Spin-orbit-driven band inversion in bilayer graphene by the van der Waals proximity effect.

Spin-orbit coupling (SOC) is the key to realizing time-reversal-invariant topological phases of matter1,2. SOC was predicted by Kane and Mele3 to stabilize a quantum spin Hall insulator; however, the weak intrinsic SOC in monolayer graphene4-7 has precluded experimental observation in this material. Here we exploit a layer-selective proximity effect-achieved via a van der Waals contact with a semiconducting transition-metal dichalcogenide8-21-to engineer Kane-Mele SOC in ultra clean bilayer graphene. Using high-resolution capacitance measurements to probe the bulk electronic compressibility, we find that SOC leads to the formation of a distinct, incompressible, gapped phase at charge neutrality. The experimental data agree quantitatively with a simple theoretical model in which the new phase results from SOC-driven band inversion. In contrast to Kane-Mele SOC in monolayer graphene, the inverted phase is not expected to be a time-reversal-invariant topological insulator, despite being separated from conventional band insulators by electric-field-tuned phase transitions where crystal symmetry mandates that the bulk gap must close22. Our electrical transport measurements reveal that the inverted phase has a conductivity of approximately e2/h (where e is the electron charge and h Planck's constant), which is suppressed by exceptionally small in-plane magnetic fields. The high conductivity and anomalous magnetoresistance are consistent with theoretical models that predict helical edge states within the inverted phase that are protected from backscattering by an emergent spin symmetry that remains robust even for large Rashba SOC. Our results pave the way for proximity engineering of strong topological insulators as well as correlated quantum phases in the strong spin-orbit regime in graphene heterostructures.

Prior differences in previous trauma exposure primarily drive the observed racial/ethnic differences in posttrauma depression and anxiety following a recent trauma.

BACKGROUND: Racial and ethnic groups in the USA differ in the prevalence of posttraumatic stress disorder (PTSD). Recent research however has not observed consistent racial/ethnic differences in posttraumatic stress in the early aftermath of trauma, suggesting that such differences in chronic PTSD rates may be related to differences in recovery over time. METHODS: As part of the multisite, longitudinal AURORA study, we investigated racial/ethnic differences in PTSD and related outcomes within 3 months after trauma. Participants (n = 930) were recruited from emergency departments across the USA and provided periodic (2 weeks, 8 weeks, and 3 months after trauma) self-report assessments of PTSD, depression, dissociation, anxiety, and resilience. Linear models were completed to investigate racial/ethnic differences in posttraumatic dysfunction with subsequent follow-up models assessing potential effects of prior life stressors. RESULTS: Racial/ethnic groups did not differ in symptoms over time; however, Black participants showed reduced posttraumatic depression and anxiety symptoms overall compared to Hispanic participants and White participants. Racial/ethnic differences were not attenuated after accounting for differences in sociodemographic factors. However, racial/ethnic differences in depression and anxiety were no longer significant after accounting for greater prior trauma exposure and childhood emotional abuse in White participants. CONCLUSIONS: The present findings suggest prior differences in previous trauma exposure partially mediate the observed racial/ethnic differences in posttraumatic depression and anxiety symptoms following a recent trauma. Our findings further demonstrate that racial/ethnic groups show similar rates of symptom recovery over time. Future work utilizing longer time-scale data is needed to elucidate potential racial/ethnic differences in long-term symptom trajectories.

Cross-correlation image analysis for real-time single particle tracking.

Accurately measuring the translations of objects between images is essential in many fields, including biology, medicine, chemistry, and physics. One important application is tracking one or more particles by measuring their apparent displacements in a series of images. Popular methods, such as the center of mass, often require idealized scenarios to reach the shot noise limit of particle tracking and, therefore, are not generally applicable to multiple image types. More general methods, such as maximum likelihood estimation, reliably approach the shot noise limit, but are too computationally intense for use in real-time applications. These limitations are significant, as real-time, shot-noise-limited particle tracking is of paramount importance for feedback control systems. To fill this gap, we introduce a new cross-correlation-based algorithm that approaches shot-noise-limited displacement detection and a graphics processing unit-based implementation for real-time image analysis of a single particle.

Childhood adversities and risk of posttraumatic stress disorder and major depression following a motor vehicle collision in adulthood.

