A new sparteine surrogate for asymmetric deprotonation of N-Boc pyrrolidine.

The s-BuLi complex of a cyclohexane-derived diamine is as efficient as s-BuLi/(-)-sparteine for the asymmetric deprotonation of N-Boc pyrrolidine. This is the first example of high enantioselectivity using a non-sparteine-like diamine in such reactions. The (S,S)-diamine is a useful (+)-sparteine surrogate and was utilized in short syntheses of (-)-indolizidine 167B and an intermediate for the synthesis of the CCK antagonist (+)-RP 66803.

Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model.

Isoniazid is an anti-tuberculosis drug that can cause hepatotoxicity in 20% of patients that is usually associated with an inflammatory response. Hepatocytes when exposed to non-toxic levels of H2O2, to simulate H2O2 formation by inflammatory cells, became twice as sensitive to isoniazid toxicity. Isoniazid cytotoxicity was prevented by 1-aminobenzotriazole, a non-selective P450 inhibitor or by bis-p-nitrophenyl phosphate (BNPP), an esterase inhibitor.

Cardiac troponin is the most effective translational safety biomarker for myocardial injury in cardiotoxicity.

There is an overwhelming weight of evidence that certifies cardiac troponin (cTn) as the preferred, defacto, translational, safety biomarker for myocardial injury in cardiotoxicity. As well as being the gold standard for cardiac injury in man, it has been widely used for clinical assessment and monitoring of cardiac toxicity in humans being treated for cancer. Furthermore, several dozen preclinical published studies have directly confirmed its effectiveness in laboratory animals for assessment of cardiotoxicity.

Tetramethylphenylenediamine-induced hepatocyte cytotoxicity caused by lysosomal labilisation and redox cycling with oxygen activation.

It has already been reported that in vivo muscle necrosis induced by various phenylenediamine derivatives correlated with their in vitro autoxidation rate [9]. Now in a more detailed investigation of the cytotoxic mechanism of a ring-methylated phenylenediamine known as tetramethylphenylenediamine or durenediamine (DD) towards isolated rat hepatocytes has been carried out. Cytotoxicity was preceded by ROS formation which was markedly increased by inactivating DT-diaphorase or catalase but were prevented by a subtoxic concentration of the mitochondrial respiratory inhibitor cyanide.

A rank-based sample size method for multiple outcomes in clinical trials.

O'Brien (Biometrics 1984; 40:1079-1087) introduced a rank-sum-type global statistical test to summarize treatment's effect on multiple outcomes and to determine whether a treatment is better than others. This paper presents a sample size computation method for clinical trial design with multiple primary outcomes, and O'Brien's test or its modified test (Biometrics 2005; 61:532-539) is used for the primary analysis. A new measure, the global treatment effect (GTE), is introduced to summarize treatment's efficacy from multiple primary outcomes.

Muscle function and functional outcome following standard antegrade reamed intramedullary nailing of isolated femoral shaft fractures.

Objective: To evaluate the functional outcomes and long-term effects on muscle strength of femoral shaft fractures treated with intramedullary (IM) antegrade nailing using a standard piriformis start point.

Design: Retrospective Outcome Study.

Setting: Tertiary Level Teaching Hospital and Referral Centre for the Province of British Columbia.

Fracture of the femoral head.

Fracture of the femoral head is a severe, relatively uncommon injury; typically, it occurs following traumatic posterior dislocation of the hip joint. The Pipkin classification is the most commonly used classification system. Diagnosis is aided by a complete history, physical examination, and imaging, including computed tomography.

Prevention of hydrogen sulfide (H2S)-induced mouse lethality and cytotoxicity by hydroxocobalamin (vitamin B(12a)).

Recently, H(2)S (an environmental toxin) was proposed to induce cytotoxicity not only by inhibiting cytochrome oxidase but also by generating reactive oxygen species [Truong, D., Eghbal, M., Hindmarsh, W.

Structure-activity relationships for thiol reactivity and rat or human hepatocyte toxicity induced by substituted p-benzoquinone compounds.

Covalent binding of toxic chemicals to cellular targets is a molecular interaction that initiates a wide array of adverse biological effects. The creation of a covalent bond can be cited as a key initiating step along many toxicity pathways which must be predicted in order to predict the potential of a chemical to cause specific harmful effects. Currently, quantitative structure-activity relationship (QSAR) models are being improved by focusing on endpoints such as simple electrophile reactivity for covalent interactions rather than on commonly used complex toxicity endpoints.

A radiation badge survey for family members living with patients treated with a (103)Pd permanent breast seed implant.

Purpose: Sixty-seven patients with early-stage breast cancer were treated in a Phase I/II clinical trial using a (103)Pd permanent breast seed implant as adjuvant radiotherapy after breast-conserving surgery. We report the dose received by family members living with these patients and compare measured doses with theoretical worst-case scenario estimates.

Methods And Materials: Exposure-rate measurements were taken at 1 m from the patient by using a calibrated low-energy survey meter.

Preventing cell death induced by carbonyl stress, oxidative stress or mitochondrial toxins with vitamin B anti-AGE agents.

Carbonyls generated by autoxidation of carbohydrates or lipid peroxidation have been implicated in advanced glycation end product (AGE) formation in tissues adversely affected by diabetes complications. Tissue AGE and associated pathology have been decreased by vitamin B(1)/B(6) in trials involving diabetic animal models. To understand the molecular cytoprotective mechanisms involved, the effects of B(1)/B(6) vitamers against cytotoxicity induced by AGE/advanced lipid end product (ALE) carbonyl precursors (glyoxal/acrolein) have been compared to cytotoxicity induced by oxidative stress (hydroperoxide) or mitochondrial toxins (cyanide/copper).

