Cerebral cortical dynamics and the quality of motor behavior during social evaluative challenge

To determine the influence of arousal on cerebral cortical dynamics and motor behavior, 58 channels of EEG were recorded in 13 college‐age men (n=6) and women during an aiming task performed alone and in a social evaluation condition. Moderate arousal, as measured by heart rate, skin conductance, and self‐reported mood, was induced during the social evaluation. In accord with the Yerkes–Dodson Hypothesis, which posits optimal performance during moderate arousal, improved performance (i.e., quality of the aiming trajectories) was observed. During social evaluation, changes in electroencephalogram dynamics included decreased coherence between the motor planning (Fz) and right temporal region (T4), increased coherence in the sensorimotor networks subserving the task, and increased local processing (gamma, 30–44 Hz) in the temporal regions. The results imply that moderate arousal promotes specific alterations in cortical dynamics that facilitate motor performance.     

Selective inhibition of carboxylesterases by isatins, indole-2,3-diones

Carboxylesterases (CE) are ubiquitous enzymes thought to be responsible for the metabolism and detoxification of xenobiotics. Numerous clinically used drugs including Demerol, lidocaine, capecitabine, and CPT-11 are hydrolyzed by these enzymes. Hence, the identification and application of selective CE inhibitors may prove useful in modulating the metabolism of esterified drugs in vivo. Having recently identified benzil (diphenylethane-1,2-dione) as a potent selective inhibitor of CEs, we sought to evaluate the inhibitory activity of related 1,2-diones toward these enzymes. Biochemical assays and kinetic studies demonstrated that isatins (indole-2,3-diones), containing hydrophobic groups attached at a variety of positions within these molecules, could act as potent, specific CE inhibitors. Interestingly, the inhibitory potency of the isatin compounds was related to their hydrophobicity, such that compounds with clogP values of <1.25 were ineffective at enzyme inhibition. Conversely, analogs demonstrating clogP values>5 routinely yielded Ki values in the nM range. Furthermore, excellent 3D QSAR correlates were obtained for two human CEs, hCE1 and hiCE. While the isatin analogues were generally less effective at CE inhibition than the benzils, the former may represent valid lead compounds for the development of inhibitors for use in modulating drug metabolism in vivo.     

Development of an etoposide prodrug for dual prodrug-enzyme antitumor therapy

Enzyme-prodrug approaches to cancer therapy, theoretically, have the potential to mediate tumor-selective cytotoxicity. However, even if tumor-specific prodrug activation is achieved, enzyme-prodrug systems investigated thus far comprised a single enzyme and a specific prodrug. Although targeted, such systems constitute single-agent therapy, which may be ineffective and/or may promote development of drug resistance. Therefore, a goal of our laboratories was to design and characterize a novel dipiperidinyl derivative of etoposide [1,4'-dipiperidine-1'-carboxylate-etoposide (dp-VP16)] that would act as a prodrug. We envisioned that dp-VP16 would be converted to the active chemotherapeutic agent VP-16 by the same rabbit carboxylesterase (rCE) that we have previously shown to efficiently activate the prodrug irinotecan (CPT-11). This dp-VP16 prodrug might then be used in combination with CPT-11, with both drugs activated by a single enzyme. We evaluated the ability of pure rCE and two human carboxylesterases, hCE1 and hiCE (hCE2), to activate dp-VP16 in vitro, and in neuroblastoma cell lines designed to express/overexpress each enzyme. In SK-N-AS neuroblastoma cell transfectants, expression of rCE or hiCE decreased the IC50 of dp-VP16 as a single agent by 8.3- and 3.4-fold, respectively, in growth inhibition assays. Purified hCE1 did not metabolize dp-VP16 in vitro and did not affect its IC50 in intact cells. The combination indices of sequential exposure to CPT-11 followed by dp-VP16 ranged from approximately 0.4 to 0.6, suggesting that this combination produced greater-than-additive cytotoxicity in neuroblastoma cells expressing rCE. These data provide proof-of-principle that enzyme-prodrug therapy approaches comprised of prodrugs with complementary mechanisms of cytotoxicity that are activated by a single enzyme can be developed.     

The Use of Early and Midpoint Adenoma-Carcinoma Sequence Biomarkers in Prediction of Neoplastic Progression in Patients with a History of Colorectal Neoplasia

Since significant neoplasia after initial colonoscopy is low, we conducted this pilot study to compare the predictive role for colorectal neoplasia recurrence of anti-DCC with that of Adnab-9 binding to colonic effluent of high-risk patients. DCC and Adnab-9 effluent ELISA were performed at baseline colonoscopies. The results of follow-up colonoscopies were reviewed. To ensure specificity, immunohistochemistry and Western blot was performed with anti-DCC and for Adnab-9 where optimal fixation times were also evaluated. Mean follow-up was 2.6 years. Of 21 patients, 6 of 10 who progressed to CRN and 2 of 11 who did not had a positive Adnab-9 ELISA result (P=0.08). Despite an initial good correlation with Adnab-9 ELISA results in a smaller dataset, we were unable to obtain consistent subsequent DCC immunohistochemistry or Western blot data using antibody from two different sources. However, the original dataset of Adnab-9 results was reproducible on repetition of the ELISA with a larger set of samples that included this initial dataset and optimal fixation time was 20 min. We conclude that Adnab-9 appears to be a promising prognostic marker for neoplasia in the high-risk population. Industry standards need to be developed for DCC monoclonal antibodies that may have similar utility.     

Cardiac pacemakers and implantable defibrillators in terminal care.

The use of cardiac pacemakers and arrhythmia control devices is increasingly common. The presence of a previously placed pacemaker or implantable cardioverter-defibrillator (ICD) in a terminally ill patient may result in medical and ethical issues for the patient, family, and healthcare provider. Two cases are presented to illustrate the complex issues that may arise in the terminally ill with a pacemaker or an ICD. Based on these cases and a review of published data, it is likely that the disabling of a previously placed pacemaker will neither hasten nor prolong the natural history of the underlying illness in most instances. There are uncommon but potentially severe adverse effects of disabling the pacemaker; therefore, pacemakers should generally be left intact in terminally ill patients. It is more difficult to generalize as to whether deactivation of an ICD is appropriate; in this case death may be hastened and the decision concerning an ICD will depend on the specific clinical scenario. Patient and family education regarding palliative care treatment goals and the function of pacemakers and other implanted arrhythmia control devices can help to alleviate anxiety surrounding the impact of this technology at the end of life.