The Effects of {alpha},{beta}-Unsaturated Aldehydes on Hepatic Thiols and Thiol-Containing Enzymes

The effects of series of ,ß-unsaturated aldehydeson hepatic giutathione, cytochrome P450, and NADPH-cytochromec reductase activity were compared with time. Male F-344 ratswere dosed with muconaldehyde (36 µmol/kg), acrolein (89µmol/ kg), crotonaldehyde (450 µmol/kg), or thesaturated aldehyde propionaldehyde (89 µmol/kg) and terminated0.5, 4, or 24 hr later. Acroiein or muconaldehyde reduced glutathioneto 51 and 75% of controls, respectively, at 4 hr; glutathionereturned control values at 24 hr. Only at 24 hr, acrolein, muconaldehyde,or crotonaldehyde decreased cytochrome P450 to 61, 71, and 67%of control values, respectively; ethylmorphine N-demethylationwas decreased to a greater extent, i.e., to 35, 60, and 23%of controls. The reductase activity was unchanged at any timefollowing the treatment with reactive aldehydes which were nothepatotoxic (as shown by glucose 6-phosphatase activity, histologicalchanges, or serum enzymes). Propionaidehyde changed none ofthese activities. Acroiein (44.5 mol/kg) given 4 hr prior tophenobarbital (50 mg/kg) for two consecutive days decreasedthe phenobarbital induction of cytochrome P450 45% of phenobarbitalalone. This treatment also decreased the 2, 2ß, 6ß,l6, and 16ß hydroxylation of testosterone as wellas androstenedione formation showing effects on individual cytochromeP450 isozymes. NADPH-cytochrome c reductase induction was notdecreased by this treatment, thus indicating that in vivo thesechanges are due to a mechanism other than generalized inhibitionof protein synthesis.     

Associations between both genetic and environmental biomarkers and lung cancer: evidence of a greater risk of lung cancer in women smokers

This molecular epidemiologic case-control study of lung cancer incorporated three complementary biomarkers: the glutathione S- transferase M1 (GSTM1) null genotype, a potential marker of susceptibility, and polycyclic aromatic hydrocarbon-DNA adducts (PAH- DNA) and sister chromatid exchanges (SCE), both indicators of environmentally induced genetic damage. Associations between biomarkers and lung cancer were investigated, as were possible gene-environment interactions between the GSTM1 null genotype and tobacco smoke exposure. Subjects included 136 primary non-small cell lung cancer surgical patients and 115 controls at the Columbia Presbyterian Medical Center. Questionnaire and Tumor Registry data, pre-treatment blood samples and biomarker measurements on blood were obtained. Overall, GSTM1 null genotype was significantly associated with lung cancer [odds ratio (OR) = 2.04, 95% confidence interval (CI) = 1.13-3.68]. ORs for GSTM1 and lung cancer were significant in females (2.50, 1.09-5.72) and smokers (2.25, 1.11-4.54) and not significant in males (1.4, 0.58-3.38) and non-smokers (0.88, 0.18-4.33). However, ORs for males versus females and smokers versus non-smokers did not differ significantly. The OR for GSTM1 and lung cancer in female smokers was 3.03 (1.09- 8.40), compared with 1.42 (0.53-4.06) in male smokers. In contrast to PAH-DNA adducts in leukocytes, SCE did not differ between cases and controls. Neither biomarker differed significantly between the two GSTM1 genotypes. The combined effect of elevated PAH-DNA adducts and GSTM1 genotype on case-control status (16.19, 1.2-115) appeared multiplicative. Results suggest that the effect of the GSTM1 null genotype is greatest in female smokers, which is consistent with other evidence that indicates that women are at higher risk of lung cancer than males, given equal smoking. Persons with both the GSTM1 deletion and elevated PAH-DNA adducts may represent a sensitive subpopulation with respect to carcinogens in tobacco smoke and other environmental media.      

Radiologically placed temporary hepatic artery catheter for treatment of liver cancer

Hepatic artery infusion (HAI) chemotherapy is associated with higher response rates compared to systemic chemotherapy in those patients with unresectable liver malignancies. Operative hepatic artery catheter (HAC) insertion has significant morbidity and mortality, especially in patients with high‐volume disease, some of whom may not respond to HAI chemotherapy. We report our experience in 45 patients with high‐volume liver disease who were initially treated with HAI chemotherapy via a radiologically placed temporary HAC to try to select the responders who then went on to have an operative HAC. In these 45 patients who had 62 radiologically placed HAC, we found very few major complications, and certainly no complications such as cholecystitis, vascular or malperfusion problems.     

