A large-scale clinical field study to evaluate the efficacy and safety of an oral formulation of the amino-acetonitrile derivative ( AAD ), monepantel , in sheep in New Zealand.

AIM: To evaluate the efficacy and safety of an oral formulation of the novel anthelmintic, monepantel (AAD 1566), in sheep, in comparison with some other anthelmintics currently registered in New Zealand. METHODS: A study was conducted on 18 farms located throughout the North and South Islands of New Zealand. On each farm, sheep naturally infected with the target nematodes were randomly assigned to groups, which were then treated with either monepantel, at a minimum dose rate of 2.5 mg/kg, or one of five other anthelmintics encompassing the range of single-entity and combination formulations that are commercially available in New Zealand, or left untreated as controls. Faecal samples were collected from all sheep pre-treatment (1-3 weeks before treatment), at the time of treatment, and approximately 1, 2 and 3 weeks after treatment (Days 7, 14 and 21). Faecal nematode egg counts (FEC) were measured in all samples, and the efficacy of treatments, as indicated by reductions in FEC, calculated. All sheep were inspected at least daily, to check for any adverse effects of treatment. RESULTS: On all 18 farms, on Days 7, 14 and 21 (54 test points), the efficacy of the monepantel solution was >95%. At Days 7 and 14 post-treatment, efficacies>99% were recorded in 15 flocks. At Day 21 post-treatment, efficacies>98% were recorded in 13 flocks. Monepantel was as effective, or more effective, than the registered anthelmintics with which it was compared. Moreover, it was effective against strains of nematodes resistant to one or more of the currently available broad-spectrum anthelmintics. The monepantel solution used in this study was well tolerated by the sheep, and no adverse events could be attributed to its use. CONCLUSIONS AND CLINICAL RELEVANCE: When administered as an oral formulation under field conditions, at a minimum dose rate of 2.5 mg/kg, monepantel appeared to be highly effective against all the major genera of gastrointestinal nematodes of sheep, including Haemonchus, Teladorsagia (=Ostertagia), Trichostrongylus, Cooperia, Nematodirus, Chabertia and Oesophagostomum. This included strains resistant to the currently available broad-spectrum anthelmintics. Monepantel is the first compound from the recently discovered amino-acetonitrile derivative (AAD) class of anthelmintics to be developed for use in sheep.

Single-site beta-diiminate zinc catalysts for the alternating copolymerization of CO2 and epoxides: catalyst synthesis and unprecedented polymerization activity.

Synthetic routes to zinc beta-diiminate complexes are reported. The synthesis of 11 beta-diimine [(BDI)-H] ligands, with varying N-aryl substituents and bridging structures, is described. These ligands are converted to (BDI)ZnX complexes (X = OAc, Et, N(SiMe3)2, Br, Cl, OH, OMe, O(i)Pr). X-ray structural data revealed that all zinc complexes examined exist as micro-X-bridged dimers in the solid state, with the exception of the zinc ethyl and amido complexes which were monomeric. Complexes of the form (BDI)ZnOR (R = alkyl, acyl) and (BDI)ZnN(SiMe3)2 are highly active catalysts for the alternating copolymerization of epoxides and CO2. Copolymerizations of cyclohexene oxide (CHO) and CO2 with (BDI-1)ZnX [(BDI-1) = 2-((2,6-diisopropylphenyl)amido)-4-((2,6-diisopropylphenyl)imino)-2-pentene)] and (BDI-2)ZnX [(BDI-2) = 2-((2,6-diethylphenyl)amido)-4-((2,6-diethylphenyl)imino)-2-pentene)], where X = OAc, Et, N(SiMe3)2, Br, Cl, OH, OMe, O(i)Pr, were attempted at 50 degrees C and 100 psi CO2. Complexes with X = OAc, N(SiMe3)2, OMe, O(i)Pr all produced polycarbonate by the alternated insertion of CHO and CO2 with similar catalytic activities, comparable molecular weights, and narrow molecular weight distributions (MWD approximately 1.1), indicating the copolymerizations are living. Furthermore, ligand effects were shown to dramatically influence the polymerization activity as minor steric changes accelerated or terminated the polymerization activity.

Polymerization of lactide with zinc and magnesium beta-diiminate complexes: stereocontrol and mechanism.

