Faculty Bibliography

OBJECTIVE:Del Nido (DN) cardioplegia solution provides a depolarized hyperkalemic arrest lasting up to 60 minutes, and the addition of lidocaine may limit intracellular calcium influx. Single-dose DN cardioplegia solution may offer an alternative myocardial protection strategy to multi-dose cold whole blood (WB) cardioplegia following acute myocardial infarction (AMI). METHODS:We retrospectively reviewed 88 consecutive patients with AMI undergoing coronary artery bypass (CABG) surgery with cardioplegic arrest between June 2010 to June 2012. Patients exclusively received WB (n = 40, June 2010-July 2011) or DN (n = 48, August 2011-June 2012) cardioplegia. Preoperative and postoperative data were retrospectively reviewed and compared using propensity scoring. RESULTS:No significant difference in age, maximum preoperative serum troponin level, ejection fraction, and STS score was present between DN and WB. A single cardioplegia dose was given in 41 DN vs. 0 WB patients (p < 0.001), and retrograde cardioplegia was used 10 DN vs. 31 WB patients (p < 0.001). Mean cardiopulmonary bypass and cross clamp times were significantly shorter in the DN group versus WB group. Transfusion rate, length of stay, intra-aortic balloon pump requirement, post-operative inotropic support, and 30-day mortality was no different between groups. One patient in the WB group required a mechanical support due to profound cardiogenic shock. CONCLUSIONS:DN cardioplegia may provide equivalent myocardial protection to existing cardioplegia without negative inotropic effects in the setting of acute myocardial infarction.

OBJECTIVE: This study analyzed how oral hygiene (i.e., brushing, rinsing, and flossing) influences the trajectories of dental caries (i.e., numbers of decayed, missing, and filled teeth) among older Americans within the context of social stratification. METHOD: Data came from Piedmont Dental Study that involved a sample of 810 older Americans who were dentate in 1988 with up to four repeated observations through 1994. Hierarchical linear models were used for data analysis. RESULTS: Brushing, flossing, and rinsing were associated with the trajectories of dental caries in distinct ways. In addition, oral hygiene was correlated with race, education, household income, and use of dental care. The effects of brushing and flossing on decayed and missing teeth remained robust, even when socio-demographic and health attributes were controlled. Conversely, socioeconomic disparities in dental caries persisted, when oral hygiene was adjusted. DISCUSSION: Both social stratification and oral hygiene need to be considered in promoting oral health.

OBJECTIVES: This study charted the trajectories of dental caries, including decayed teeth, missing teeth and filled teeth among older Americans over a 5-year period. In particular, it focused on racial differences in the levels of and rates of change in dental caries experience. METHODS: Data came from the Piedmont Dental Study. The sample included 810 older Americans who were dentate at the baseline with up to 4 repeated observations between 1988 and 1994. Hierarchical linear models were employed in depicting intrapersonal and interpersonal differences in dental caries experience. RESULTS: Different measures of caries outcomes exhibited distinct trajectories. On average, the number of decayed teeth decreased over time, whereas missing teeth increased. In contrast, the number of filled teeth remained stable during a 5-year period. Relative to their white counterparts, older black Americans had more decayed teeth and missing teeth but fewer filled teeth. Blacks and whites differed in the levels of dental caries but not in their rates of change except for missing teeth. Even when demographic and socioeconomic attributes were adjusted, racial variations in dental caries experience remained significant. CONCLUSIONS: Although significantly correlated, various dental caries outcomes move along different paths over time. In view of the persistent racial disparities in dental caries trajectories, future interventions to minimize such variations among older Americans in the levels of and the rates of change in dental caries experience are clearly warranted.

Periodontal disease (PD) has been shown to be associated with incident stroke. We investigated whether PD is independently associated with recurrent vascular events and certain inflammatory markers in stroke/transient ischemic attack (TIA) patients. In this prospective, longitudinal, hospital-based cohort study, PD was assessed in stroke/TIA patients. High periodontal disease (HPD) was defined as the highest tertile of extent (% of sites) with an attachment loss of 5 mm or more. Serum interleukin-6 (IL-6), high-sensitivity C-reactive protein, and soluble intracellular adhesion molecule 1 (s-ICAM) were measured. The patients were followed for recurrent vascular events-stroke, TIA, myocardial infarction, and vascular death. In the 106 patients who were evaluated, 40 (38%) showed HPD and 27 (26%) had recurrent vascular events over a median of 24 months (range, 12-24 months). HPD patients had higher levels of IL-6 (P=.01) and s-ICAM (P=.03). HPD was associated with recurrent vascular events before (log-rank P=.01; hazard ratio [HR], 2.6; 95% confidence interval [CI], 1.2-5.7) and after adjustment for significant confounders-age and stroke status (HR, 2.5; 95% CI, 1.1-5.5; P=.03); adjustment for possible confounders-age, male, years of education, and cardioembolic strokes (HR, 2.8; 95% CI, 1.2-6.5; P=.02); and adjustment for propensity score that accounted for all potential measured confounders (HR, 2.8; 95% CI, 1.2-6.5; P=.02). There is an independent association between HPD and recurrent vascular events in stroke/TIA patients. HPD is also associated with higher serum levels of IL-6 and s-ICAM.

