Progesterone inactivation in decidual stromal cells: A mechanism for inflammation-induced parturition.

The process of human parturition involves inflammation at the interface where fetal chorion trophoblast cells interact with maternal decidual stromal (DS) cells and maternal immune cells in the decidua (endometrium of pregnancy). This study tested the hypothesis that inflammation at the chorion-decidua interface (CDI) induces labor by negating the capacity for progesterone (P4) to block labor and that this is mediated by inactivation of P4 in DS cells by aldo-keto reductase family 1 member C1 (AKR1C1). In human, Rhesus macaque, and mouse CDI, AKR1C1 expression increased in association with term and preterm labor. In a human DS cell line and in explant cultures of term human fetal membranes containing the CDI, the prolabor inflammatory cytokine, interleukin-1ß (IL-1ß), and media conditioned by LPS-stimulated macrophages increased AKR1C1 expression and coordinately reduced nuclear P4 levels and P4 responsiveness. Loss of P4 responsiveness was overcome by inhibition of AKR1C1 activity, inhibition of AKR1C1 expression, and bypassing AKR1C1 activity with a P4 analog that is not metabolized by AKR1C1. Increased P4 activity in response to AKR1C1 inhibition was prevented by the P4 receptor antagonist RU486. Pharmacologic inhibition of AKR1C1 activity prevented parturition in a mouse model of inflammation-induced preterm parturition. The data suggest that inflammatory stimuli at the CDI drive labor by inducing AKR1C1-mediated P4 inactivation in DS cells and that inhibiting and/or bypassing of AKR1C1-mediated P4 inactivation is a plausible therapeutic strategy to mitigate the risk of inflammation-associated preterm birth.

The impact of HBB-related hemoglobinopathies carrier status on fetal fraction in noninvasive prenatal screening.

OBJECTIVE: We evaluated whether there is an association between ß-globin (HBB) pathogenic variants and fetal fraction (FF), and whether the association has a clinically relevant impact on non-invasive prenatal screening (NIPS). METHOD: A whole-genome sequencing NIPS laboratory database was retrospectively queried for women who underwent NIPS and carrier screening of both HBB and the α-globin genes (HBA1/HBA2). Women affected with either condition were excluded from the study, yielding a cohort size of 15,853. A "corrected FF" was obtained via multivariable linear regression adjusted for the systematic impacts of maternal age, gestational age and BMI. Corrected FF distributions of HBB and HBA1/HBA2 carriers were each compared to non-carriers using the Kolmogorov-Smirnov test. RESULTS: In this cohort, 291 women were carriers for HBB alone, and 1016 were carriers for HBA1/HBA2 alone. The HBB carriers had a lower corrected FF when compared to non-carriers (p < 0.0001). There was no difference in corrected FF among carriers and non-carriers of HBA1/HBA2. CONCLUSION: Carriers of pathogenic variants in the HBB gene, but not the HBA1/HBA2 genes, are more likely to have lower FF when compared to women with structurally normal hemoglobin. This decrease in FF could result in an elevated test-failure rate if FF thresholds were used.

Role of C-reactive protein in effective utilization of emergent MRI for spinal infections.

PURPOSE: Emergent spinal MRI is recommended for patients with back pain and red flags for infection. However, many of these studies are negative due to low prevalence of spinal infections. Our purpose was to assess if C-reactive protein (CRP) can be used to guide effective utilization of emergent MRI for spinal infections. METHODS: 316/960 (33%) MRIs performed for infection by the emergency department over 75-month period had CRP levels obtained at presentation, after excluding patients receiving antibiotic or had spinal surgery in < 1 month. An MRI was considered positive when there was imaging evidence of spinal infection confirmed on follow-up by surgery/biopsy/drainage or definitive therapy. A CRP of ≤ 10 mg/L was considered normal and > 100 mg/L as highly elevated. RESULTS: CRP was normal in 95/316 (30%) and abnormal in 221/316 (70%) patients. MRI was positive in 43/316 (13.6%) patients, all of whom had abnormal CRP. CRP (p < 0.001) and intravenous drug use (IVDU; p = 0.002) were independently associated with a positive MRI. Receiver operator characteristic (ROC) analysis showed AUC of 0.76 for CRP, slightly improving with IVDU. Sensitivity, specificity, and negative predictive values for CRP level cut-off: 10 mg/L, 100%, 35%, and 100%, and 100 mg/L, 58%, 70% and 91%, respectively. CONCLUSION: Abnormal CRP, although extremely sensitive, lacks specificity in predicting a positive MRI for spinal infection unless highly elevated. However, a normal CRP (absent recent antibiotic or surgery) makes spinal infection unlikely, and its routine use as a screening test can help reducing utilization of emergent MRI for this purpose.

