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.     

Contractor Prebid Planning Principles

Planning is an essential function of project management. Yet, many small- and medium-sized contractors do a relatively poor job of operational planning. Better prebid plans will reduce costs, shorten schedules, and improve labor productivity. Unfortunately, the published literature offers little guidance for smaller contractors on what constitutes effective planning. Most papers describe planning as a macrolevel process for owners. Most emphasize scope definition for industrial projects. This paper describes a microlevel planning process for contractors. It consists of eight steps which are: (1) assess contract risks; (2) develop a preliminary execution plan; (3) develop site layout plans; (4) identify the sequences that are essential-to-success; (5) develop detailed operational plans; (6) develop proactive strategies to assure construction input into design; (7) revise the preliminary plan; and (8) communicate and enforce the plan. The entire process is illustrated with a case study project and is fully illustrated with figures which show how to integrate the work of multiple contractors, keep key resources (crews or equipment) fully engaged with no downtime, provide time buffers so the work of follow on crews can be efficiently done, expedite the schedule using multiple work stations and concurrent work, ways to communicate the work plan to the superintendent and foremen, and how to assess the feasibility of various work methods. The steps are easy to understand and implement. They will yield immediate positive results.     

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.     

Denial of illness in stroke

BACKGROUND: The effects of stroke on classically nondominant hemisphere functions have received less attention than those on the dominant hemisphere, but visuospatial neglect and denial of illness both produce significant morbidity. SUMMARY OF COMMENT: The early literature on denial of illness is discussed and the etiological theories are examined. These are explanations based on deficits of higher mental function, impaired sensory input (especially proprioceptive), an abnormal representation of body image, psychodynamic defense mechanisms, and/or premorbid personality factors. CONCLUSIONS: Denial of illness is an important consequence of stroke. No explanation thus far proposed is entirely satisfactory. The consequences on rehabilitation and strategies for therapy have not been adequately investigated.     

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.     

High-dose busulfan, melphalan, thiotepa and peripheral blood stem cell infusion for the treatment of metastatic breast cancer

The purpose of this study was to determine the outcome of patients with metastatic breast cancer treated with high-dose busulfan (Bu), melphalan (Mel) and thiotepa (TT) followed by peripheral blood stem cell (PBSC) infusion. Fifty-one patients with chemotherapy refractory (n = 32) or responsive (n = 19) metastatic breast cancer received Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC collected after chemotherapy and growth factor (n = 43) or growth factor alone (n = 8). The 100 day treatment-related mortality was 8% including one death from cytomegalovirus pneumonia, one from aspiration pneumonia and two from regimen-related toxicity (RRT). Seven of 28 refractory (25%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft tissue disease with at least improvement in bone lesions (PR*). Fifteen of 51 patients (29%) are alive and progression-free a median of 423 days (range 353-934) after treatment, 5/32 (16%) with refractory disease and 10/19 (53%) with responsive disease. The probabilities of progression-free survival (PFS) at 1.5 years for the patients with refractory (n = 32) and responsive (n = 19) disease were 0.24 and 0.53, respectively. These preliminary data suggest that high-dose Bu/Mel/TT has significant activity in patients with advanced breast cancer and may be superior to some previously published regimens.