A series of zinc(II) and magnesium(II) alkoxides based upon a beta-diiminate ligand framework has been prepared. [(BDI-1)ZnO(i)Pr](2) [(BDI-1) = 2-((2,6-diisopropylphenyl)amido)-4-((2,6-diisopropylphenyl)imino)-2-pentene] exhibited the highest activity and stereoselectivity of the zinc complexes studied for the polymerization of rac- and meso-lactide to poly(lactic acid) (PLA). [(BDI-1)ZnO(i)()Pr](2) polymerized (S,S)-lactide to isotactic PLA without epimerization of the monomer, rac-lactide to heterotactic PLA (P(r) = 0.94 at 0 degrees C), and meso-lactide to syndiotactic PLA (P(r) = 0.76 at 0 degrees C). The polymerizations are living, as evidenced by the narrow polydispersities of the isolated polymers in addition to the linear nature of number average molecular weight versus conversion plots and monomer-to-catalyst ratios. The substituents on the beta-diiminate ligand exert a significant influence upon the course of the polymerizations, affecting both the degree of stereoselectivity and the rate of polymerization. Kinetic studies with [(BDI-1)ZnO(i)Pr](2) indicate that the polymerizations are first order with respect to monomer (rac-lactide) and 1.56 order in catalyst. Polymerization experiments with [(BDI-1)MgO(i)Pr](2) revealed that this complex is extremely fast for the polymerization of rac-lactide, polymerizing 500 equiv in 96% yield in less than 5 min at 20 degrees C.

Magnetic resonance imaging assessment of the rotator cuff: is it really accurate?

Magnetic resonance imaging (MRI) is used increasingly for evaluating the rotator cuff. This study of 39 shoulders (38 patients) compared the accuracy of MRI interpretation of rotator cuff integrity by a group of community hospital radiologists (clinical community scenario, CCS) with that of a musculoskeletal radiologist (experienced specialist scenario, ESS), relative to arthroscopy. For the CCS subgroup, the sensitivity, specificity, positive predictive value (PV), negative PV, and accuracy for partial tears were: 0%, 68%, 0%, 82%, and 59%, respectively; for complete tears: 56%, 73%, 36%, 86%, and 69%, respectively; and for all tears combined: 85%, 52%, 50%, 87%, and 64%, respectively. For the ESS subgroup, the respective values for partial tears were: 20%, 88%, 20%, 88%, and 79%, respectively; for complete tears: 78%, 83%, 58%, 92%, and 82%, respectively; and for all tears: 71%, 71%, 59%, 81%, and 71%, respectively. We concluded that MRI assessment of the rotator cuff was not accurate relative to arthroscopy. MRI was most helpful if the result was negative, and MRI diagnosis of partial tear was of little value. Considering the high cost of shoulder MRI, this study has significant implications for the evaluation of patients with possible rotator cuff pathology.

Acute effect of altered tryptophan levels and alcohol on aggression in normal human males.

Normal males received amino acid mixtures designed to raise or lower tryptophan availability, and thus to raise or lower brain serotonin synthesis. They also received alcoholic or non-alcoholic drinks. The subjects were tested in the Taylor Competitive Reaction Time Task in which they competed against a (non-existent) partner in a reaction time task. The magnitude of electric shocks that the subjects were willing to give to their bogus partner was used as a measure of aggression. Lowered tryptophan levels and ingestion of alcohol were associated with increased aggression. Our data support the idea that low serotonin levels may be involved in the etiology of aggression. They suggest that subjects with low brain serotonin levels may be particularly susceptible to alcohol-induced violence.

Total porphyrin and coproporphyrin and uroporphyrin fractions in urine measured by second-derivative spectroscopy.

A second-derivative scan of an acidified urine sample allows the amplitude of deflection (delta A) and the minimum wavelength of the trough (lambda min) to determine the correct porphyrin concentration and the coproporphyrin:uroporphyrin (copro:uro) ratio, respectively, from a nomogram constructed from calibrator solutions. We measured 24 urine samples for total porphyrin as coproporphyrin equivalents and adjusted the results with factors from the nomogram. The adjusted results (x) (mean +/- SE, 501 +/- 57 nmol/L) compared favorably with the expected results (y) (514 +/- 57). The regression equation and correlation coefficient were: y = 0.993x - 8.9 (r = 0.998, S(y/x) = 16.2). Results of the copro:uro ratio derived by second-derivative spectroscopy and HPLC showed no significant difference (chi 2-test) from samples with various copro:uro ratios. Recovery studies on four urine samples supplemented with known proportions of coproporphyrins and uroporphyrins gave good agreement between the measured and the expected porphyrin ratios. The overall imprecision (CV) of the assay ranged from 3.6% to 6.0% for coproporphyrin and from 3.2% to 9.1% for uroporphyrin.

Subperiosteal osteoid osteoma of the hamate: a case report.

Osteoid osteoma is uncommon in the hand. The lesion can arise from either cortical or cancellous bone or subperiosteally. The latter localization is extremely rare in the hand, with only 4 reported cases in the English-language literature. Furthermore, characteristic radiographic findings of a central lucency surrounded by reactive sclerosis often emerge only late in the process, or not at all. Consequently, the diagnosis of osteoid osteoma of the hand can be delayed. We report a case of a subperiosteal osteoid osteoma of the hamate in which the diagnosis was delayed 2 years.

A sensitive method of screening for urinary porphobilinogen.

