Hypertension and Heart Failure with Preserved Ejection Fraction: Connecting the Dots.
Heart failure (HF) with preserved ejection fraction (EF) (HFpEF) accounts for approximately 50% of HF cases and its prevalence relative to HF with reduced EF is rising. Hypertension (HT) is the most common co-morbidity in HFpEF patients and it is implicated in both the pathogenesis and the prognosis of the disease. Therefore, HT is a modifiable risk factor of high yield in HFpEF. We reviewed the literature for epidemiologic data supporting the co-aggregation of the two entities as well as patho-physiologic mechanisms linking HT to HFpEF. Most importantly, we focused on treatment options targeting HT as a preventive strategy for delaying the progression of diastolic dysfunction or decreasing the odds for developing HFpEF. Along this line, we summarized the evidence and efficacy associated with different classes of antihypertensive medications in HFpEF patients. Finally, non-pharmacological approaches, including renal denervation and lifestyle modifications, to achieve optimal blood pressure (BP) control in HFpEF patients are reported. Unfortunately, no specific antihypertensive treatment has established a major survival benefit in this high risk subjects. Until the results of the efficacy of the novel drug LCZ696 (valsartan/ sacubitril) are available, the continuous monitoring and lowering of the BP by pharmacological and non-pharmacological means should be considered the major preventive and treatment strategy in HFpEF patients.


Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML.
The identification of patients with inherited cancer susceptibility syndromes facilitates early diagnosis, prevention, and treatment. However, in many cases of suspected cancer susceptibility, the family history is unclear and genetic testing of common cancer susceptibility genes is unrevealing. To apply whole-genome sequencing to a patient without any significant family history of cancer but with suspected increased cancer susceptibility because of multiple primary tumors to identify rare or novel germline variants in cancer susceptibility genes. DESIGN, SETTING, AND PARTICIPANT: Skin (normal) and bone marrow (leukemia) DNA were obtained from a patient with early-onset breast and ovarian cancer (negative for BRCA1 and BRCA2 mutations) and therapy-related acute myeloid leukemia (t-AML) and analyzed with the following: whole-genome sequencing using paired-end reads, single-nucleotide polymorphism (SNP) genotyping, RNA expression profiling, and spectral karyotyping. Structural variants, copy number alterations, single-nucleotide variants, and small insertions and deletions (indels) were detected and validated using the described platforms. RESULTS; Whole-genome sequencing revealed a novel, heterozygous 3-kilobase deletion removing exons 7-9 of TP53 in the patient's normal skin DNA, which was homozygous in the leukemia DNA as a result of uniparental disomy. In addition, a total of 28 validated somatic single-nucleotide variations or indels in coding genes, 8 somatic structural variants, and 12 somatic copy number alterations were detected in the patient's leukemia genome. Whole-genome sequencing can identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome.


Characteristics of Smartphone Applications for Nutrition Improvement in Community Settings: A Scoping Review.
Smartphone applications are increasingly being used to support nutrition improvement in community settings. However, there is a scarcity of practical literature to support researchers and practitioners in choosing or developing health applications. This work maps the features, key content, theoretical approaches, and methods of consumer testing of applications intended for nutrition improvement in community settings. A systematic, scoping review methodology was used to map published, peer-reviewed literature reporting on applications with a specific nutrition-improvement focus intended for use in the community setting. After screening, articles were grouped into 4 categories: dietary self-monitoring trials, nutrition improvement trials, application description articles, and qualitative application development studies. For mapping, studies were also grouped into categories based on the target population and aim of the application or program. Of the 4818 titles identified from the database search, 64 articles were included. The broad categories of features found to be included in applications generally corresponded to different behavior change support strategies common to many classic behavioral change models. Key content of applications generally focused on food composition, with tailored feedback most commonly used to deliver educational content. Consumer testing before application deployment was reported in just over half of the studies. Collaboration between practitioners and application developers promotes an appropriate balance of evidence-based content and functionality. This work provides a unique resource for program development teams and practitioners seeking to use an application for nutrition improvement in community settings.


Nursing leadership: bringing caring back to the future.
Leadership, whether it is nursing, medical or healthcare leadership, is about knowing how to make visions become reality. The vision that many nurses hold dear to their hearts is one where patients are treated with dignity and respect at all times; where systems are designed for the benefit of individual needs; and where the work performed by nurses and other carers is valued and respected. Achieving such a vision will require a paradigm shift in the philosophy, priorities, policies, and power relationships of the health service. Fundamentally, it will require the rhetoric of patient centred care to become a reality. The following scenario is set in the UK in the year 2012 and describes a health service that is on the pathway to achieving this vision. It tells the story from a nursing perspective and outlines the three key foundation stones that helped nursing achieve the vision of a patient centred health service: (1) development of patient centred care measures as part of performance management and the clinical governance agenda; (2) leadership based on personal growth and development principles; (3) new clinical career and competency framework for nursing.


