cells, and all were found to possess activity in this tissue culture system. These studies pave the way for further studies aimed at using small-molecule inducers of heterodimerization to effect novel biological responses in intact cells.

Synthesis and structure-activity relationships of 2-pyrazinylcarboxamidobenzoates and beta-ionylideneacetamidobenzoates with retinoidal activity.

The structure-activity relationships of two series of novel retinoids (2-pyrazinylcarboxamidobenzoates and beta-ionylideneacetamidobenzoates) have been investigated by evaluating their ability to induce differentiation in both human promyelocytic leukemia (HL60) cells and mouse embryonal carcinoma (P19) cells. The most active compound (ED50 = 8.3 x 10(-9) M) of the 2-pyrazinylcarboxamidobenzoates is 4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethylquinoxalyl)carboxamido]benzoic acid (9u), while the most active analogue of the beta-ionylideneacetamidobenzoates is 4-[3-methyl-5-(2',6',6'-trimethyl-1'-cyclohexen-1'-yl)-(2E, 4E)-pentadienamido]benzoic acid (10a, ED50 = 3.2 x 10(-8) M). Our studies identify an absolute requirement for the carboxylic acid moiety on the aromatic ring to be para relative to the amide linkage for activity. Benzoate substitutions in the ortho position relative to the terminal carboxylate (9d,k,r) are well-tolerated; however, a methoxy substituent meta relative to the terminal carboxylate gives rise to only weakly active analogues (9x). Conformational studies (NMR, X-ray crystallography) of the 2-pyrazinylcarboxamidobenzoates indicate that the preferred conformation exhibits a trans-amide bond and an internal hydrogen bond between the quinoxaline N1 and HN amide which locks the torsional angle between C2 and CO in the s-trans conformation. N-Methylation (9y) results in loss of activity. Studies indicate that there is now a cis-amide bond present which redirects the carboxylate toward the pharmacophoric gem-dimethyl groups. The distance between the gem-dimethyl group and the terminal carboxylate appears to be too short to activate the retinoid receptor. N-Methylation in the beta-ionylideneacetamidobenzoate series (10c) also results in the formation of a cis-amide bond and loss of activity.