In this screening method for urinary porphobilinogen (PBG), urine is added to Dowex 2 resin under alkaline conditions in a test tube and mixed. The supernate is removed and the adsorbed PBG is eluted with acid and reacted with Ehrlich's reagent. We compared results with those by the Watson-Schwartz screening method, using urine samples from normal people with and without added PBG. At a PBG concentration of about five times the upper limit of normal, the resin method gave a sensitivity of 100%; the Watson-Schwartz method gave a sensitivity of 51%. At lower PBG concentrations of just over and twice the upper limit of normal, the sensitivity by the resin method was respectively 97% and 100%. With normal urine samples, the resin method gave negative results for all samples (100% specificity) and the Watson-Schwartz had 95% specificity. Our data indicate that the resin method is sensitive, specific, and reliable and is superior to the Watson-Schwartz method.

Relationship between corticosteroid exposure and plasma lipid levels in heart transplant recipients.

PURPOSE: Accelerated coronary atherosclerosis is a major cause of heart graft failure two years and more after heart transplantation, yet its etiology remains undetermined. We conducted this study to determine the prevalence of coronary risk-associated lipid abnormalities, and the relationship between lipid levels and exposure to corticosteroids and cyclosporine, in heart transplant recipients. PATIENTS AND METHODS: The records of 92 consecutive heart transplant recipients from three different transplantation centers were reviewed. Patients from the three centers varied in age, in corticosteroid regimens, and in the proportion undergoing transplantation for ischemic cardiomyopathy. Although 11 patients were not receiving corticosteroids at the time of the study, all patients had received them immediately after transplantation. In addition to information pertaining to demographics, pretransplant medical history, rejection episodes, drug doses, renal function, and blood glucose levels, data on dietary intake and body weight were collected and plasma lipid levels were measured at the time of record review. RESULTS: A significant number, 48 (52 percent), of heart transplant recipients were above the sex- and age-adjusted 75th percentile, and 35 (38 percent) were above the 90th percentile for total cholesterol in comparison with a general reference population. Similar elevations were found in low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol levels. Bivariate analysis demonstrated cumulative prednisone exposure (r = 0.40, p = 0.0001) and cumulative cyclosporine exposure (r = 0.22, p = 0.04) but not diet or etiology of pretransplant heart disease to be significantly associated with age- or sex-adjusted total cholesterol percentiles. Low-density lipoprotein cholesterol percentiles were also correlated with cumulative prednisone (r = 0.37, p = 0.001) and cumulative cyclosporine exposure (r = 0.24, p = 0.02). Stepwise multiple linear regression analysis, however, demonstrated cumulative prednisone exposure to be the strongest predictor of both total and low-density lipoprotein cholesterol levels and percentiles (p = 0.0001), independent of cumulative cyclosporine exposure and other clinical variables. CONCLUSION: These data suggest that long-term corticosteroid exposure may result in an increased prevalence of unfavorable lipid profiles in heart transplant recipients.

A simple enzymatic method for the measurement of abnormal levels of formate in plasma.

A simple and practical method designed to measure abnormal concentrations of plasma formate is described. The method uses formate dehydrogenase and a color reagent to produce a stable formazan color. The method requires no deproteinization and has a one-point standard calibration. The precision at 1.0 and 5.0 mmol/L formate is 2.9% and 1.7% within-day and 5.5% and 2.3% between-day. Recovery averages 100% for formate concentrations of 2.0 to 10.0 mmol/L. The proposed method is inexpensive, robust, and suitable for routine use and shares the color reagent used for the assay of plasma lactate and 3-hydroxybutyrate, both important analytes in metabolic acidosis.

Binding of fluorescent phosphatidylcholine in amniotic fluid.

Fetal lung maturity can be predicted by the technique of fluorescence polarization using fluorescent phosphatidylcholine instead of diphenylhexatriene. To further elucidate the mechanism of this assay, we used high-speed centrifugation to isolate amniotic fluid lamellar bodies. Each of 75 amniotic fluid samples was separated into two fractions: a lamellar body pellet and a lamellar body-free supernatant fluid. Amniotic fluid and these fractions were assessed in a fluorescence polarization assay using a fluorescent phosphatidylcholine. Regardless of the maturity of the fetal lung, the lamellar body fractions had low polarization values (0.127-0.216), whereas the lamellar body-free fractions had high polarization values (0.266-0.344). Compared with the polarization of amniotic fluid, the fluorescence intensity of the lamellar body fractions had a strong inverse correlation (r = -0.871). The polarization of lamellar body pellets was not linearly related to the polarization of amniotic fluids. These findings do not support the theory that this fluorescence polarization assay measures the microviscosity of surfactant lipids. Instead, we propose that this assay indicates the quantity of surfactant relative to the quantity of nonsurfactant receptors of fluorescent phosphatidylcholine in amniotic fluid.