Vascular disease risk factors in multiple sclerosis: Effect on metabolism and brain volumes.

BACKGROUND: Vascular disease risk factors (VDRF) such as hypertension, hyperlipidemia, obesity, diabetes and heart disease likely play a role in disease progression in people with multiple sclerosis (PwMS) (Marrie, Rudick et al. 2010). Studies exploring the mechanistic connection between vascular disease and MS disease progression are scant. We hypothesized that phosphate energy metabolism impairment in PwMS with VDRFs (VDRF+) will be greater compared to PwMS without VDRFs (VDRF-) and is related to increased brain atrophy in VDRF+. To test this hypothesis, we planned to study the differences in the high energy phosphate (HEP) metabolites in cerebral gray matter as assessed by 31P magnetic resonance spectroscopic imaging (MRSI) and MRI brain volumetric in the VDRF+ and VDRF- PwMS at four different timepoints over a 3 yearlong period using a 7T MR system. We present here the results from the cross-sectional evaluation of HEP metabolites and brain volumes. We also evaluated the differences in clinical impairment, blood metabolic biomarkers and quality of life in VDRF+ and VDRF- PwMS in this cohort. METHODS: Group differences in high energy phosphate metabolites were assessed from a volume of interest in the occipital region using linear mixed models. Brain parenchymal and white matter lesion volumes were determined from MR anatomic images. We present here the cross-sectional analysis of the baseline data collected as part of a longitudinal 3 yearlong study where we obtained baseline and subsequent 6-monthly clinical and laboratory data and annual 7T MRI volumetric and 31P MR spectroscopic imaging (MRSI) data on 52 PwMS with and without VDRF. Key clinical and laboratory outcomes included: body mass index (BMI), waist and thigh circumferences and disability [Expanded Disability Status Scale (EDSS)], safety (complete blood count with differential, complete metabolic), lipid panel including total cholesterol and HbA1C. We analyzed clinical and laboratory data for the group differences using student's t or χ2 test. We investigated relationship between phosphate metabolites and VDRF using mixed effect linear regression. RESULTS: Complete MRI data were available for 29 VDRF+, age 56.3 (6.8) years [mean (SD)] (83% female), and 23 VDRF-, age 52.5 (7.5) years (57% female) individuals with MS. The mean value of normalized adenosine triphosphate (ATP) (calculated as the ratio of ATP to total phosphate signal in a voxel) was decreased by 4.5% (p < .05) in VDRF+ compared to VDRF- MS group. White matter lesion (WML) volume fraction in VDRF+ individuals {0.007 (0.007)} was more than doubled compared to VDRF- participants {0.003 (0.006), p= .02}. CONCLUSIONS: We found significantly lower brain ATP and higher inorganic phosphate (Pi) in those PwMS with VDRFs compared to those without. ATP depletion may reflect mitochondrial dysfunction. Ongoing longitudinal data analysis from this study, not presented here, will evaluate the relationship of phosphate metabolites, brain atrophy and disease progression in PwMS with and without vascular disease.

Proof testing to improve the reliability and lifetime of ceramic dental prostheses.

