A noncompetitive peptide inhibitor of the nicotinic acetylcholine receptor from Conus purpurascens venom

A paralytic peptide, psi-conotoxin Piiie has been purified and characterized from Conus purpurascens venom. Electrophysiological studies indicate that the peptide inhibits the nicotinic acetylcholine receptor (nAChR). However, the peptide does not block the binding of alpha-bungarotoxin, a competitive nAChR antagonist. Thus, psi-conotoxin Piiie appears to inhibit the receptor at a site other than the acetylcholine-binding site. As ascertained by sequence analysis, mass spectrometry, and chemical synthesis, the peptide has the following covalent structure: HOOCCLYGKCRRYOGCSSASCCQR* (O = 4-trans hydroxyproline; * indicates an amidated C-terminus). The disulfide connectivity of the toxin is unrelated to the alpha- or the alphaA-conotoxins, the Conus peptide families that are competitive inhibitors of the nAChR, but shows homology to the mu-conotoxins (which are Na+ channel blockers).     

Long-term follow-up of a randomized post-induction therapy trial in acute myelogenous leukemia (a Southeastern Cancer Study Group trial)

A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.     

Alpha 2 mRNA of Na+K+ ATPase is increased in astroctyes of rat hippocampus after treatment with kainic acid

The Na+K+ ATPase (Na+ pump) plays a central role in regulating cation homeostasis and is thought to have an important role in cell proliferation. The multitude of subunit isoforms comprising the functional Na+K+ ATPase has raised the possibility that specific subunit isoform combinations may be involved in different cellular processes. We have investigated the involvement of the specific isoforms in neurons and glia at the site of a CNS lesion. Intracerebroventricular injection of kainic acid was used to induce neuronal cell loss and reactive gliosis in rat hippocampus and levels of Na+K+ ATPase subunit isoform mRNA levels were determined in cells of rat hippocampus using in situ hybridization. alpha 2 mRNA levels increased 35-40% in CA1 and CA3 astrocytes between 1-3 weeks after KA injection with no significant change in other subunit isoform mRNA levels. In addition alpha 3 mRNA levels in CA1 pyramidal neurons were decreased by approx. 35%. Small neurons in the CA1 and CA3 region showed no changes in mRNA levels for any of the Na+K+ ATPase subunit isoforms. These results may indicate a possible role for alpha 2 subunit isoform in the conversion of glial cells from a normal phenotype to the reactive phenotype characteristic in this model of CNS injury.     

Longitudinal bone mineral density changes in early rheumatoid arthritis

A prospective longitudinal study of patients with early RA was performed to examine the influence of disease duration, disease activity and physical activity on bone loss. Sixty-seven patients with non-steroid treated RA of less than 5 yr duration, including 16 patients with disease duration less than 6 months, had BMD measurements of the femoral neck and the lumbar spine over a 12-month period using dual energy X-ray absorptiometry. The BMD changes were compared with values from 72 control patients and were also correlated with serial measurements of disease activity (measured by the Stoke Index) and disability [measured by the Health Assessment Questionnaire (HAQ) score], at 3-monthly intervals over the 12-month period. No significant differences in BMD changes were found between RA patients and controls overall. Patients with disease duration of less than 6 months had significantly greater loss of BMD at the femoral neck (-3.9%, S.E.M. 1.5) than the remainder of the cohort (-0.2%, S.E.M. 0.7) (P = 0.02) and controls (-0.8%, S.E.M. 0.6). Lumbar spine BMD changes correlated with the initial Stoke Index (Rs-0.373, P = 0.01) but not mean Stoke Indices. There was no correlation of BMD changes with age or HAQ scores. These findings suggest that significant bone loss occurs within the first few months of disease in patients with RA.     

A little less sodium is not without hazard

Surgical thrombectomy is not a rational approach to neonatal renal vein thrombosis since the occlusion mainly involves intrarenal branches rather than the main renal vein, which is even patent in some instances. Conservative management combines supportive therapy for renal failure and systemic hypertension, if needed, and either heparin or thrombolytic agents. Streptokinase has proven difficult to handle in neonates and should not be used. Urokinase has been used in 18 patients but results are difficult to interpret because these cases occurred over an 18-year period. Plasminogen tissue activator, the latest thrombolytic agent developed, has been used in few pediatric patients. An international task force is currently studying whether or not a randomized study is warranted to provide data for standardizing thrombolytic therapy in pediatric renal vein thrombosis.     

Coronary arteries: retrospective cardiac gating technique to reduce cardiac motion artifact at spiral CT

Coronary artery calcification is a marker of atherosclerosis. Detection and quantification has previously been accomplished with electron-beam computed tomography (CT). Use of spiral CT for this application has been limited by cardiac motion. The authors evaluated a retrospective cardiac-gated postprocessing technique that necessitates no modification of scanner hardware or software. At spiral CT in 26 patients, motion artifact was reduced, coronary arteries were consistently visualized, and quantification of calcification could be performed in those patients with prominent deposits. Coronary artery calcification screening can therefore be offered in sites that have access to only spiral CT.     

Development of an animal model for across-herd genetic evaluation of number born alive in swine

An animal model and computer software were developed to conduct across-herd genetic evaluations using data from producers participating in the Sow Productivity Index program of the American Yorkshire Club. The final data set consisted of 61,596 litter records from 1986 to early 1990. The animal model included fixed contemporary group effects and random additive direct, service sire, permanent environmental, and residual effects. Additive genetic relationships among animals were included. A separate relationship matrix for service sires and their sires was also included. A data set similar to the Yorkshire field data was simulated to use in testing the animal model. The simulated data set consisted of 40 herds, each with 120 reproducing dams and either four or five sires. Six generations of simulated data were produced, resulting in 20,605 litter records. These records were then evaluated using the animal model for number of pigs born alive. Finally, correlations between the true breeding values from the simulation and the predicted breeding values were computed. The correlation between the 918 true and predicted sire breeding values was considerably lower for the animal model without a service sire effect than when it was included (.53 vs .74, respectively). However, the difference was cut in half (.66 vs .77) when only sires with greater than five daughter records were included. The high accuracy of the animal model with a random service sire effect indicates that the proposed model adequately accounts for the variation found in records for number of pigs born alive.