A Case-Control Study of Peripartum Cardiomyopathy Using the Rochester Epidemiology Project

BackgroundThe incidence of peripartum cardiomyopathy (PPCM) is known through referral center databases that may be affected by referral, misclassification, and other biases. We sought to determine the community-based incidence and natural history of PPCM using the Rochester Epidemiology Project.Methods and ResultsIncident cases of PPCM occurring between January 1, 1970, and December 31, 2014, were identified in Olmsted County, Minnesota. A total of 15 PPCM cases were confirmed yielding an incidence of 20.3 cases per 100,000 live births in Olmsted County, Minnesota. Clinical information, disease characteristics, and outcomes were extracted from medical records in a 27-county region of the Rochester Epidemiology Project including Olmsted County and matched in a 1:2 ratio with pregnant women without PPCM. A total of 48 women were identified with PPCM in the expanded 27-county region. There was 1 death and no transplants over a median of 7.3 years of follow-up. Six of the 23 women with subsequent pregnancies developed recurrent PPCM, all of whom recovered. Migraine and anxiety were identified as novel possible risk factors for PPCM.ConclusionsThe population-based incidence of PPCM was 20.3 cases per 100,000 live births in Olmsted County, Minnesota. Cardiovascular outcomes were generally excellent in this community cohort.     

The diagnostic value of the fibrinogen/fibrin fragment E antigen assay in clinically suspected deep vein thrombosis

We have evaluated the fibrinogen/fibrin fragment E antigen assay as a diagnostic test in patients with clinically suspected venous thrombosis by comparing the results of this assay with venography in 272 patients. The result of the fragment E antigen assay was elevated in 79 of 80 patients with positive venograms for recent venous thrombosis (sensitivity 99%) and within the normal range in 161 of 192 patients with normal venograms (specificity 84%). The fragment E assay was also evaluated in 130 medical and surgical controls without evidence of venous thrombosis by leg scanning and the test was found to be relatively nonspecific. However, in the patient group under study, a correct clinical diagnosis of no thrombosis, based on a normal fragment E result, was made in 161 of 162 cases (negative predictive value of 99%). Therefore, a normal test result effectively excludes a diagnosis of venous thrombosis in clinically symptomatic patients. The assay, as currently performed, is technically demanding and takes 24 hr to complete. Therefore, it will have to be simplified before it can be applied to clinical practice.     

Ventricular Tachycardia/Ventricular Fibrillation Ablation in the Setting of Ischemic Heart Disease

Recurrent ventricular tachycardia (VT) in the setting of coronary artery disease is frequently a life-threatening electrophysiologic emergency. Even in patients with an implantable defibrillator, recurrent VT is frequently accompanied by repeated and disabling shock therapy. Catheter ablative therapy offers the ability to provide immediate control of recurrent VT. Long-term elimination of VT should be anticipated in most patients. This article reviews the strategies, tools, techniques, and expected outcome for catheter ablation of stable and unstable ventricular arrhythmias in the setting ischemic heart disease.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice [published erratum appears in Blood 1995 Apr 1;85(7):1983]

CD11b is the alpha chain of the Mac-1 integrin and is preferentially expressed in myeloid cells (neutrophils, monocytes, and macrophages). We have previously shown that the CD11b promoter directs cell-type- specific expression in myeloid lines using transient transfection assays. To confirm that these promoter sequences contain the proper regulatory elements for correct myeloid expression of CD11b in vivo, we have used the -1.7-kb human CD11b promoter to direct reporter gene expression in transgenic mice. Stable founder lines were generated with two different reporter genes, a Thy 1.1 surface marker and the Escherichia coli lacZ (beta-galactosidase) gene. Analysis of founders generated with each reporter demonstrated that the CD11b promoter was capable of driving high levels of transgene expression in murine macrophages for the lifetime of the animals. Similar to the endogenous gene, transgene expression was preferentially found in mature monocytes, macrophages, and neutrophils and not in myeloid precursors. These experiments indicate that the -1.7 CD11b promoter contains the regulatory elements sufficient for high-level macrophage expression. This promoter should be useful for targeting heterologous gene expression to mature myeloid cells.