Term Labor Outcomes after Cerclage Placement in a Multi-institutional Cohort.

OBJECTIVE: The placement of a cervical cerclage in early pregnancy could influence subsequent labor outcomes at term. Prior studies have yielded conflicting results regarding the potential association with adverse labor outcomes such as cesarean delivery (CD), cervical laceration, and prolonged labor. Our objective was to evaluate rate of CD and adverse maternal outcomes in women who labored at term with and without a cerclage within the Consortium on Safe Labor (CSL) cohort. We hypothesize that women with a cerclage in the incident pregnancy will have an increased frequency of CD and other adverse term labor outcomes. STUDY DESIGN: A retrospective cohort study was performed using data from the CSL. Women with live nonanomalous singleton gestations≥ 37 weeks with induced or spontaneous labor were identified. The risk of CD and other maternal and neonatal outcomes were compared between women with and without cerclage placement during pregnancy. Univariable and multivariable analyses were performed with adjustment for confounding factors. Planned subgroup analysis by history of CD was performed. RESULTS: A total of 374 of the 147,463 patients who met study inclusion criteria in the CSL (0.25%) had a cerclage. In univariable analysis, cerclage placement was associated with a significant increase in the frequency of CD (17.1 vs. 12.8%, p = 0.016, odds ratio: 1.4, 95% CI: 1.07-1.84), cervical lacerations, infectious morbidity, and blood loss. The association with CD persisted in multivariable regression. Cerclage placement was not associated with an increased risk of neonatal morbidity. CONCLUSION: Cerclage placement in pregnancy is associated with an increased risk of CD, cervical laceration, and infectious morbidity among women delivering at term. These findings suggest that cerclage placement may impact labor progression and outcomes. However, the magnitude of the association may not alter clinical decisions regarding cerclage placement in appropriate candidates.

Comparison of Automated CT Perfusion Softwares in Evaluation of Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Automated imaging software is integral to decision-making in acute ischemic stroke (AIS) during extended time windows. RAPID software is the most widely used and has been validated in landmark endovascular trials. Olea software is another commercially available and FDA-approved software, but has not been studied in AIS trials. We aimed to compare the diagnostic utility and accuracy of RAPID and Olea in everyday clinical practice outside of a clinical trial. METHODS: We analyzed prospectively-collected data from a consecutive cohort of 141 patients with suspected AIS who underwent computed tomography perfusion upon presentation followed by diffusion-weighted magnetic resonance imaging (DWI-MRI) within 24-48 hours. Core infarct was defined as the region with a relative cerebral blood flow (rCBF) less than 30% on RAPID and rCBF less than 40% on Olea (default settings). We also evaluated rCBF less than 30% on Olea to match RAPID's default setting. Infarct volume on DWI-MRI was measured using a semiautomated segmentation method. RESULTS: Twenty-one patients were excluded; 14 due to poor bolus tracking and/or motion artifact, and 7 due to software failure. The software failure rate was 4.7% [6/127] with RAPID versus .78% [1/127] with Olea (P = .12). For the remaining 120 patients, the sensitivity and specificity for detecting an acute infarct were 40.5% and 97.6% for RAPID; 50.6% and 85.4% for Olea; and for detecting large infarcts (≥70 mL on DWI-MRI) 73.7% and 81.2% for RAPID; 73.7% and 68.3% for Olea. Core infarct volume on RAPID was more closely correlated with DWI-MRI infarct volume (rho = .64) than Olea (rho = .42). CONCLUSIONS: Our head-to-head comparison of these 2 commonly-used softwares in the clinical setting elucidates the pros and cons of their use to guide decision-making for AIS management in the acute setting.