The impact of familial expressed emotion on clinical and personal recovery among patients with psychiatric disorders: The mediating roles of self-stigma content and process.
The present study examined the associations of familial expressed emotion (EE) with clinical and personal recovery among patients with psychiatric disorders, as well as the potential mechanisms underlying these associations. Guided by the content-process theory of self-stigma, we hypothesized that EE would be negatively associated with clinical and personal recovery and that these associations would be mediated by self-stigma content and process. A total of 311 patients with psychiatric disorders completed questionnaires on their perceptions of EE, self-stigma, and recovery. Structural equation modeling demonstrated that EE was positively associated with self-stigma content and process, which were in turn negatively associated with clinical and personal recovery. The indirect effects of EE on clinical and personal recovery, via self-stigma content and process, were also significant. Multigroup analyses further demonstrated that the impact of EE on self-stigma and recovery was generalizable across patients with psychotic and nonpsychotic disorders. Theoretically, our findings revealed the potential pathways through which EE may adversely affect psychiatric recovery. Practically, our findings highlighted the importance of designing multipronged intervention programs to reduce familial EE and its potential harmful impact on psychiatric patients. In addition to helping family members improve their knowledge about psychiatric disorders and adjust their communication styles, practitioners should help psychiatric patients develop resilience against EE, mitigate self-stigma, and achieve recovery. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Impact of ghrelin on body composition and muscle function in a long-term rodent model of critical illness.
Patients with multiple injuries or sepsis requiring intensive care treatment invariably develop a catabolic state with resultant loss of lean body mass, for which there are currently no effective treatments. Recovery can take months and mortality is high. We hypothesise that treatment with the orexigenic and anti-inflammatory gastric hormone, ghrelin may attenuate the loss of body mass following critical illness and improve recovery. Male Wistar rats received an intraperitoneal injection of the fungal cell wall derivative zymosan to induce a prolonged peritonitis and consequent critical illness. Commencing at 48h after zymosan, animals were randomised to receive a continuous infusion of ghrelin or vehicle control using a pre-implanted subcutaneous osmotic mini-pump, and continued for 10 days. Zymosan peritonitis induced significant weight loss and reduced food intake with a nadir at Day 2 and gradual recovery thereafter. Supra-physiologic plasma ghrelin levels were achieved in the treated animals. Ghrelin-treated rats ate more food and gained more body mass than controls. Ghrelin increased adiposity and promoted carbohydrate over fat metabolism, but did not alter total body protein, muscle strength nor muscle morphology. Muscle mass and strength remained significantly reduced in all zymosan-treated animals, even at ten days post-insult. Continuous infusion of ghrelin increased body mass and food intake, but did not increase muscle mass nor improve muscle function, in a long-term critical illness recovery model. Further studies with pulsatile ghrelin delivery or additional anabolic stimuli may further clarify the utility of ghrelin in survivors of critical illness.


A venous outflow method for measurement of rapid changes of the cerebral blood flow and oxygen consumption in the rat.
A technique for continuous measurement of cerebral venous outflow in the rat is described. The method involves cannulation of one retroglenoid vein close to its exit from the skull, and diversion of cerebral venous blood through a closed extracorporal circuit with a drop recording device, the blood being returned to the central venous circulation via a catheter in the external jugular vein. Occlusion of the contralateral retroglenoid vein increases measured flow and minimizes extracerebral contamination of the diverted cerebral venous blood. The venous outflow system is not further isolated from cerebral or potential extracerebral collaterals. Thus, the mass of tissue drained cannot be exactly defined anatomically. However, the experiments involving changes of PP, arterial CO2 tension, and induction of epileptic seizure activity, and simultaneous indirect measurements with radioactive tracer technique, indicate that significant extracerebral contamination does not occur and that in short term measurements the venous outflow represents cerebral blood flow (CBF) in a constant mass of (dorsal and central, mainly forebrain) cerebral tissue. Measurement of arterial blood pressure and pressure in the cisterna magna allows calculation of cerebral perfusion pressure (PP). By simultaneous measurement of arterial and cerebral venous oxygen content changes in cerebral oxygen consumption (CMRO2) can be calculated. The method has been applied to document several situations of transient CBF and CMRO2 changes.


