Assessing the accuracy and reliability of direct height measurement for use in adult neurological patients with contractures: a comparison with height from ulna length.

BACKGROUND: It is not possible to measure the height of a patient with contractures in the normal way. On occasions, health professionals need to measure the height directly of patients with contractures because: (i) the patient is unable to report his/her height as a result of a lack of mental capacity and (ii) there is no-one available to report the height or the reported height is obviously inaccurate. Height derived from ulna length is an option but, in some individuals, it can be conspicuously inaccurate. Therefore, we have attempted to develop and validate a simple bedside method using a tape measure. METHODS: Twenty-four normal healthy adult volunteers were recruited into the study. They were positioned on a hospital bed in three different standardised positions simulating patients with typical contractures. They were measured in each position by four measurers using blanked out tape measures. The participants were then measured standing giving a 'true' height. Ulna length was also measured. RESULTS: The mean of the tape-measured heights was 2.3 cm taller than the 'true' height (95% confidence interval = 4.6-9.3). The measurement in all three positions gave an over-estimate of the height, whereas the ulna-derived height gave an under-estimate (2.2 cm). The estimated reliability between measurers (intraclass correlation coefficient) was 0.94 with a 95% confidence interval (0.91-0.96). CONCLUSIONS: This new method is giving an acceptable estimate of the height of contracted patients with a good inter-rater reliability. It comprises a useful additional tool for measuring the height of people with contractures.

Synthesis and SAR of new 5-phenyl-3-ureido-1,5-benzodiazepines as cholecystokinin-B receptor antagonists.

A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition of substituents at the urea side chain provided in some cases more potent compounds. Moreover the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the racemic ureas resulted in our lead compound GV150013.

Lead in umbilical blood, indoor air, tap water, and gasoline in Boston.

A strong statistical correlation was found among the monthly averages of lead concentrations in umbilical cord blood (about 500 births/month), indoor air (12 sites/month), and gasoline lead sales between March, 1980 and April, 1981 in Boston. Tap water lead (24/month) variations did not correlate with blood lead in this population.

Cadmium content of umbilical cord blood.

Cadmium was measured in the umbilical cord blood at birth from 94 healthy babies. Samples were dried and ashed at low temperatures with an oxygen plasma prior to atomic absorption spectrometry. The concentration of cadmium ranged from 0.003 to 0.210 microgram/dl, with a mean of 0.045 +/- 0.063 (SD). Blood lead, maternal smoking, and proximity of residence to automobile traffic were not statistically related to cadmium levels.

A single physician's experience with four thousand six hundred genetic amniocenteses.

OBJECTIVE: We sought to assess changes in indications, technique, successful fluid aspiration, and pregnancy outcomes in a large cohort of genetic amniocenteses performed by a single physician. STUDY DESIGN: Records were reviewed regarding 4600 women who underwent genetic amniocentesis by a single physician between 1972 and 2000. Changes in indications, procedural technique, ease of performance, amniotic fluid reports, and pregnancy loss rates were tabulated and compared over time. RESULTS: The indications for amniocentesis changed significantly (P < .0001) over time with the increasing use of maternal serum screening studies and fetal assessment by ultrasonography. The ease with which clear amniotic fluid was aspirated increased with experience, improvements in ultrasound technology, and modifications of amniocentesis technique. Procedure-related total pregnancy loss rate was 0.95%, and loss rate within 60 days of the procedure was 0.55%. Increasing operator experience did not improve the pregnancy loss rate significantly. CONCLUSIONS: Successful aspiration of clear amniotic fluid increases with amniocentesis experience. Pregnancy outcome did not change significantly with increasing amniocentesis experience.

Penetration of penicillin into human phagocytes containing Neisseria gonorrhoeae: intracellular survival and growth at optimum concentrations of antibiotic.