Female Human Spines with Simulated Osteolytic Defects: CT-based Structural Analysis of Vertebral Body Strength.

Purpose To evaluate a CT structural analysis protocol (SAP) for estimating the strength of human female cadaveric spines with lytic lesions. Materials and Methods Osteolytic foci was created in the middle vertebra of 44 thoracic and lumbar three-level segments from 11 female cadavers (age range, 50-70 years). The segments underwent CT by using standard clinical protocol and their failure strength was assessed at CT SAP. The spines were mechanically tested to failure in pure axial compression or in compression with torsion. The relationships of defect size, bone mineral density, and predicted failure load (at CT SAP) with measured vertebral strength were assessed with linear regression. Analysis of variance and Tukey test were used to evaluate the effect of region and mechanical test on spine strength. Results With axial compression, CT SAP predictions of vertebral strength correlated with the thoracic (r = 0.84; P < .001) and lumbar (r = 0.85; P < .001) segment-measured strength. Bone mineral density correlated with the lumbar (r = 0.64; P = .003) and thoracic (r, 0.51; P = .050) strength. At compression with torsion, CT SAP predictions of strength were moderately correlated with vertebral strength (r = 0.66; P = .018). At compression with torsion, bone mineral density was not correlated with spinal strength (thoracic and lumbar: r = 0.31 and r = 0.26, respectively; P = .539 and .610, respectively). The lytic focus size (range, 28%-41%) was not associated with vertebral strength. Conclusion CT SAP assessment of strength in vertebrae with lytic lesions correlated with the measured strength of female vertebral bodies. © RSNA, 2018 Online supplemental material is available for this article.

Cervical ripening balloon with and without oxytocin in multiparas: a randomized controlled trial.

BACKGROUND: The optimal method for induction of labor for multiparous women with an unfavorable cervix is unknown. OBJECTIVE: We sought to determine if induction of labor with simultaneous use of oxytocin and a cervical ripening balloon, compared with sequential use, increases the likelihood of delivery within 24 hours in multiparous women. STUDY DESIGN: We performed a randomized controlled trial from November 2014 through June 2017. Eligible participants were multiparous women with a vertex presenting, nonanomalous singleton gestation ≥34 weeks undergoing induction of labor. Women were excluded for admission cervical examination >2 cm, ruptured membranes, chorioamnionitis or evidence of systemic infection, placental abruption, low-lying placenta, >1 prior cesarean delivery, or contraindication to vaginal delivery. Patients were randomly allocated to the following cervical ripening groups: simultaneous (oxytocin with cervical ripening balloon) or sequential (oxytocin following cervical ripening balloon expulsion). The primary outcome was delivery within 24 hours of cervical ripening balloon placement. Secondary outcomes included induction-to-delivery interval, time to cervical ripening balloon expulsion, mode of delivery, and adverse maternal or neonatal outcomes. RESULTS: In all, 180 patients were randomized (90 simultaneous, 90 sequential). Baseline demographic and obstetric characteristics were similar between study groups. Women in the simultaneous group were significantly more likely to deliver within 24 hours of cervical ripening balloon placement compared to the sequential group (87.8% vs 73.3%, P = .02). The simultaneous group also had a significantly shorter induction-to-delivery interval and greater cervical dilation at cervical ripening balloon expulsion. There were no differences in mode of delivery, chorioamnionitis, or adverse maternal or neonatal outcomes. CONCLUSION: In multiparous women with an unfavorable cervix, the simultaneous use of cervical ripening balloon and oxytocin results in an increased frequency of delivery within 24 hours and a shorter induction-to-delivery interval.

Chlamydia trachomatis and Adverse Pregnancy Outcomes: Meta-analysis of Patients With and Without Infection.