AIMS: Childhood adversities (CAs) predict heightened risks of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) among people exposed to adult traumatic events. Identifying which CAs put individuals at greatest risk for these adverse posttraumatic neuropsychiatric sequelae (APNS) is important for targeting prevention interventions. METHODS: Data came from n = 999 patients ages 18-75 presenting to 29 U.S. emergency departments after a motor vehicle collision (MVC) and followed for 3 months, the amount of time traditionally used to define chronic PTSD, in the Advancing Understanding of Recovery After Trauma (AURORA) study. Six CA types were self-reported at baseline: physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect and bullying. Both dichotomous measures of ever experiencing each CA type and numeric measures of exposure frequency were included in the analysis. Risk ratios (RRs) of these CA measures as well as complex interactions among these measures were examined as predictors of APNS 3 months post-MVC. APNS was defined as meeting self-reported criteria for either PTSD based on the PTSD Checklist for DSM-5 and/or MDE based on the PROMIS Depression Short-Form 8b. We controlled for pre-MVC lifetime histories of PTSD and MDE. We also examined mediating effects through peritraumatic symptoms assessed in the emergency department and PTSD and MDE assessed in 2-week and 8-week follow-up surveys. Analyses were carried out with robust Poisson regression models. RESULTS: Most participants (90.9%) reported at least rarely having experienced some CA. Ever experiencing each CA other than emotional neglect was univariably associated with 3-month APNS (RRs = 1.31-1.60). Each CA frequency was also univariably associated with 3-month APNS (RRs = 1.65-2.45). In multivariable models, joint associations of CAs with 3-month APNS were additive, with frequency of emotional abuse (RR = 2.03; 95% CI = 1.43-2.87) and bullying (RR = 1.44; 95% CI = 0.99-2.10) being the strongest predictors. Control variable analyses found that these associations were largely explained by pre-MVC histories of PTSD and MDE. CONCLUSIONS: Although individuals who experience frequent emotional abuse and bullying in childhood have a heightened risk of experiencing APNS after an adult MVC, these associations are largely mediated by prior histories of PTSD and MDE.

Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study.

BACKGROUND: The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study showed a similar percentage of intracranial hemorrhage and good outcome in patients 3 months after stroke treatment given 0 to 90 minutes and 91 to 180 minutes after stroke onset. At 24 hours after stroke onset more patients treated 0 to 90 compared to 91 to 180 minutes after stroke onset had improved by four or more points on the NIH Stroke Scale (NIHSS). The authors performed further analyses to characterize the relationship of onset-to-treatment time (OTT) to outcome at 3 months, early improvement at 24 hours, and intracranial hemorrhage within 36 hours. METHODS: Univariate analyses identified potentially confounding variables associated with OTT that could mask an OTT-treatment interaction. Tests for OTT-treatment interactions adjusting for potential masking confounders were performed. An OTT-treatment interaction was considered significant if p < or = 0.10, implying that treatment effectiveness was related to OTT. RESULTS: For 24-hour improvement, there were no masking confounders identified and there was an OTT-treatment interaction (p = 0.08). For 3-month favorable outcome, the NIHSS met criteria for a masking confounder. After adjusting for NIHSS as a covariate, an OTT-treatment interaction was detected (p = 0.09): the adjusted OR (95% CI) for a favorable 3-month outcome associated with recombinant tissue-type plasminogen activator (rt-PA) was 2.11 (1.33 to 3.35) in the 0 to 90 minute stratum and 1.69 (1.09 to 2.62) in the 91 to 180 minute stratum. In the group treated with rt-PA, after adjusting for baseline NIHSS, an effect of OTT on the occurrence of intracranial hemorrhage was not detected. CONCLUSIONS: If the NINDS rt-PA Stroke Trial treatment protocol is followed, this analysis suggests that patients treated 0 to 90 minutes from stroke onset with rt-PA have an increased odds of improvement at 24 hours and favorable 3-month outcome compared to patients treated later than 90 minutes. No effect of OTT on intracranial hemorrhage was detected within the group treated with rt-PA, possibly due to low power.

Results of in vivo and in vitro studies for assessing prenatal toxicity.

Examples of a combined approach using in vivo as well as in vitro methods for the assessment of prenatal toxicity are presented. The topics discussed include the analysis of the possible embryotoxic potential of valproic acid (VPA), female sex hormones, bis(tri-n-butyltin) oxide (TBTO), and acyclovir and the problem of supplementing in vitro systems with drug-metabolizing activity.

Outcome of stroke patients without angiographically revealed arterial occlusion within four hours of symptom onset.

