Fabrication of multiple Bragg gratings in microstructured polymer fibers using a phase mask with several diffraction orders.

We demonstrate for the first time a possibility of fabrication of Bragg gratings in polymer microstructured fibers with multiple reflection peaks by using He-Cd laser (λ = 325 nm) and a phase mask with higher diffraction orders. We experimentally studied the growth dynamics of the grating with the primary Bragg peak at λ(B) = 1555 nm, for which we also observed good quality peaks located at λ(B)/2 = 782 nm and 2λ(B)/3 = 1040 nm. Temperature response of all the Bragg peaks was also investigated. Detailed numerical simulations of the interference pattern produced by the phase mask suggests that the higher order Bragg peaks originate from interference of UV beams diffracted in ± 1st, ± 2nd orders. We also demonstrated the grating with the reflection peak at λ(B)/2 = 659 nm, which is the shortest Bragg wavelength ever reported for polymer microstructured fibers. This peak was observed for the grating with primary Bragg wavelength at λ(B) = 1309 nm.

Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-alpha-amino acid competitive NMDA antagonists of the AP-6 type.

A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.

Design and models for estimating antagonist potency (pA2, Kd and IC50) following the detection of antagonism observed in the presence of intrinsic activity.

The antagonist activity of the metabotropic glutamate receptor ligand (2S,1'S,2'S)-2-methyl-2(carboxycyclopropyl)glycine (MCCG) was examined using the [35S]GTPgammaS binding and forskolin (FSK)-stimulated adenosine 3':5'-cyclic monophosphate (cAMP) assays with recombinant Chinese hamster ovary (CHO) cells expressing the G protein-coupled human subtype 2 metabotropic glutamate (hmGlu2) receptor. Whereas MCCG proved to be a partial agonist in the GTPgammaS binding assay, it not only antagonized the agonist effect of (IS,3R)-ACPD in the cAMP assay but further produced an anomalous increase of the cAMP level relative to baseline. The anomalous MCCG response was also observed following treatment of the cells with MCCG in the absence of added agonist. Determination of the glutamate concentration in the incubate at the start and end of the cAMP reaction revealed the existence of micromolar concentrations of cellularly released glutamate throughout the course of the assay, reaching levels which exceeded its reported affinity for the mGlu2 receptor. Considering MCCG's partial agonist effect in the GTPgammaS binding assay and its pseudo-inverse agonist effect in the cAMP assay, available methods of estimating its antagonist potency were inappropriate since the classical Schild method and the alternative model suggested by Waud both assume the antagonist to lack a concentration-response relationship. We derived an alternate design and models that permit estimation of the pA2 (pAx), Kd and IC50 for antagonists which produce a concentration related effect when applied by themselves. With their use, the data acquired in both assays support the designation of MCCG as a competitive antagonist of the hmGlu2 receptor and provide similar pA2 estimates between assays. In addition, the newly derived models and design permit the determination of antagonist potency for partial and inverse agonists so characterized in studies employing the Schild design.

A [35S]GTPgammaS binding assessment of metabotropic glutamate receptor standards in Chinese hamster ovary cell lines expressing the human metabotropic receptor subtypes 2 and 4.

The activities of metabotropic glutamate receptor (mGluR) standards were evaluated in the [35S]GTPgammaS binding assay and in the forskolin (FSK)-enhanced cyclic AMP assay using Chinese hamster ovary (CHO) cells or homogenates which expressed the human mGluR (hmGluR) subtypes 2 and 4. Though distinct rank orders of activities were determined for the agonists between the cell lines expressing individual hmGluRs, similar rank orders of agonist activities were determined for the standards between assays. O-phospho-L-serine (L-SOP) and (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4) antagonized agonist EC90 responses in the cell lines expressing the hmGluR 2 and 4 subtypes, respectively. In addition to its antagonist effect, L-SOP increased the baseline level of cAMP when tested in the absence of agonist. In spite of this anomalous effect, L-SOP was found to be a competitive antagonist in the cAMP assay as well as in the [35S]GTPgammaS binding assay with a pA2 value of 5.2 in both assays. MAP4 was a competitive antagonist of L(+)-2-amino-4-phosphonobutyric acid (L-AP4)-induced responses in the CHO cell line expressing hmGluR4 with pA2 values of 4.4 and 4.5 determined in the [35S]GTPgammaS binding and cAMP assays, respectively.

Design and synthesis of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-cyclobutene-1,2-dione as an achiral alpha-amino acid bioisostere.

The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice. A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57%. Structure-activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity. Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl group. Replacement of the phosphonic acid group by either a carboxylic acid or a tetrazole group was unproductive. The potent bicyclic NMDA antagonists were synthesized efficiently by virture of their achiral nature and the ease of vinylgous amide formation from squaric acid esters. Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Compound 15 is currently under clinical evaluation as a neuroprotective agent for stroke.

The major trauma management study: an analysis of the efficacy of current trauma care.