OBJECTIVES: We conducted a meta-analysis to determine the association between Chlamydia trachomatis and adverse perinatal outcomes. METHODS: Electronic databases were searched between 1970 and 2013. Included studies reported perinatal outcomes in women with and without chlamydia. Summary odds ratios were calculated using fixed- and random-effects models. Study bias was assessed using a Funnel Plot and Begg's test. RESULTS: Of 129 articles identified, 56 studies met the inclusion criteria encompassing 614,892 subjects. Chlamydia infection in pregnancy was associated with preterm birth (OR = 1.27, 95% CI 1.05, 1.54) with a large quantity of heterogeneity (I2 = 61%). This association lost significance when limiting the analysis to high-quality studies based on the Newcastle-Ottawa Scale. Chlamydia infection in pregnancy was also associated with preterm premature rupture of membranes (OR = 1.81, 95% CI 1.0, 3.29), endometritis (OR 1.69, 95% CI 1.20, 2.38), low birthweight (OR 1.34, 95% CI 1.21, 1.48), small for gestational age (OR 1.14, 95% CI 1.05, 1.25) and intrauterine fetal demise (OR 1.44, 95% CI 1.06, 1.94). CONCLUSIONS: This review provides evidence that chlamydia in pregnancy is associated with a small increase in the odds of multiple adverse pregnancy outcomes. The literature is complicated by heterogeneity and the fact that the association may not hold in higher quality and prospective studies or those that use more contemporary nucleic acid testing.

Pregnancy Outcomes after Endometrial Ablation in a Multi-institutional Cohort.

OBJECTIVE: The objective of this study was to determine the incidence of morbidly adherent placenta in pregnancies after endometrial ablation. STUDY DESIGN: We performed a retrospective cohort analysis using a large, multiinstitutional deidentified clinical database, IBM EPM: Explore (IBM Corporation, Somers, NY). We identified women who underwent endometrial ablation and had a subsequent delivery between 1999 and 2016. Patients with a delivery and no prior ablation were used as controls. The association between morbidly adherent placenta, ablation, and other known risk factors for morbidly adherent placenta was analyzed using multivariable logistic regression. RESULTS: Of 162,100 reproductive-aged women who underwent endometrial ablation, 2,770 women (1.71%) subsequently had a delivery. The rate of morbidly adherent placenta was 1 in 13.9 pregnancies after ablation compared with 1 in 838.7 pregnancies in the control group (adjusted odds ratio [aOR], 20.22, p < 0.0001). CONCLUSION: Pregnancies that occurred after endometrial ablation were associated with increased rates of morbidly adherent placenta.

Detection and Predictive Value of Fractional Anisotropy Changes of the Corticospinal Tract in the Acute Phase of a Stroke.

BACKGROUND AND PURPOSE: A decrease in fractional anisotropy (FA) of the ipsilesional corticospinal tract (CST) distal to stroke lesions in the subacute (eg, 30 days) and chronic phase has been correlated with poor motor outcomes, but it is unclear whether FA values obtained within the acute stroke phase (here defined as 80 hours after onset) can predict later outcome. METHODS: Fifty-eight patients underwent an assessment of motor impairment in the acute phase and at 3 months using the upper extremity Fugl-Meyer assessment. FA values, obtained within 80 hours after stroke onset, were determined in 2 regions of interest: cerebral peduncle and a stretch of the CST caudal to each stroke lesion (nearest-5-slices). RESULTS: The FA laterality index for the cerebral peduncle-regions of interest was a poor predictor of 3-month outcome (R(2)=0.044; P=0.137), whereas the slope over the FA laterality index of the nearest-5-slices showed a relatively weak but significant prediction (R(2)=0.11; P=0.022) with the affected side having lower FA values. Initial upper extremity Fugl-Meyer (R(2)=0.69; P<0.001) and the weighted CST lesion load (R(2)=0.71; P<0.001) were strong predictors of 3-month outcome. In multivariate analyses, controlling for initial upper extremity Fugl-Meyer, weighted CST lesion load, and days-of-therapy, neither the FA laterality index of the cerebral peduncle nor the slope over the FA laterality index of the nearest-5-slices significantly contributed to the prediction of 86% of the variance in the upper extremity Fugl-Meyer at 3 months. CONCLUSIONS: FA reductions of the CST can be detected near the ischemic lesion in the acute stroke phase, but offer minimal predictive value to motor outcomes at 3 months.

Nucleotide-free kinesin motor domains reversibly convert to an inactive conformation with characteristics of a molten globule.