BACKGROUND AND PURPOSE: Follow-up imaging data from stroke patients without angiographically apparent arterial occlusions at symptom onset are lacking. We reviewed our Emergency Management of Stroke (EMS) trial experience to determine the clinical and imaging outcomes of patients with ischemic stroke who showed no arterial occlusion on angiograms obtained within 4 hours of symptom onset. METHODS: All patients in this report were participants in the EMS trial that was designed to address the safety and potential efficacy of combined IV and intraarterial thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke. RESULTS: Thirty-five patients were randomized to receive either IV rt-PA (n = 17) or placebo (n = 18), followed by cerebral angiography. No symptomatic arterial occlusion was evident in 10 (29%) of the 34 patients. Eight (80%) of 10 patients without angiographically apparent clot within 4 hours of symptom onset had a new cerebral infarction confirmed on follow-up brain imaging. The median 72-hour infarction volume was 2.4 cc (range, 1-30 cc). Four of the 10 "no-clot" patients had a favorable 3-month outcome as assessed by Barthel Index (score, 95 or 100) and modified Rankin Scale (score, 0 or 1). The six remaining patients had 3-month Rankin Scale scores of 1 (Barthel of 90), 2, 3, 4, or 5. CONCLUSION: Acute ischemic stroke patients with a neurologic deficit but a negative angiogram during the first 4 hours after symptom onset usually develop image-documented cerebral infarction, and approximately half suffer from long-term functional disability. The two most likely explanations for negative angiograms are very early irreversible ischemic damage despite recanalization or ongoing ischemia secondary to clot in non-visible penetrating arterioles or in the microvasculature.

Pharmacokinetic aspects of drug effects in vitro (II) placental transfer to the embryo and activity of some carboxylic acids structurally related to valproic acid in whole embryos in culture.

The transfer of a group of short/medium chain-length carboxylic acids, related to the antiepileptic drug valproic acid (VPA), to the whole rat embryo in vitro was investigated. The protein binding of the drugs in the culture medium determined the placental transfer in vitro: at comparable total concentrations, the substances that bound to a lesser degree (VPA and its metabolite 2-propyl-4-pentenoic acid; 4-en-VPA) reached higher embryonic levels than the more highly bound substances, octanoic acid (OA), 2-methyl-2-ethylcaproic acid (MEC), and the VPA metabolite, 2-propyl-2-pentenoic acid (2-en-VPA). Consequently, the amount of drug added to the culture did not correlate with the transfer to the embryo, but the concentration of the free drug in the culture medium correlated highly with embryonic exposure. The concentration of the drugs in the cultured embryos, the embryonic membranes and the subembryonic fluid were higher than the corresponding free concentrations in the medium. The difference in the teratogenic potency of the substances tested was clearly related to their intrinsic activity, since even high embryonic concentrations of 2-en-VPA, MEC and OA did not produce adverse effects in contrast to VPA and 4-en-VPA which were effective at levels several-fold lower. The effective concentrations of VPA in the cultured embryos were almost ten times lower than those in embryos in vivo. The factors responsible for the high vulnerability of the cultured embryos to the action of VPA are as yet unknown. Our results indicate that the determination of drug concentrations in cultured embryonic tissue is imperative for a rational interpretation of experimental data obtained from in vitro studies; a full validation of in vitro systems must incorporate pharmacokinetic studies.

Bovine serum: An alternative to rat serum as a culture medium for the rat whole embryo culture.

The results reported here demonstrate the ability of supplemented bovine serum to serve as a culture medium for rat whole embryos. After 48 hours' culture in bovine serum supplemented with Tyrode's buffer and methionine, 9.5-day-old rat embryos were at a stage of development comparable with that of embryos cultivated in homologous serum, although some deficiency in the formation of haemoglobin in embryonic blood cells could be observed. However, supplementation of the culture medium with haemoglobin overcame this deficiency. The procedure used for preparing the culture medium is described in detail and some advantages of bovine serum are discussed.

Angioedema related to angiotensin-converting enzyme inhibitors.