OBJECTIVES: Ceramic dental prostheses exhibit increasing failure rates with service time. In particular, veneered crowns and bridges are susceptible to chipping and other fracture modes of failure. The purpose of this manuscript is to introduce a computational methodology and associated software that can predict the time-dependent probability of failure for ceramic prostheses and subsequently design proof test protocols to significantly enhance their reliabilities and lifetimes. METHODS: Transient reliability and corresponding proof testing theories are introduced. These theories are coded in the Ceramic Analysis and Reliability Evaluation of Structures (CARES/Life) code. This software will be used to demonstrate the predictive capability of the theory as well as its use in designing proof test protocols to significantly improve the reliability (survival probability) and lifetime for dental prostheses. A three-unit fixed dental prosthesis (FDP) with zirconia core (ZirCAD) and veneering ceramic (ZirPress) are used to compare the predicted probabilities of failure to general clinical results. In addition, the capability to use proof testing to significantly improve the performance (reliability and lifetime) for this restoration is demonstrated. RESULTS: The probability of failure, Pf, after five years without proof testing is predicted to be 0.337. This compares to clinical studies showing the failure rate to be between 0.2 and 0.23 after 5 years. After 10 years, reference 18 found the clinical failure rate for similar bridges (but not the same) to be up to 0.28 compared to the predicted Pf of 0.38. The difference may be due to the analysis applying the load at an inclination of 75° which is more critical than vertical loading. In addition, clinical studies often report a simple survival rate instead of using Kaplan-Meier analysis to properly account for late enrollees. Therefore, true clinical failure rates may be higher than reported and may more closely match the predictions of this manuscript. The effectiveness of proof testing increases with selecting materials less susceptible to slow crack growth (higher SCG exponent, N). For example, proof testing the ZirPress glass-veneered bridges with N = 43.4 analyzed in this manuscript at 400 N bite force for 1 s which induces a failure rate during proof testing of 0.31, reduces the Pf of bridges not proof tested from 0.45 to an attenuated-proof-tested probability of failure Pfa of 0.21 after 20 years of usage. If another material is selected with improved resistance to SCG of N = 60 and the same loading conditions, the failure rate for the proof tested bridges after 20 years of service drops to 2 in 10,000 from 2.4 in 100 had they been not proof tested. The failure rate during proof testing for this material would be 5.1 in 100. Proof testing a material with absolutely no susceptibility to SCG at the same service load (in this case 285 N, not even the 400 N load used above) results in 0 % failure rate and is of course independent of time. SIGNIFICANCE: The transient reliability and proof test theory presented in this paper and associated computational software CARES/Life were successful in predicting the performance of ceramic dental restorations when compared to clinical data. Well-designed proof test protocols combined with proper material selection can significantly enhance the reliabilities and lifetimes of ceramic prostheses. This proof test capability can be a translational technology if properly applied to dental restorations.

Metabolic activity diffusion imaging (MADI): I. Metabolic, cytometric modeling and simulations.

Evidence mounts that the steady-state cellular water efflux (unidirectional) first-order rate constant (kio [s-1 ]) magnitude reflects the ongoing, cellular metabolic rate of the cytolemmal Na+ , K+ -ATPase (NKA), c MRNKA (pmol [ATP consumed by NKA]/s/cell), perhaps biology's most vital enzyme. Optimal 1 H2 O MR kio determinations require paramagnetic contrast agents (CAs) in model systems. However, results suggest that the homeostatic metabolic kio biomarker magnitude in vivo is often too large to be reached with allowable or possible CA living tissue distributions. Thus, we seek a noninvasive (CA-free) method to determine kio in vivo. Because membrane water permeability has long been considered important in tissue water diffusion, we turn to the well-known diffusion-weighted MRI (DWI) modality. To analyze the diffusion tensor magnitude, we use a parsimoniously primitive model featuring Monte Carlo simulations of water diffusion in virtual ensembles comprising water-filled and -immersed randomly sized/shaped contracted Voronoi cells. We find this requires two additional, cytometric properties: the mean cell volume (V [pL]) and the cell number density (ρ [cells/µL]), important biomarkers in their own right. We call this approach metabolic activity diffusion imaging (MADI). We simulate water molecule displacements and transverse MR signal decays covering the entirety of b-space from pure water (ρ = V = 0; kio undefined; diffusion coefficient, D0 ) to zero diffusion. The MADI model confirms that, in compartmented spaces with semipermeable boundaries, diffusion cannot be described as Gaussian: the nanoscopic D (Dn ) is diffusion time-dependent, a manifestation of the "diffusion dispersion". When the "well-mixed" (steady-state) condition is reached, diffusion becomes limited, mainly by the probabilities of (1) encountering (ρ, V), and (2) permeating (kio ) cytoplasmic membranes, and less so by Dn magnitudes. Importantly, for spaces with large area/volume (A/V; claustrophobia) ratios, this can happen in less than a millisecond. The model matches literature experimental data well, with implications for DWI interpretations.

Metabolic activity diffusion imaging (MADI): II. Noninvasive, high-resolution human brain mapping of sodium pump flux and cell metrics.