Nucleotide-free kinesin motor domains from several kinesin families convert reversibly to a refractory conformation that cannot rapidly rebind ADP. In the absence of glycerol, the refractory conformation of Drosophila kinesin motor domains is favored by 50-fold with conversion of the active to the refractory species at ∼0.052 s(-1) and reactivating in the presence of ADP at ∼0.001 s(-1). This reactivation by ADP is due to conformational selection rather than induced fit because ADP is not bound to the refractory species at concentrations of ADP that are sufficient to saturate the rate of reactivation. Glycerol stabilizes the active conformation by reducing the rate of inactivation, while having little effect on the reactivation rate. Circular dichroism indicates a large conformational change occurs on formation of the refractory species. The refractory conformation binds ANS (8-anilino-1-napthalenesulfonic acid) with a large increase in fluorescence, indicating that it has molten globule character. High ANS binding is also observed with the refractory forms of Eg5 (a kinesin-5) and Ncd (a kinesin-14), indicating that a refractory conformation with molten globule characteristics may be a common feature of nucleotide-free kinesin motor domains.

Maternal and neonatal outcomes of attempted vaginal compared with planned cesarean delivery in triplet gestations.

BACKGROUND: The prevailing obstetric practice of planned cesarean delivery for triplet gestations is largely empiric and data on the optimal route of delivery are limited. OBJECTIVE: The primary objectives of this study are to determine the likelihood of success in an attempted vaginal delivery and assess maternal and neonatal outcomes of attempted vaginal vs planned cesarean delivery of triplets using a multiinstitution obstetric cohort. STUDY DESIGN: We performed a retrospective cohort study using data from the Consortium on Safe Labor, identifying triplet pregnancies with delivery at a gestational age ≥28 weeks. Women with a history of cesarean delivery and pregnancies complicated by chromosomal or congenital anomalies, twin-twin transfusion syndrome, or a fetal demise were excluded. The attempted vaginal group included all women with spontaneous or induced labor and excluded all women delivering by prelabor cesarean delivery, including those coded as elective or for fetal malpresentation. Primary maternal outcomes included infection (composite of chorioamnionitis, endometritis, wound separation, and wound infection), blood transfusion, or transfer to the intensive care unit. Primary neonatal outcomes included neonatal asphyxia, mechanical ventilation, and composite neonatal morbidity, consisting of ≥1 of the following: birth injury, 5-minute Apgar <4, arterial pH <7.0 or base excess <-12.0, neonatal asphyxia, or neonatal death. For neonatal outcomes, Poisson regression was performed with clustering to account for correlation between neonates within a triplet pregnancy, controlling for confounders as outcome rates allowed. A sensitivity analysis was performed in the subcohort delivering at gestational age ≥34 weeks in which the attempted vaginal delivery group was restricted to include only women with evidence of induction or augmentation or labor. RESULTS: 188 triplet sets were identified of which 80 sets (240 neonates) met inclusion criteria and 24 sets (30%) had an attempted vaginal delivery. The rate of successful attempted vaginal delivery was 16.7% (4 triplet sets; 12 neonates). No women had a combined mode of delivery. Women attempting vaginal delivery were more likely to have preterm labor (45.8 vs 12.5%, P < .001) and receive antenatal corticosteroids (45.8 vs 21.4%, P = .03), however gestational age at delivery did not differ by mode of delivery. Attempted vaginal delivery was associated with a higher risk of maternal transfusion (20.8% vs 3.6%, P = .01) and neonatal mechanical ventilation (26.4% vs 7.7%; adjusted incidence rate ratio, 1.12; 95% confidence interval, 1.01-1.24). There was no significant difference in the risk of asphyxia or composite neonatal morbidity by mode of delivery. In the subcohort sensitivity analysis, attempted vaginal delivery was associated with an increased risk of composite neonatal morbidity (adjusted incidence rate ratio, 12.44; 95% confidence interval, 1.22-127.20) but not maternal transfusion (22.2% vs 3.5%, P = .06) or neonatal mechanical ventilation (adjusted incidence rate ratio, 1.02; 95% confidence interval, 0.89-1.17). CONCLUSION: In a multicenter US cohort, attempted vaginal delivery of triplets is associated with higher risks of maternal transfusion and neonatal mechanical ventilation. Composite severe neonatal morbidity may be higher with attempted vaginal delivery although studies with greater power are required. The low probability of successful vaginal delivery raises questions regarding the utility of attempted vaginal delivery in triplet gestations. Our data support planned prelabor cesarean delivery as the preferred mode of delivery for triplet gestations.