Phagocytes obtained from fresh human buffy coat (predominantly polymorphonuclear phagocytes) or from human buffy coat which had been incubated on a glass surface for 1 to 3 days (predominantly mononuclear phagocytes) were allowed to ingest gonococci, and then incubated with penicillin. More intracellular gonococci were killed at high than at low penicillin concentrations, indicating that penicillin penetrated the phagocytes. This was supported by autoradiography experiments with radiolabelled penicillin. A pilated, small-colony-forming gonococcal strain survived and multiplied for at least 15 h in polymorphonuclear phagocytes which were incubated with penicillin at the optimum concentration for killing the extracellular bacteria but not the intracellular ones; whereas a non-pilated, large-colony-forming strain survived for only 10 h. The former strain survived for at least 6 h in similar experiments with mononuclear phagocytes. Intracellular survival and in growth may be an important facet of the pathogenicity of gonococci.

Axoplasmic asymmetry at the node of Ranvier.

The previously described unilateral condensation of axoplasmic organelles at the node of Ranvier of large diameter fibres in spinal nerve roots has been confirmed in a single normal rabbit. The tendency for this phenomenon to occur on the proximal (neuronal) side of the node, as implied in previous studies, could not be supported by numerical analysis which failed to show statistical significance for any one distribution pattern. This absence of polarization may be related to the existence of both anterograde and retrograde traffic in large diameter fibres.

Resistance of Neisseria gonorrhoeae grown in vivo to ingestion and digestion by phagocytes of human blood.

Attempts to study quantitatively the phagocytosis of gonococci from urethral pus failed because of the small numbers of organisms and technical difficulties. However, gonococci from chambers implanted subcutaneously in guinea pigs, which were similar to gonococci from urethral pus in their resistance to killing by human serum, were obtained in sufficient quantities for comparison in phagocytosis tests with the in vitro grown strains from which they were derived. Microscopic and viable counts of gonococci in phagocytes showed that in vivo grown organisms (strain BSV) were readily phagocytosed by human polymorphonuclear phagocytes. There was little difference betweee to ingestion. There was, however, a marked difference in the intracellular survival of strains BSV and BS during the first hour of phagocytosis. Whereas BSV organisms survived well, many BS organisms were killed. Subsequently, strain BSV and the survivors of the strain BS inoculum responded similarly to the intracellular bactericidins. These results were supported by electron microscopy of infected phagocytes. Resistance of gonococci in vivo to ingestion and digestion by human phagocytes seem to be important facets of the pathogenesis of gonorrhoea.

Actual vs perceived EMS response time.

OBJECTIVE: To compare patients' perceptions of ambulance response times with the actual ambulance response times to aid quality assurance efforts in EMS management. METHODS: A convenience sample of patients presenting to an urban ED via EMS were asked a series of four questions pertaining to response time, scene time, time to definitive care, and their expectations of response time. These times were then compared with actual times from the EMS dispatch center. Times were analyzed using multivariate analysis of variance (MANOVA) followed by discriminant analysis. RESULTS: There was a significant difference between the perceived and actual times for all three questions, by both multivariate analysis and univariate analysis (p < 0.0001). Patients tended to overestimate the actual response times (12.4 min vs 9.1 min) but underestimate the on-scene times (9.1 min vs 12.4 min) and times to definitive care (29.4 min vs 35.0 min). CONCLUSION: Patients are inaccurate in their estimations of time. Response times are generally overestimated, while scene times and times to definitive care are underestimated. Actual response times often meet patients' expectations (mean 10.8 min), although the patients may not perceive that they have.

Elimination kinetics of blood lead in workers with chronic lead intoxication.

Blood lead elimination half-lives were determined for 65 patients with occupational chronic lead intoxication who were removed from exposure, treated with intravenous EDTA, and followed for periods of up to 2,419 days. The median overall blood lead elimination half-life was 619 days in patients with normal renal function and 1,907 days in patients with renal impairment. Slow-phase elimination half-lives in patients followed for longer than 5 years ranged from 1,658 to 7,189 days. Blood lead concentrations declined during periods of chelation with a mean half-life of 7 days and rebounded to near prechelation concentrations following termination of chelation with a mean doubling time of 27 days. The overall blood lead elimination half-life was positively associated with length of follow-up (p less than 0.001), age (p = 0.04), and duration of exposure (p = 0.02), but was not associated with the initial blood lead concentration following cessation of exposure or the total amount of EDTA received.