Lag correction model and ghosting analysis for an indirect-conversion flat-panel imager.

Cone-beam digital tomosynthesis (CBDT) is a new approach that was recently proposed for rapid tomographic imaging of soft-tissue targets in the radiotherapy treatment room. One of the potential problems in implementing CBDT using, for example, megavoltage (MV) X rays is the possibility of artifacts caused by image lag and ghosting of the X-ray detector used. In the present work, we developed a model to correct for image lag with indirect-conversion flat-panel imagers (FPIs) used for MV-CBDT.

Influence of glycemic variables on hemoglobin A1c.

Objective: To assess the influences of a wide variety of glucose variables on hemoglobin A1c (A1C).

Methods: The Diabetes Control and Complications Trial database, restricted to volunteers whose 7-point daily capillary glucose profiles were complete in >or=80% of quarterly collections and who were in the study for >or=4 years, was used for analysis. Regression analyses were done to develop an equation for estimating A1C based on concurrent and prior mean blood glucose (MBG) values.

A thermolyzed diet increases oxidative stress, plasma alpha-aldehydes and colonic inflammation in the rat.

A thermolyzed diet has the potential of providing exogenous oxidative stress in the form of advanced glycation end-products (AGE) and decreased thiamin. There is then a possibility that it could result in intracellular exposure to alpha-oxoaldehydes (glyoxal and methylglyoxal (MG)) with metabolic and genetic consequences. Two groups of Fischer 344 rats were fed the following diets: group A was given an AIN93G diet (control diet), while group B was given a thermolyzed AIN93G diet for 77 days.

Challenges in design of multicenter trials: end points assessed longitudinally for change and monotonicity.

Objective: Assessing clinimetric performance of diabetic sensorimotor polyneuropathy (DSPN) end points in single and multicenter trials.

Research Design And Methods: Assessed were placebo-treated patients with DSPN in the Viatris and Eli Lilly trials and an epidemiologic cohort.

Results: Test reproducibility in clinical trial cohorts (r(I) approximately 0.

Breast edema in patients undergoing breast-conserving treatment for breast cancer: assessment via high frequency ultrasound.

To identify factors that can influence breast edema in women undergoing breast-conserving therapy. Breast edema was assessed clinically and via high frequency ultrasound (HFUS) prior to, during and following radiotherapy. Fifty-four women were assessed.

Plastic deformation of the forearm in an adult: treatment with multiple osteotomies.

Plastic deformation of the forearm is a rare and frequently missed injury in adults that can result in significant loss of forearm rotation. We report on a skeletally mature 19-year-old man with traumatic plastic deformation of the radius and ulna resulting in complete loss of forearm pronation. The patient was treated with multiple-level osteotomies of the radius and ulna 7 months postinjury.

Molecular cytotoxic mechanisms of catecholic polychlorinated biphenyl metabolites in isolated rat hepatocytes.

Polychlorinated biphenyl (PCB) and PCB metabolites are highly lipophilic and accumulate easily in the lipid bilayer and fat deposits of the body. The molecular cytotoxic mechanisms of these metabolites are still not understood. The aim of the present study was to compare the cytotoxicity and toxicological properties of six dihydroxylated metabolites using isolated rat hepatocytes.

Copper-catalyzed ascorbate oxidation results in glyoxal/AGE formation and cytotoxicity.

Previously we showed that 10 muM glyoxal compromised hepatocyte resistance to hydrogen peroxide (H(2)O(2)) by increasing glutathione (GSH) and NADPH oxidation and decreasing mitochondrial membrane potential (MMP) before cytotoxicity ensued. Since transition metal-catalyzed oxidation of ascorbate (Asc) has been shown to result in the generation of both glyoxal and H(2)O(2), we hypothesized that glyoxal formation during this process compromises hepatocyte resistance to H(2)O(2). We used isolated rat hepatocytes and incubated them with Asc/copper and measured cytotoxicity, glyoxal levels, H(2)O(2), GSH levels, and MMP.

Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial.

Background: It is not known whether rigorous intraoperative glycemic control reduces death and morbidity in cardiac surgery patients.

Objective: To compare outcomes of intensive insulin therapy during cardiac surgery with those of conventional intraoperative glucose management.

Design: A randomized, open-label, controlled trial with blinded end point assessment.

Structure-activity relationships for halobenzene induced cytotoxicity in rat and human hepatocytes.

Halobenzenes are ubiquitous environmental contaminants, which are hepatotoxic in both rodents and humans. The molecular mechanism of halobenzene hepatotoxicity was investigated using Quantitative structure-activity relationships (QSAR) and accelerated cytotoxicity mechanism screening (ACMS) techniques in rat and human hepatocytes. The usefulness of isolated hepatocytes for prediciting in vivo xenobiotic toxicity was reassessed by correlating the LC(50) of 12 halobenzene congeners in phenobarbital (PB) induced rat hepatocytes in vitro determined by ACMS to the hepatotoxicities reported in vivo in PB-induced male Sprague-Dawely (SD) rats.

Contamination during a brachytherapy procedure.

This paper describes an unusual contamination incident that occurred during the treatment of a prostate cancer patient with seeds containing 125I. The incident became particularly interesting as the radiation safety procedures in place prior to the incident were, in fact, inappropriate for the type of incident that occurred, resulting in a series of response errors. Strands containing 108 125I seeds with a total activity of 1.