Dopamine (DA) transporter (DAT) imaging has been studied as a diagnostic tool for degenerative parkinsonism. Our aim was to measure the prognostic value of imaging for motor and nonmotor outcomes in Parkinson's disease (PD). We prospectively evaluated a Parkinson's cohort after enrollment in a de novo clinical trial with a battery of motor (UPDRS), cognitive (Montreal Cognitive Assessment), and behavioral measures. DAT imaging with [(123)I][beta]-CIT and single-photon emission computerized tomography (SPECT) was performed at baseline and after 22 months. In total, 491 (91%) of the 537 subjects had evidence of DA deficiency on their baseline scan, consistent with PD, and were included in the analyses. The cohort was followed for 5.5 (0.8) years, with a mean duration of diagnosis of 6.3 (1.2). Lower striatal binding at baseline was independently associated with higher risk for clinical milestones and measures of disease severity, including motor-related disability, falling and postural instability, cognitive impairment, psychosis, and clinically important depressive symptoms. Subjects in the bottom quartile for striatal binding, compared to the top quartile, had an odds ratio (95% confidence interval) of 3.3 (1.7, 6.7) for cognitive impairment and 12.9 (2.6, 62.4) for psychosis. Change from baseline in imaging after 22 months was also independently associated with motor, cognitive, and behavioral outcomes. DAT imaging with [(123)I][beta]-CIT and SPECT, shortly after the diagnosis of PD, was independently associated with clinically important long-term motor and nonmotor outcomes. These results should be treated as hypothesis generating and require confirmation.

BACKGROUND: Although adult vertebrates sense changes in head position by using two classes of accelerometer, at larval stages zebrafish lack functional semicircular canals and rely exclusively on their otolithic organs to transduce vestibular information. RESULTS: Despite this limitation, we find that larval zebrafish perform an effective vestibulo-ocular reflex (VOR) that serves to stabilize gaze in response to pitch and roll tilts. By using single-cell electroporations and targeted laser ablations, we identified a specific class of central vestibular neurons, located in the tangential nucleus, that are essential for the utricle-dependent VOR. Tangential nucleus neurons project contralaterally to extraocular motoneurons and in addition to multiple sites within the reticulospinal complex. CONCLUSIONS: We propose that tangential neurons function as a broadband inertial accelerometer, processing utricular acceleration signals to control the activity of extraocular and postural neurons, thus completing a fundamental three-neuron circuit responsible for gaze stabilization.

Semicircular canals have been sensors of angular acceleration for 450 million years. This vertebrate adaptation enhances survival by implementing postural and visual stabilization during motion in a three-dimensional environment. We used an integrated neuroethological approach in larval Xenopus to demonstrate that semicircular canal dimensions, and not the function of other elements, determines the onset of angular acceleration detection. Before angular vestibuloocular function in either the vertical or horizontal planes, at stages 47 and 48, respectively, each individual component of the vestibuloocular system was shown to be operational: extraocular muscles could be activated, central neural pathways were complete, and canal hair cells were capable of evoking graded responses. For Xenopus, a minimum semicircular canal lumen radius of 60 microm was necessary to permit endolymph displacement sufficient for sensor function at peak accelerations of 400 degrees /s(2). An intra-animal comparison demonstrated that this size is reached in the vertical canals earlier in development than in the horizontal canals, corresponding to the earlier onset of vertical canal-activated ocular motor behavior. Because size constitutes a biophysical threshold for canal-evoked behavior in other vertebrates, such as zebrafish, we suggest that the semicircular canal lumen and canal circuit radius are limiting the onset of vestibular function in all small vertebrates. Given that the onset of gravitoinertial acceleration detection precedes angular acceleration detection by up to 10 d in Xenopus, these results question how the known precise spatial patterning of utricular and canal afferents in adults is achieved during development