Morphology of mouse subplate cells with identified projection targets changes with age.
During embryonic and early postnatal development subplate neurons integrate into the developing intra- and extracortical circuitry in a dynamic fashion. They extend long-range projections to adjacent cortical regions, the contralateral hemisphere through the corpus callosum, and to subcortical structures through the internal capsule. Here we studied the developmental changes of the somatodendritic morphology of subplate neurons with specified projection target in the mouse. To do so we used carbocyanine dye tracing from the callosum, the internal capsule, or the primary somatosensory cortex. The morphology of subplate cells with projections to any of these targets is very diverse and includes pyramidal, multipolar, and neurogliaform cells. Here we demonstrate that a subpopulation of subplate cells in the mouse cortex undergoes significant changes in somatodendritic morphology during the critical period for experimental modification of the cytoarchitectonic development of the barrel cortex. Between P2 and P7 the mean maximal extent of the primary dendrite decreases significantly for subplate cells with an axon projecting through the internal capsule. Moreover, at P2 some subplate cells extend a primary dendrite to the marginal zone, whereas all dendrites of P7 subplate cells end in or below layer 4. Additionally, by tracing connections from multiple targets with different carbocyanine dyes we identified subplate cells with multiple long-range projections.


Ocean acidification ameliorates harmful effects of warming in primary consumer.
Climate change-induced warming and ocean acidification are considered two imminent threats to marine biodiversity and current ecosystem structures. Here, we have for the first time examined an animal's response to a complete life cycle of exposure to co-occurring warming (+3°C) and ocean acidification (+1,600 μatm CO 2), using the key subarctic planktonic copepod, Calanus finmarchicus, as a model species. The animals were generally negatively affected by warming, which significantly reduced the females' energy status and reproductive parameters (respectively, 95% and 69%-87% vs. control). Unexpectedly, simultaneous acidification partially offset the negative effect of warming in an antagonistic manner, significantly improving reproductive parameters and hatching success (233%-340% improvement vs. single warming exposure). The results provide proof of concept that ocean acidification may partially offset negative effects caused by warming in some species. Possible explanations and ecological implications for the observed antagonistic effect are discussed.


Image Guidance in Ventricular Cerebrospinal Fluid Shunt Catheter Placement: A Systematic Review and Meta-Analysis.
Ventricular shunt placement for treating hydrocephalus is one of the most common neurosurgical procedures. The rate of shunt failure, however, has not appreciably changed with time. To investigate whether intraoperative image guidance using ultrasound or stereotaxy contributes to accurate shunt catheter placement and survival. We performed a systematic literature review using PubMed and MEDLINE databases for studies that use ultrasound and frameless stereotaxy for ventricular catheter placement for hydrocephalus. All articles assessed the accuracy of catheter tip placement and/or overall shunt survival, and the rate of accurate shunt catheter placement, the overall failure rate, and the average time to shunt failure were extracted for analysis. Although each modality (ultrasound/stereotaxy) did not increase catheter placement accuracy, a combined random-effects meta-analysis of 738 catheters (136 guided by ultrasound, 168 guided by frameless stereotaxy, and 434 freehand) demonstrated a weak benefit of image guidance (risk ratio: 1.19, 95% confidence interval: 1.02-1.39, P = .02), but this result was limited by considerable heterogeneity among studies (I² = 86%, P < .001 by Cochrane's Q test). A meta-analysis could not be performed for shunt survival due to heterogeneity in data reporting. Although image guidance offers a promising solution to lower the risk of inaccurate catheter placement, which could lead to lower premature failure of ventricular shunts, our review demonstrated that there is not yet a clear benefit of these technologies. Current literature is limited to case series and cohort studies, and significant between-study heterogeneity in methodology and reporting currently limits a higher order analysis.


Towards fast-charging technologies in Li+/Na+ storage: from the perspectives of pseudocapacitive materials and non-aqueous hybrid capacitors.
Since the discovery of the pseudocapacitive behavior in RuO2 by Sergio Trasatti and Giovanni Buzzanca in 1971, materials with pseudocapacitance have been regarded as promising candidates for high-power energy storage. Pseudocapacitance-involving energy storage is predominantly based on faradaic redox reactions, but at the same time the charge storage is not limited by solid-state ion diffusion. Besides the search for pseudocapacitive materials, their implementation into non-aqueous hybrid capacitors stands for the strategy to increase power density by a rational design of the battery structure. Composed of a battery-type anode and a capacitor-type cathode, such devices show great promise to integrate the merits of both batteries and capacitors. Today, the availability of fast-charging technologies is of fundamental importance for establishing electric vehicles on a mass scale. Therefore, from the perspective of materials and battery design, understanding the basics and the recent developments of pseudocapacitive materials and non-aqueous hybrid capacitors is of great importance. With this goal in mind, we introduce here the fundamentals of pseudocapacitance and non-aqueous hybrid capacitors. In addition, we provide an overview of the latest developments in this fast growing research field.