Does pregnancy increase the risk of abdominal hernia recurrence after prepregnancy surgical repair?

BACKGROUND: By increasing intraabdominal pressure, pregnancy may increase the risk of abdominal hernia recurrence. Current data are limited to studies with small sample size and thus the impact of pregnancy on recurrence is unclear. OBJECTIVE(S): The objective of this analysis was to evaluate the impact of pregnancy on clinically significant abdominal hernia recurrence in a large multicenter cohort. STUDY DESIGN: A multiinstitution deidentified electronic health record database, EPM: Explore (Explorys Inc, Cleveland, OH) was utilized to perform a retrospective cohort study of women aged 18-45 years with a history of an abdominal hernia repair from 1999 through 2013. Abdominal hernia was defined to include ventral and incisional hernias, and other types were excluded. The presence or absence of a pregnancy following primary hernia repair was elucidated from the database. Subjects were excluded if a hernia repair occurred during pregnancy. The rate of hernia recurrence, defined as reoperation, was calculated. The association between pregnancy and hernia recurrence was evaluated with logistic regression, both unadjusted and adjusted for diabetes, obesity (body mass index >30 kg/m(2)), tobacco abuse, and wound complication at the time of initial hernia repair. RESULTS: A total of 11,020 women with a history of hernia repair were identified, of whom 840 had a subsequent pregnancy. Overall, 915 women in the cohort had a hernia recurrence (8.3%). Women with a history of pregnancy following primary hernia repair were more likely to have a body mass index >30 kg/m(2), a history of tobacco abuse, and a wound complication at the time of primary repair. In an unadjusted analysis, pregnancy was associated with an increase in the risk of hernia recurrence (13.1% vs 7.1%, odds ratio, 1.96, 95% confidence interval, 1.60-2.42). The association between pregnancy and hernia recurrence was attenuated but persisted after adjusting for confounding factors (adjusted odds ratio, 1.73, 95% confidence interval, 1.40-2.14). CONCLUSION: Pregnancy is associated with an increased risk of abdominal hernia recurrence after adjusting for confounding factors. The magnitude of this association is likely underestimated, given that the risk of recurrence was defined as reoperation, which captures only the most clinically significant group of recurrences. This information will facilitate counseling for reproductive-aged women planning elective ventral or incisional hernia repair. The risk of recurrence and subsequent reoperation should be balanced against the risk of incarceration and emergent surgery during pregnancy. As such, the desire for future pregnancy and/or contraception should be considered when planning asymptomatic hernia repair for women of reproductive age.

Obstetrician Attitudes, Experience, and Knowledge of Planned Home Birth: An Exploratory Study.

BACKGROUND: The incidence of planned home birth is increasing in the United States. The American College of Obstetricians and Gynecologists acknowledges a woman's right to make an informed choice about place of delivery, including home birth. This exploratory study measures obstetricians' attitudes, experiences, and knowledge about planned home birth, identifies associations between these factors, and compares obstetricians' responses in Ohio to those in Arizona and New Mexico. METHODS: A survey about attitudes, experiences, and knowledge of planned home birth was distributed to obstetricians in Ohio, Arizona, and New Mexico. Attitude and knowledge scores were calculated for each respondent and used to evaluate associations through linear regression. Attitude and knowledge scores in states that have regulation of direct entry midwives (Arizona and New Mexico) were compared to a state which does not (Ohio). RESULTS: Obstetricians in all three states reported little experience and knowledge of planned home birth and overall negative attitudes. Obstetricians with stronger knowledge did not differ in their attitudes from those with less knowledge. No statistically significant differences were found when comparing attitude and knowledge scores in Ohio to Arizona and New Mexico, but Ohio obstetricians responded most negatively to the attitude questions. CONCLUSIONS: Obstetricians have limited knowledge and experience and hold very negative attitudes about planned home birth. Research is necessary to determine: 1) whether negative obstetrician attitudes would be modified by exposure to home birth education and experience, and, 2) whether negative obstetrician beliefs deter safe and timely transfer from home or compromise hospital care for transferred parturients.