Angioedema is a disorder characterized by well-demarcated nonpitting edema involving the tongue, floor of the mouth, larynx, lips, and face. This condition can progress to upper airway obstruction and death. Angiotensin-converting enzyme inhibitors (ACEIs), relatively new antihypertensive agents, act by blocking the formation of angiotensin II, a potent vasoconstrictor and stimulator of aldosterone formation. ACEIs also retard the breakdown of bradykinin, a potent vasodilator, which may lead to the edema seen in nonhereditary angioedema. These ACEIs include enalapril, captopril, lisinopril, saralasin acetate, and a combination of ACEI with diuretics (for example, Capozide). From August 1987 to January 1989, we treated six patients with a nonhereditary form of angioedema related to ingestion of angiotensin-converting enzyme inhibitors. Symptoms developed in all patients within 12 hours after their initial dose of an ACEI. They presented with shortness of breath and dysphagia associated with tongue and floor of the mouth edema. Two of the six required intubation and monitoring in the surgical intensive care unit for 36 to 48 hours. Three required supportive treatment and observation in an intermediate care unit, and one received supportive care in the clinic and was discharged the same day. Specifically, treatment consisted of cessation of inciting agent, steroids, antihistamines, and epinephrine, if not otherwise contraindicated. Assays of C1 esterase inhibitor levels and C4 were normal in all six patients; this was important in order to rule out hereditary forms of angioedema. These cases will be discussed, including a review of the literature, methods of diagnosis, pathophysiology, and treatment of angioedema.

Dissecting cellulitis of the scalp.

Dissecting cellulitis of the scalp or perifolliculitis capitis abscedens et suffodiens is a rare, chronic, progressive, suppurative disease of the scalp of unknown etiology. It is characterized by painful nodules, purulent drainage, burrowing interconnecting abscesses, and cicatricial alopecia. The pathogenesis is unknown, although it is probably related to follicular occlusion, secondary infection, and deep inflammation. Black men in their second to fourth decade are predominantly affected. Treatment varies from systemic antibiotics to incision and drainage, x-ray epilation of the affected areas, systemic steroid administration, and surgical excision. Our experience with four patients with extensive scalp disease is presented. Wide excision of the affected areas and splitthickness skin graft are favored as our treatment of choice.

Prolonged hyperinsulinism and hypoglycemia. In an asphyxiated, small for gestation infant. Case management and literature review.

The authors describe a term female, asphyxiated, small for gestational age (SGA) infant with documented hyperinsulinism and hypoglycemia occurring at approximately 45 hours of age. The hypoglycemia was refractory to a high rate glucose infusion and steroid administration but responded to diazoxide. The subsequent hospital course was complicated by right-sided heart failure and sepsis. With the onset of sepsis, a transient hyperglycemia was noted that required intermittent insulin therapy for 10 days. Hypoglycemia and hyperinsulinism reemerged and responded to diazoxide therapy. An attempt to discontinue diazoxide at age 6 months was aborted at 2 weeks when hyperinsulinism and hypoglycemia recurred. The infant required diazoxide for 7 more months, then she recovered without having any sequelae. The review of this uncommon hypoglycemia etiology in an SGA and asphyxiated infant and the merits of long-term diazoxide treatment are discussed.

Nutritional rickets among breast-fed black and Alaska Native children.

Although nutritional rickets remains a problem primarily in developing countries, children in northern climates in developed countries may also be at risk. We reviewed the case histories of five children diagnosed in Alaska during 1993-96. Three of the children were black and two Alaska Native. Their ages ranged from 11 to 20 months and they presented during January, April, and September. All of the children were breast-fed but only two received their milk intake exclusively from breast milk. The presenting complaint included abnormal gait in two children and seizures, bowed legs, and growth delay in one child each. All five children demonstrated a decrease in their height-for-age percentile. The most common physical finding was a rachitic rosary which was present in four children. In Alaska, all black and Alaska Native children (and other more pigmented children) less than two years of age who receive all or part of their milk intake from breast milk should receive vitamin D supplementation regardless of the time of year.

MRI-guided, open trial of abciximab for ischemic stroke within a 3- to 24-hour window.

The authors assessed the effect of IV abciximab on early neurologic improvement and ischemic lesion growth in 29 patients with supratentorial stroke and NIH stroke scale score (NIHSSS) > or = 4 (11.1 +/- 5.9), treated within 3 to 24 (13.6 +/- 5.5) hours of onset. The 48 to 72-hour NIHSSS improvement was 4.4 +/- 3.2 and the 24-hour lesion growth on DWI was +23% (-50%, +103%); 7/26 (27%) patients experienced lesion size decrease. Treatment of sub-24-hour stroke with abciximab improves early post-treatment neurologic status and often attenuates ischemic lesion growth.

Treatment of acute ischemic stroke.

Acute ischemic stroke is the third leading cause of death in the United States and the leading cause of adult disability. The direct and indirect costs of stroke care exceed $51 billion annually. In 1996, the US Food and Drug Administration approved the first treatment for acute ischemic stroke, intravenous tissue plasminogen activator. Later that year, the National Institute of Neurologic Disorders and Stroke (a branch of the National Institutes of Health) convened a consensus conference on the Rapid Identification and Treatment of Acute Ischemic Stroke, setting goals for stroke care in the United States. Since then, it has become imperative that emergency physicians understand the pathophysiology of stroke, the basis and rationale for treatment, and the therapeutic approaches. This article reviews the state of the art of acute stroke treatment, its foundation, as well as its future.