Lead neurotoxicity: exploring the potential impact of lead substitution in zinc-finger proteins on mental health.
Childhood lead poisoning is a costly and largely preventable public health problem that lowers IQs, decreases attention spans, and leads to the development of other childhood intellectual disabilities. Furthermore, recent evidence links developmental lead poisoning with the etiology of disorders that appear much later in life, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Little is known about how lead influences the onset of these disorders. This paper reviews the evidence that lead substitution for zinc in zinc-finger proteins contributes to the development of Alzheimer's disease, Parkinson's disease, and schizophrenia. The zinc-finger proteins potentially impacted by lead include DNA methyltransferase 1 (DNMT1) and Presenilin 1 and 2 (PSEN1/2) in Alzheimer's disease, the dopamine receptor in Parkinson's disease, and the NMDA receptor, zinc-finger protein 804A (ZNF804A), and disrupted-in-schizophrenia 1 (DISC1)-binding zinc-finger (DBZ) in schizophrenia.


The use of CT density changes at internal tissue interfaces to correlate internal organ motion with an external surrogate.
The purpose of this paper is to describe a non-invasive method to monitor the motion of internal organs affected by respiration without using external markers or spirometry, to test the correlation with external markers, and to calculate any time shift between the datasets. Ten lung cancer patients were CT scanned with a GE LightSpeed Plus 4-Slice CT scanner operating in a ciné mode. We retrospectively reconstructed the raw CT data to obtain consecutive 0.5 s reconstructions at 0.1 s intervals to increase image sampling. We defined regions of interest containing tissue interfaces, including tumour/lung interfaces that move due to breathing on multiple axial slices and measured the mean CT number versus respiratory phase. Tumour motion was directly correlated with external marker motion, acquired simultaneously, using the sample coefficient of determination, r(2). Only three of the ten patients showed correlation higher than r(2) = 0.80 between tumour motion and external marker position. However, after taking into account time shifts (ranging between 0 s and 0.4 s) between the two data sets, all ten patients showed correlation better than r(2) = 0.8. This non-invasive method for monitoring the motion of internal organs is an effective tool that can assess the use of external markers for 4D-CT imaging and respiratory-gated radiotherapy on a patient-specific basis.


Functional magnetic resonance imaging and optical imaging for dominant-hemisphere perisylvian arteriovenous malformations.
In this study, we developed an a priori system to stratify surgical intervention of perisylvian arteriovenous malformations (AVMs) in 20 patients. We stratified the patients into three categories based on preoperative functional magnetic resonance imaging (fMRI) language activation pattern and relative location of the AVM. In Group I (minimal risk), the AVM was at least one gyrus removed from language activation, and patients subsequently underwent asleep resection. In Group II (high risk), the AVM and language activation were intimately associated. Because the risk of postoperative language deficit was high, these patients were then referred to radiosurgery. In Group III (indeterminate risk), the AVM and language were adjacent to each other. The risk of language deficit could not be predicted on the basis of the fMRI alone. These patients underwent awake craniotomy with electrocortical stimulation mapping and optical imaging of intrinsic signals for language mapping. All patients from Group I (minimal risk) underwent asleep resection without deficit. All Group II (high-risk) patients tolerated radiosurgery without complication. In Group III (indeterminate risk), three patients underwent successful resection, whereas two underwent aborted resection after intracranial mapping. We advocate the use of fMRI to assist in the preoperative determination of operability by asleep versus awake craniotomy versus radiosurgery referral. In addition, we advocate the use of all three functional mapping (fMRI, electrocortical stimulation mapping, and optical imaging of intrinsic signals) techniques to clarify the eloquence score of the Spetzler-Martin system before definitive treatment (anesthetized resection versus radiosurgery versus intraoperative resection versus intraoperative closure and radiosurgery referral).