STUDY AIM: To analyse the parallel use of transcranial electrical stimulation (TES) and direct cortical stimulation (DCS) for eliciting muscle motor evoked potentials (MMEPs) in intracranial aneurysm surgery; to correlate permanent or transient TES- and/or DCS-MMEP changes with surgical maneuvers and clinical motor outcome. PATIENTS AND METHODS: TES and DCS were intraoperatively performed in 108 patients (51.5+/-14.7 years); MMEPs were obtained in muscles belonging to the vascular territory of interest. Monopolar, anodal stimulation was achieved with a train of five stimuli consisting of an individual pulse width of 0.5ms, an interstimulus interval of 4ms, a train repetition rate of 0.5-2Hz, and maximum stimulation intensities up to 200mA (TES) versus 25mA (DCS). RESULTS: In 95/108 (88%) patients, no changes in MMEPs occurred and none of these patients suffered a permanent severe motor deficit. In 14/108 (12%) patients, we observed nine (64%) temporary changes, four (29%) permanent deteriorations and one (7%) permanent MMEP loss. Out of 14 MMEP changes, nine (64%) occurred with TES, compared to 13 (93%) with DCS (Fishers'p=0.165). Parallel changes in TES- and DCS-MMEPs occurred in 8/14 patients (57%), in which case a permanent loss was always followed by a permanent severe motor deficit. Sixty-seven percent of all permanent changes occurred with DCS-MMEPs, compared to 33% with TES-MMEPs (p=0.567, NS). DISCUSSION AND CONCLUSIONS: In aneurysm surgery, provided that close-to-motor-threshold stimulation and the most focal stimulating electrode montage are used, TES- and DCS-MMEPs do not differ in their capacity to detect an impending lesion of the motor cortex or its efferent pathways. TES stimulation can cause significant muscular contraction during surgery, potentially disrupting the operating surgeon. DCS maintains the singular advantage of stimulating a very focal and superficial motor cortex stimulation that does not result in patient movement.

Ziconotide, a potent, selective, reversible blocker of neuronal N-type voltage-sensitive calcium channels, is approved in the United States for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. In the European Union, ziconotide is indicated for the treatment of severe chronic pain in patients who require intrathecal analgesia. Nonclinical investigations of ziconotide included a comprehensive characterization of its toxicology, incorporating acute and subchronic toxicity studies in rats, dogs, and monkeys; reproductive toxicity assessments in rats and rabbits; and mutagenic, carcinogenic evaluations performed in vivo and in vitro. Additional investigations assessed the potential for cardiotoxicity (rats) and immunogenicity (mice, rats, and guinea pigs), and the presence or absence of intraspinal granuloma formation and local cell proliferation and apoptosis (dogs). The resulting nonclinical toxicology profile was predictive of human adverse events reported in clinical trials and consistent with ziconotide's pharmacological activity. Frequently observed nonclinical behavioral effects included tremoring, shaking, ataxia, and hyperreactivity. Occurrences were generally transient and reversible upon cessation of treatment, and intolerable effects occurred at doses more than 45 times the maximum recommended clinical dose. Ziconotide was not associated with target organ toxicity, teratogenicity, or treatment-related gross or histopathological changes; it displayed no mutagenic or carcinogenic potential and no propensity to induce local cell proliferation or apoptosis. Although guinea pigs developed systemic anaphylaxis, antibodies to ziconotide were not detected in mice, rats, or guinea pigs, indicating low immunogenic potential. No evidence of granuloma formation was observed with intrathecal ziconotide treatment. In summary, the results from these nonclinical safety assessments revealed no significant toxicological risk to humans treated with ziconotide as recommended

Intracellular recording and single-cell labeling were combined to investigate the oculomotor circuitry of the goldfish cerebellar vestibulolateral lobe, consisting of the eminentia granularis (Egr) and caudal lobe. Purkinje cells exhibiting highly conserved vertebrate electrophysiological and morphological properties provide the direct output from the caudal lobe to the vestibular nuclei. Biocytin labeling of the Egr distinguished numerous hindbrain precerebellar sources that could be divided into either putative mechano- or vestibulosensitive nuclei based on cellular location and axon trajectories. Precerebellar neurons in a hindbrain nucleus, called Area II, were electrophysiologically characterized after antidromic activation from the Egr (>50% bilateral) and their morphology analyzed after intracellular biocytin labeling (n = 28). Bipolar spindle-shaped somas ranged widely in size with comparably scaled dendritic arbors exhibiting largely closed field configuration. Area II neurons (85%) projected to the ipsilateral Egr with most (93%) sending a collateral through the cerebellar commissure to the contralateral Egr; however, 15% projected to the contralateral Egr by crossing in the ventral hindbrain. Axon terminals in the vestibular nucleus were the only collaterals within the hindbrain. Every Area II neuron received a disynaptic EPSP after contralateral horizontal canal nerve stimulation and a disynaptic IPSP, preceded by a small EPSP (>50%), after ipsilateral activation. Vestibular synaptic potentials were of varying shape/amplitude, unrelated to neuron location in the nucleus, and thus likely a correlate of somadendritic size. The exceptional separation of eye position and eye velocity signals into two separate hindbrain nuclei represents an ideal model for understanding the precerebellar projection to the vestibulocerebellum