Hyperintense cortical signal on magnetic resonance imaging reflects focal leukocortical encephalitis and seizure risk in progressive multifocal leukoencephalopathy.

OBJECTIVE: To determine the frequency of hyperintense cortical signal (HCS) on T1-weighted precontrast magnetic resonance (MR) images in progressive multifocal leukoencephalopathy (PML) patients, its association with seizure risk and immune reconstitution inflammatory syndrome (IRIS), and its pathologic correlate. METHODS: We reviewed clinical data including seizure history, presence of IRIS, and MR imaging scans from PML patients evaluated at our institution between 2003 and 2012. Cases that were diagnosed either using cerebrospinal fluid JC virus (JCV) polymerase chain reaction, brain biopsy, or autopsy, and who had MR images available were included in the analysis (n=49). We characterized pathologic findings in areas of the brain that displayed HCS in 2 patients and compared them with isointense cortex in the same individuals. RESULTS: Of 49 patients, 17 (34.7%) had seizures and 30 (61.2%) had HCS adjacent to subcortical PML lesions on MR images. Of the 17 PML patients with seizures, 15 (88.2%) had HCS compared with 15 of 32 (46.9%) patients without seizures (p=0.006). HCS was associated with seizure development with a relative risk of 4.75 (95% confidence interval=1.2-18.5, p=0.006). Of the 20 patients with IRIS, 16 (80.0%) had HCS compared with 14 of 29 (49.3%) patients without IRIS (p=0.04). On histological examination, HCS areas were associated with striking JCV-associated demyelination of cortical and subcortical U fibers, significant macrophage infiltration, and a pronounced reactive gliosis in the deep cortical layers. INTERPRETATION: Seizures are a frequent complication in PML. HCS is associated with seizures and IRIS, and correlates histologically with JCV focal leukocortical encephalitis.

MR diffusion is sensitive to mechanical loading in human intervertebral disks ex vivo.

PURPOSE: To use T2 and diffusion MR to determine the change in the mechanical function of human disks with increased degenerative state. MATERIALS AND METHODS: Spatial changes in T2 and diffusion were quantified in five cadaveric human lumbar disks under compressive loads. Regression models were used to investigate the relationship between the change in MR parameters and the disk's dynamic and viscoelastic properties. RESULTS: Compressive loading caused a significant reduction in the disk's mean diffusivity ([11.3 versus 9.7].10(-4) .mm(2) /s, P < 0.001) but little change in T2 (P < 0.05). Diffusivity and T2 were correlated with the disk's dynamic (P < 0.01 and P < 0.05) and long-term viscoelastic (P < 0.05 and P < 0.05) stiffness. Diffusivity but not T2, was correlated with its viscoelastic dampening (r(2) = 0.45, P < 0.01) and instantaneous stiffness (r(2) = 0.44, P < 0.05). Nucleus diffusivity was significantly higher than the annulus's (-21% to -4%, P < 0.01). MR-estimated hydration was correlated with the instantaneous viscoelastic stiffness of the nucleus (r(2) = 0.35, P < 0.05) and the dynamic (r(2) = 0.44, P < 0.05) and long-term viscoelastic (r(2) = 0.42, P < 0.05) stiffness in the annulus. T2 correlated with diffusivity at low load (r(2) = 0.66, P < 0.05), but not at high load. CONCLUSION: The strong correlations between diffusivity and the rheological assessments of disk mechanics suggest that MR might permit quantitative assessment of disk functional status and structural integrity.

Direct magnetic resonance detection of myelin and prospects for quantitative imaging of myelin density.