We introduce a new 1 H2 O magnetic resonance approach: metabolic activity diffusion imaging (MADI). Numerical diffusion-weighted imaging decay simulations characterized by the mean cellular water efflux (unidirectional) rate constant (kio ), mean cell volume (V), and cell number density (ρ) are produced from Monte Carlo random walks in virtual stochastically sized/shaped cell ensembles. Because of active steady-state trans-membrane water cycling (AWC), kio reflects the cytolemmal Na+ , K+ ATPase (NKA) homeostatic cellular metabolic rate (c MRNKA ). A digital 3D "library" contains thousands of simulated single diffusion-encoded (SDE) decays. Library entries match well with disparate, animal, and human experimental SDE decays. The V and ρ values are consistent with estimates from pertinent in vitro cytometric and ex vivo histopathological literature: in vivo V and ρ values were previously unavailable. The library allows noniterative pixel-by-pixel experimental SDE decay library matchings that can be used to advantage. They yield proof-of-concept MADI parametric mappings of the awake, resting human brain. These reflect the tissue morphology seen in conventional MRI. While V is larger in gray matter (GM) than in white matter (WM), the reverse is true for ρ. Many brain structures have kio values too large for current, invasive methods. For example, the median WM kio is 22s-1 ; likely reflecting mostly exchange within myelin. The kio •V product map displays brain tissue c MRNKA variation. The GM activity correlates, quantitatively and qualitatively, with the analogous resting-state brain 18 FDG-PET tissue glucose consumption rate (t MRglucose ) map; but noninvasively, with higher spatial resolution, and no pharmacokinetic requirement. The cortex, thalamus, putamen, and caudate exhibit elevated metabolic activity. MADI accuracy and precision are assessed. The results are contextualized with literature overall homeostatic brain glucose consumption and ATP production/consumption measures. The MADI/PET results suggest different GM and WM metabolic pathways. Preliminary human prostate results are also presented.

Changes in Visceral and Ectopic Adipose Tissue Stores Across Pregnancy and Their Relationship to Gestational Weight Gain.

BACKGROUND: Excessive gestational weight gain has been associated with increased total body fat (TBF), metabolic syndrome, and abdominal obesity. However, little is known about the relationship of gestational weight gain with changes in metabolically active visceral or ectopic (hepatic and skeletal muscle) lipid stores. OBJECTIVES: In a prospective study of 50 healthy, pregnant women, we assessed whether changes in weight were associated with changes in total, visceral, and ectopic lipid stores. METHODS: Participants (ages 19-39) were primarily White (84%). The mean preconception BMI was 25.8 kg/m2 (SD, 4.5 kg/m2; min-max, 17.1-35.9 kg/m2). Measurements were completed at visits 1 and 2 at means of 16 and 34 weeks gestation, respectively, and included TBF using BOD POD; abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) using MRI; and intrahepatic lipids (IHL), intramyocellular lipids (IMCL), and extramyocellular lipids (EMCL) using magnetic resonance spectroscopy. We used paired t-tests to examine changes in adipose tissue and Pearson's correlation to examine associations of adipose tissue changes and weight changes. We also examined whether changes in adipose tissue stores differed by preconception BMI (normal, overweight, and obese), using 1-way ANOVA. RESULTS: The TBF (mean change, +3.5 kg; 95% CI: 2.4-4.6 kg), SAT (mean change, +701 cm3; 95% CI: 421-981 cm3), VAT (mean change, +275 cm3; 95% CI: 170-379 cm3), and IHL (percentage water peak; median, +0.15; IQR = -0.01 to 0.32) values increased significantly; the IMCL and EMCL values did not change. Changes varied by BMI strata, with the least increase (or, for SAT, net loss) among women with obesity. Weight change was positively correlated with changes in TBF (r = 0.83; P < 0.001), SAT (r = 0.74; P < 0.001), and VAT (r = 0.63; P < 0.001) but not significantly correlated with changes in ectopic lipids (IHL, IMCL, and EMCL; -0.14 < r < 0.26). CONCLUSIONS: Preferential deposition of adipose tissue to the viscera in pregnancy, as seen in our sample, could serve an important metabolic function; however, excessive deposition in this region could negatively affect maternal health.

A unique and effective method of anatomy education: Small-group learning with prosected plastinated specimens.