Synthetic [5,5] trans-fused indane lactones as inhibitors of thrombin.

Synthesis of trans-fused lactones containing the indane nucleus has resulted in a series of potent acylating inhibitors of thrombin. As an example compound 11e has an apparent second order rate constant of 11 x 10(6) M(-1)sec(-1) for the inhibition of thrombin. The anticoagulant activity of these compounds is discussed.

Novel natural product 5,5-trans-lactone inhibitors of human alpha-thrombin: mechanism of action and structural studies.

High-throughput screening of methanolic extracts from the leaves of the plant Lantana camara identified potent inhibitors of human alpha-thrombin, which were shown to be 5,5-trans-fused cyclic lactone euphane triterpenes [O'Neill et al. (1998) J. Nat. Prod. (submitted for publication)]. Proflavin displacement studies showed the inhibitors to bind at the active site of alpha-thrombin and alpha-chymotrypsin. Kinetic analysis of alpha-thrombin showed tight-binding reversible competitive inhibition by both compounds, named GR133487 and GR133686, with respective kon values at pH 8.4 of 1.7 x 10(6) s-1 M-1 and 4.6 x 10(6) s-1 M-1. Electrospray ionization mass spectrometry of thrombin/inhibitor complexes showed the tight-bound species to be covalently attached, suggesting acyl-enzyme formation by reaction of the active-site Ser195 with the trans-lactone carbonyl. X-ray crystal structures of alpha-thrombin/GR133686 (3.0 A resolution) and alpha-thrombin/GR133487 (2.2 A resolution) complexes showed continuous electron density between Ser195 and the ring-opened lactone carbonyl, demonstrating acyl-enzyme formation. Turnover of inhibitor by alpha-thrombin was negligible and mass spectrometry of isolated complexes showed that reversal of inhibition occurs by reformation of the trans-lactone from the acyl-enzyme. The catalytic triad appears undisrupted and the inhibitor carbonyl occupies the oxyanion hole, suggesting the observed lack of turnover is due to exclusion of water for deacylation. The acyl-enzyme inhibitor hydroxyl is properly positioned for nucleophilic attack on the ester carbonyl and therefore relactonization; furthermore, the higher resolution structure of alpha-thrombin/GR133487 shows this hydroxyl to be effectively superimposable with the recently proposed deacylating water for peptide substrate hydrolysis [Wilmouth, R. C., et al. (1997) Nat. Struct.Biol. 4, 456-462], suggesting the alpha-thrombin/GR133487 complex may be a good model for this reaction.

5,5-trans lactone-containing inhibitors of serine proteases: identification of a novel, acylating thrombin inhibitor.

Synthesis of a variety of 5,5-trans fused lactones, related to compounds found in extracts of Lantana camara, has provided a series of novel acylating inhibitors of human thrombin, trypsin, chymotrypsin and human leucocyte elastase. The most effective thrombin inhibitor is 7 with an IC50 of 130 nM and a Kobs/[1] of 4,000 M-1 s-1.

Intracellular inhibition of human neutrophil elastase by orally active pyrrolidine-trans-lactams.

Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.

The discovery of a potent, intracellular, orally bioavailable, long duration inhibitor of human neutrophil elastase--GW311616A a development candidate.

The discovery of a potent intracellular inhibitor of human neutrophil elastase which is orally active and has a long duration of action is described. The pharmacodynamic and pharmacokinetic properties of a trans-lactam development candidate, GW311616A, are described.

Thrombin inhibitors based on [5,5] trans-fused indane lactams.

A series of trans-fused lactams containing the indane nucleus has been prepared. Compound 19 has much enhanced plasma stability compared with its lactone counterpart and shows appreciable in vitro anticoagulant activity.