Modification and standardization of the culture of early postimplantation embryos for toxicological studies.

The method of culturing "whole" rat embryos (days 9.5-11.5 of gestation, i.e. at the early stage of organogenesis) as modified and standardized in our laboratory is presented; We have succeeded in using bovine serum as culture medium instead of rat serum as recommended in the original procedure. Experimental conditions are described for obtaining reproducible results; An improved scoring system was developed which, in connection with a computerized documentation, greatly facilitates the evaluation of the data.

All-trans retinoic acid and 13-cis-retinoic acid in the rat whole-embryo culture: abnormal development due to the all-trans isomer.

9.5-day-old rat embryos were exposed to 3 micrograms 13-cis retinoic acid (13-cis-RA)/ml culture medium or 1 microgram all-trans retinoic acid (all-trans-RA)/ml culture medium for different time intervals of the culture period (test substance-exposure periods alternated with test substance-free periods). These studies were performed to confirm the hypothesis (Klug et al. 1989) that the effect of 13-cis-RA on embryonic development in vitro is predominantly caused by its isomerisation to all-trans-RA. A 12 h exposure of the rat embryos to 13-cis-RA during different periods of culture did not interfere with normal development. However, a 12 h exposure of the embryos to all-trans-RA in the first three quarters of the culture period significantly interfered with normal development and caused clear-cut and typical abnormalities. Embryonic exposure to 13-cis-RA, for periods of more than 12 h, caused severe interference with normal development and led to branchial effects very similar to those observed following to a 12 h exposure to all-trans-RA.

Post-hoc Rasch analysis of optimal categorization of an ordered-response scale.

The purpose of this study was to determine the optimal categorization of a self-efficacy ordered-response scale using the Rasch analysis and compare the performance of the Rasch statistics and parameter estimates with conventional statistics. A 50-item scale to measure psychomotor self-efficacy was administered to a total of 2,022 children, including 1,009 boys and 1,013 girls. The data analysis started by collapsing the original five adjacent categories into two, three, and four categories, and a total of 14 data sets were derived. Each of these data sets, including the original one, was analyzed using the Rasch rating scale model, and a set of Rasch model-data fit, category, and separation statistics and parameter estimates, as well as three conventional statistics, were computed and compared. It was found that, instead of the five-category construct designed, the best order of category meanings of the scale in respondents' perceptions was a three-category construct. The Rasch threshold estimates were sensitive indexes in determining the order of the categorization, and that item separation statistics were useful in determining the optimal categorization after its order was confirmed. The commonly used coefficient alpha was found not helpful at all in determining the optimal categorization. The Rasch analysis was demonstrated to be a useful post-hoc analytic approach in determining the optimal categorization of an ordered-response scale.

Pharmacokinetic aspects of drug effects in vitro: effects of serum protein binding on concentration and teratogenicity of valproic acid and 2-en-valproic acid in whole embryos in culture.

Pharmacokinetic studies were performed in connection with culture experiments. Using the technique of cultivating whole rat embryos of the early postimplantation stage, we measured the concentration of valproic acid (VPA) and 2-en-VPA in the culture medium (free and protein-bound form) and in embryonic tissue. The following results were obtained: The concentrations of VPA and 2-en-VPA reached in the embryos were lower than corresponding total concentrations added to the culture medium, but exceeded the free concentrations in the medium. The concentrations of 2-en-VPA found in the embryo were lower than the comparable VPA total levels because of the more extensive protein binding of 2-en-VPA in the culture serum. The percentage of binding to serum proteins decreased with increasing total drug concentrations in the medium; the concentration of the free drug in the medium increased overproportionally with increasing total drug concentrations. Therefore, the free drug concentrations in the medium were not proportional to the dose of the drug dissolved in the medium (for a drug bound to plasma proteins). The concentrations of VPA and 2-en-VPA found in the embryos after incubation in vitro were not proportional to the drug concentrations dissolved in the medium. This result has to be taken into account when dose-response relationships are evaluated. VPA concentrations of 40 micrograms/g wet weight and above in the embryos clearly induced abnormal development in about 30% of the embryos, while 2-en-VPA concentrations as high as 200 micrograms/g embryo (wet weight) were inactive.(ABSTRACT TRUNCATED AT 250 WORDS)