BACKGROUND: An audit of the management and outcome of major trauma patients was carried out to determine ways in which the system of care may be improved. METHODS: The Major Trauma Management Study (MTMS) collected data prospectively on all consecutively admitted major trauma patients at eight major hospitals during a 12-month period. Outcome was studied using trauma and injury severity score (TRISS) and a severity characterization of trauma (ASCOT) analyses, as well as a preventable outcome analysis, which looked at survivors with complications or with a Glasgow Coma Score < 15 on discharge from hospital, as well as studying deaths. RESULTS: The group of 859 patients was more severely injured than most described previously, with a mortality of 14.8% and a mean injury severity score of 19.8. Formal ASCOT analysis indicated 2.25% fewer survivors than would be predicted by Major Trauma Outcome Study norms. Extrapolating the TRISS and ASCOT process to include those patients with missing data, and then comparing groups of matched severity with the norms, gave no statistically different outcome in the MTMS group of patients. Preventable outcome analysis revealed rates of preventable and potentially preventable (P/PP) outcomes of 32% among deaths and 8% among survivors. The types of management deficiencies responsible for P/PP outcomes are identified. CONCLUSIONS: The points of deficiency in a system of care have been identified, and the development of an integrated trauma system in Victoria, based upon these facts, is recommended. Children, the elderly, patients with head injuries and patients being transferred between hospitals would benefit from improvements to the system of care. The calculation of efficacy rate (0.95 for the MTMS patients) is recommended to accurately assess the system of care. Preventable Outcome Analysis is more relevant to auditing a system of trauma care in detail, than is ASCOT or TRISS. The MTMS has refined and defined the process so that it is reproducible in further comparative studies.

Potent quinoxaline-spaced phosphono alpha-amino acids of the AP-6 type as competitive NMDA antagonists: synthesis and biological evaluation.

A series of alpha-amino-3-(phosphonoalkyl)-2-quinoxalinepropanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H] CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Some analogues also were evaluated in the [3H]-glycine binding assay. Several compounds of the AP-6 type show potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular alpha-amino-7-chloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (1) displayed an ED50 of 1.1 mg/kg ip in the NMDA lethality model. Noteworthy is alpha-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinoxalinepropanoic++ + acid (3) with a unique dual activity, displaying in the NMDA receptor binding assay an IC50 of 3.4 nM and in the glycine binding assay an IC50 of 0.61 microM.

Bioisosteric replacement of the alpha-amino carboxylic acid functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-1,2-dione containing NMDA antagonists.

In this report, a novel bioisostere of the alpha-amino acid, 3,4-diamino-3-cyclobutene-1,2-dione, has been incorporated into a series of compounds which are NMDA antagonists. These compounds, which are achiral and easily prepared, demonstrated good affinity at the NMDA receptor by their ability to displace [3H]CPP binding in vitro. In particular, the phosphonic acid 24 provided protection against NMDA-induced lethality in mice equivalent to 2-amino-7-phosphonoheptanoic acid (5). This was considered an encouraging result in lieu of the fact that 24, like 5, lacks the conformational rigidity of the more potent NMDA antagonists. In addition, analogs that incorporate the 1,2,4-oxadiazolidine-3,5-dione heterocycle of quisqualic acid and the unsaturation of kainic acid were prepared to explore selectivity at the non-NMDA receptor subtypes.

Acute glaucomas: diagnosis and treatment.

Acute angle-closure glaucoma is an uncommon disorder that must be diagnosed and managed quickly and effectively to prevent visual loss. Several conditions may appear as an acute angle-closure glaucoma and must be recognized since, in certain cases, treatment may be different from that required for an acute angle-closure attack. Once an acute angle-closure attack has been successfully managed through medical treatment, a laser iridotomy is indicated to prevent an attack from recurring.

The effect of conjugated equine estrogens on ovariectomy-induced osteopenia in the rat.

The effect of estrogen replacement on ovariectomy-induced bone loss was evaluated in mature Sprague-Dawley rats. Undecalcified tibia of ovariectomized rats were processed for quantitative histologic assessment of cancellous bone in longitudinal sections from the primary and secondary spongiosa of the proximal metaphysis. Bone content in tissue specimens was quantified as the parameter B. Ar, two-dimensional bone mineral area. Estrogen, supplied as orally administered conjugated equine estrogens, prevented bone loss through 6 weeks of treatment. The effect of conjugated equine estrogens was dose-dependent, with significant protection against bone loss observed at doses of 10 micrograms/kg/day and higher.

A glaucoma control chart.

A control sheet is presented to aid in the long-term management of the patient with glaucoma. It provides a means to easily assess the current and past management status as well as to review 21 consecutive visits with examination data on one form.

The effect of two years' training on aerobic power and muscle strength in male and female cadets.

During their first 2 years of training at the U.S. Military Academy, 11 male and 7 female cadets were studied on five occasions. VO2 max (1/min), lean body mass and body weight increased significantly in both groups. Percent body fat was significantly reduced only after the first summer of training and then returned to initial values. VO2 max (ml/kg.min) did not change in males during the study. However, females increased significantly after the initial 6 weeks of training (44.2 to 48.8 ml/kg.min). They remained at this level through the second summer of training. However, by the end of their second academic year, females' values dropped to 45.9 ml/kg.min. Maximal isometric strength measured 30-40% higher in males than in females. During the last year of training, arm and shoulder strength increased 10.2% in males, but was unchanged in females. Our results suggest that even extended military training did not enable females to significantly narrow the difference with male cadets in muscle strength and aerobic power.

The influence of U.S. Army Basic Initial Entry Training on the muscular strength of men and women.

The influence of U.S. Army Basic Initial Entry Training on the maximum voluntary isometric strength (MVIS) and anthropometric parameters of men and women was investigated. Significant increases in weight and lean body mass (LBM) and decreases in percent body fat were found for both sexes during training. Significant increases in the MVIS of the upper torso (UT), leg extensors (LE), and trunk extensors (TE) were also found for both sexes. Females and males improved about the same amount on the LE (12.4% and 9.7%, respectively) but females improved significantly more than males on the UT (9.3% and 4.2%, respectively) and TE (15.9% and 8.1%, respectively). The greater gains in the females were presumably due to their lower initial strength levels and the consequently greater relative training stimulus. When strength was expressed relative to LBM, both sexes were able to exert similar amounts of strength on the LE and TE, suggesting that differences in strength between the sexes may primarily be a function of muscle mass.