Magnetic resonance imaging has previously demonstrated its potential for indirectly mapping myelin density, either by relaxometric detection of myelin water or magnetization transfer. Here, we investigated whether myelin can be detected and possibly quantified directly. We identified the spectrum of myelin in the spinal cord in situ as well as in myelin lipids extracted via a sucrose gradient method, and investigated its spectral properties. High-resolution solution NMR spectroscopy showed the extract composition to be in agreement with myelin's known chemical make-up. The 400-MHz (1)H spectrum of the myelin extract, at 20 °C (room temperature) and 37 °C, consists of a narrow water resonance superimposed on a broad envelope shifted ∼3.5 ppm upfield, suggestive of long-chain methylene protons. Superimposed on this signal are narrow components resulting from functional groups matching the chemical shifts of the constituents making up myelin lipids. The spectrum could be modeled as a sum of super-Lorentzians with a T(2)* distribution covering a wide range of values (0.008-26 ms). Overall, there was a high degree of similarity between the spectral properties of extracted myelin lipids and those found in neural tissue. The normalized difference spectrum had the hallmarks of membrane proteins, not present in the myelin extract. Using 3D radially ramp-sampled proton MRI, with a combination of adiabatic inversion and echo subtraction, the feasibility of direct myelin imaging in situ is demonstrated. Last, the integrated signal from myelin suspensions is shown, both spectroscopically and by imaging, to scale with concentration, suggesting the potential for quantitative determination of myelin density.

Three-dimensional brain MRI for DBS patients within ultra-low radiofrequency power limits.

BACKGROUND: For patients with deep brain stimulators (DBS), local absorbed radiofrequency (RF) power is unknown and is much higher than what the system estimates. We developed a comprehensive, high-quality brain magnetic resonance imaging (MRI) protocol for DBS patients utilizing three-dimensional (3D) magnetic resonance sequences at very low RF power. METHODS: Six patients with DBS were imaged (10 sessions) using a transmit/receive head coil at 1.5 Tesla with modified 3D sequences within ultra-low specific absorption rate (SAR) limits (0.1 W/kg) using T2 , fast fluid-attenuated inversion recovery (FLAIR) and T1 -weighted image contrast. Tissue signal and tissue contrast from the low-SAR images were subjectively and objectively compared with routine clinical images of six age-matched controls. RESULTS: Low-SAR images of DBS patients demonstrated tissue contrast comparable to high-SAR images and were of diagnostic quality except for slightly reduced signal. CONCLUSIONS: Although preliminary, we demonstrated diagnostic quality brain MRI with optimized, volumetric sequences in DBS patients within very conservative RF safety guidelines offering a greater safety margin.

Diffusion restriction in the human spinal cord characterized in vivo with high b-value STEAM diffusion imaging.

Restricted or hindered motion of water across axonal membranes as characterized with diffusion-weighted (DW) imaging may be a potential marker of axonal damage in white matter (WM) injury due to trauma, neurodegeneration, or other causes. This study sought to determine whether high b-value DW imaging with a stimulated echo (STEAM) sequence could improve the spatially resolved assessment of tissue architecture in the human spinal cord in vivo. Diffusion times from 76 ms to 1000 ms and b-values of up to 14,750 s/mm(2) were used to acquire axial DW images in six healthy volunteers, and four additional healthy volunteers were studied with a protocol focused on high b-value, higher-resolution imaging. Mono-exponential, diffusional kurtosis, and mono-exponential with an additive constant (MEC) models were fit individually to diffusion decay curves obtained at different diffusion times. Diffusion restriction, characterized with the diffusional kurtosis and MEC models, was measured more precisely using higher b-value ranges. DW images at high b-value and fitting parameters using the large range of b-values available at the diffusion time of 1000 ms demonstrated signal and restriction differences between gray and white matter and even across white matter regions. These white matter differences may reflect variations in axonal density, diameter, or alignment. We conclude that high b-value DW imaging with a STEAM sequence on a conventional clinical scanner can provide accurate measures of diffusion hindrance and restriction in human spinal cord in vivo.

Structural insights into a unique inhibitor binding pocket in kinesin spindle protein.

Human kinesin Eg5 is a target for drug development in cancer chemotherapy with compounds in phase II clinical trials. These agents bind to a well-characterized allosteric pocket involving the loop L5 region, a structural element in kinesin-5 family members thought to provide inhibitor specificity. Using X-ray crystallography, kinetic, and biophysical methods, we have identified and characterized a distinct allosteric pocket in Eg5 able to bind inhibitors with nanomolar K(d). This pocket is formed by key structural elements thought to be pivotal for force generation in kinesins and may represent a novel site for therapeutic intervention in this increasingly well-validated drug target.