OBJECTIVE: At the New York University College of Dentistry, we are faced with the challenge of teaching Head and Neck Anatomy to a class of approximately 380 first-year students. We have developed an innovative anatomy curriculum that has proven effective in facilitating students' learning and long-term retention of the material. It has the added benefit of being time- and cost-efficient. Here, we share the structure of our curriculum and examine the student outcomes and student feedback. MATERIALS AND METHODS: In this paper, we describe the evidence-based methods used in our course and present measures of student success. We also surveyed students about aspects of the anatomy curriculum. RESULTS: Our curriculum efficiently manages cost, instructional time, and classroom space, while promoting student success. Over the last 9 years, NYU Dentistry students have achieved a mean first-time pass rate of 98.6% and an average anatomy score of 1.74 standard deviations above the national mean on the National Board Dental Examination Part I. Students agree with instructor assessments of which features of the curriculum are valuable and state that the course helps them prepare for clinical courses. CONCLUSION: We believe that the main factors in the success of our course are the small group setting, the benefits of spaced repetition and frequent quizzes, and the use of plastinated specimens in place of wet cadavers.

An innovative method for teaching anatomy in the predoctoral dental curriculum.

New methods of teaching gross anatomy are being evaluated as medical and dental schools attempt to find time in their curricula for new content without sacrificing essential anatomical knowledge. This article reports on an innovative method of teaching anatomy at New York University College of Dentistry. In 2005, the instructors completely replaced the dissection of wet cadavers with the study of dissected and sliced plastinated specimens. The shift from cadaver dissection to the study of plastinated specimens was accompanied by other changes in the anatomy course: students study in small, consistent groups; frequent, low-impact quizzes are administered; and the role of the computer is increased as a tool for self-directed study. To assess the course, this study considered students' long-term understanding of anatomy as demonstrated by performance on the National Board Dental Examination (NBDE) Part I, hours of instruction, and student evaluation. The results show that, since 2005, students have had higher NBDE Part I scores, their overall performance has been above the national mean while hours of instruction were 60 percent of the national mean, and student satisfaction increased.

Main and interaction effects of iron, zinc, lead, and parenting on children's cognitive outcomes.

This study examined relations of blood lead < 10 microg/dL, iron, zinc, and parenting to Head Start children's (N = 112) scores on Peabody Picture Vocabulary Test-III (PPVT-III) and McCarthy Scales of Children's Abilities (MSCA). Venous whole blood and plasma samples were analyzed for lead and zinc by ICP-MS and iron status was assessed by serum transferrin receptors. Hierarchical regressions revealed significant effects of lead on MSCA perceptual scores and iron on PPVT-III and MSCA verbal scores. Children with lead > 2.5 microg/dL had significantly lower MSCA perceptual scores than children < 2.5 microg/dL. Permissive parenting significantly exacerbated negative effects of higher lead or lower iron on children's perceptual or verbal scores, respectively.

Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia.

Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring < or =5 min after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia.

Cholinergic modulation of trace conditioning trained in serial compound: A developmental analysis.

In four experiments the effects of serial compound conditioning on responding to a trace-conditioned CS were evaluated using a fear conditioning paradigm. The subjects were 18- and 25-day-old Sprague-Dawley rats, previously shown to exhibit little or no trace fear conditioning. Here, animals as young as 18 days of age were shown to be capable of trace conditioning between a visual CS1 and a shock US, provided the trace interval was filled with a non-target CS2 during serial conditioning trials (CS1-->CS2-->US). To explore cholinergic mechanisms involved in trace and serial conditioning, additional experiments assessed conditioned responding following pre-training administration of the muscarinic receptor antagonist scopolamine. Scopolamine produced a dose-dependent reduction in responding to the trace CS1, regardless of whether subjects were trained with standard trace (CS1-->trace interval-->US) or serial (CS1-->CS2-->US) trials. Responding to CS2 was unaffected by scopolamine. These data suggest that central cholinergic systems are functional in the young animals, but are not normally sufficiently activated by standard trace conditioning procedures. The results suggest that serial compound conditioning can promote trace conditioning in young rats, as it does in adults, perhaps by enhancing cholinergic activity during training. Implications for the late ontogenetic emergence of trace conditioning as it relates to maturation of neural pathways and their role in the potentiating effects of a gap filler are discussed.