Alteration of clinical outcome and histopathology of yellow fever virus infection in a hamster model by previous infection with heterologous flaviviruses.
Using a recently described hamster model of severe yellow fever (YF), we examined the hypothesis that prior infection with heterologous flaviviruses protects against severe or fatal YF. Hamsters were singly or sequentially infected with Japanese encephalitis, St. Louis encephalitis, West Nile, and/or dengue-1 viruses, and then challenged with a virulent strain of yellow fever virus (YFV). In contrast to control (naive) hamsters, many of which appeared clinically ill or died after YFV infection, the flavivirus-immune animals remained asymptomatic. The flavivirus-immune hamsters also had a reduced viremia and lower serum levels of alanine aminotransferase and total bilirubin, compared with naive hamsters, following YFV infection. Histologically, livers of animals in the flavivirus-immune and control groups showed comparable levels of multifocal necrapoptosis. However, steatosis was not observed in the flavivirus-immune animals, whereas naive hamsters developed extensive microvesicular steatosis in the liver following YFV infection. These findings suggest that hepatocytic steatosis is an adverse microscopic feature associated with severe disease in YFV infection. Our experimental results support earlier anecdotal reports that prior exposure of humans to heterologous flaviviruses reduces subsequent risk of fatal YFV infection.


Comparison of two cotside methods for the detection of hypoglycaemia among neonates in Nepal.
To compare two cotside methods of blood glucose measurement (HemoCue and Reflolux II) against a standard laboratory method for the detection of neonatal hypoglycaemia in a developing country maternity hospital where hypoglycaemia is common. 94 newborn infants and 75 of their mothers had blood glucose assessed on the same venous sample using three different methods in the Special Care Baby Unit and postnatal wards, Prasuti Griha Maternity Hospital, Kathmandu, Nepal: HemoCue and Reflolux II at the cotside; Roche Ultimate glucose oxidase method (GOM) in the laboratory. The mean (SD) values for blood glucose in newborn infants were GOM 2.5 (1.1) mmol/l; Reflolux II 2.1 (0.9); and HemoCue 4.2 (1.2). For mothers the values were GOM 5.3 (1.2) mmol/l; Reflolux II 3.6 (1.2); and HemoCue 5.6 (1.0). Bland-Altman plots showed that Reflolux II consistently underreads GOM blood glucose in neonates by 0.5 mmol/l (SD 0.7) and that HemoCue overreads glucose by 1.7 mmol/l (SD 0.8). For the detection of hypoglycaemia (< 2.0 mmol/l), Reflolux II achieved a sensitivity of 83%, a specificity of 62%, and a likelihood ratio of 2.2. HemoCue produced a sensitivity of 0% and a specificity of 100% using measured values. If 2.0 mmol were subtracted from all Hemocue values this rose to 81% and 68% and a likelihood ratio of 2.5. Although more accurate than Reflolux II for the measurement of blood glucose in mothers, HemoCue overreads glucose concentrations in neonates and is therefore potentially dangerous as a screening method for neonatal hypoglycaemia. Reflolux II is useful as a screening method for high risk infants (low birthweight, post-term) and could achieve a post-test probability of detecting hypoglycaemia in a high risk setting like Nepal of 50-60%.


Point-of-care diagnostics to improve maternal and neonatal health in low-resource settings.
Each day, approximately 830 women and 7400 newborns die from complications during pregnancy and childbirth. Improving maternal and neonatal health will require bringing rapid diagnosis and treatment to the point of care in low-resource settings. However, to date there are few diagnostic tools available that can be used at the point of care to detect the leading causes of maternal and neonatal mortality in low-resource settings. Here we review both commercially available diagnostics and technologies that are currently in development to detect the leading causes of maternal and neonatal mortality, highlighting key gaps in development where innovative design could increase access to technology and enable rapid diagnosis at the bedside.


Is the attendance of paediatricians at all elective caesarean sections an effective use of resources?
To determine the need for resuscitation at the birth of babies delivered by elective caesarean section (CS) and to record the time spent by doctors attending such deliveries. Data were collected prospectively on all elective CSs performed at Groote Schuur Hospital over a 3-month period. Data collected included: total time involved for paediatrician from call to leaving theatre, management of infant (requiring any form of resuscitation), Apgar scores and neonatal outcome (e.g. admission to nursery). The CSs were classified as low-risk or high-risk (multiple pregnancy, prematurity, growth restriction, abnormal lie, general anaesthetic or known congenital abnormality). Data were recorded for 138 deliveries. Three were excluded as they were not elective CS. One hundred and fifteen deliveries were classified as uncomplicated and 20 as high-risk. Only 1 of the babies born from the 115 low-risk CSs needed brief resuscitation, whereas 9 of the 20 high-risk deliveries resulted in newborn resuscitation. The reasons for low-risk CS were: previous CS (81); infant of diabetic mother (IDM) and previous CS (16); IDM alone (6); estimated big baby (10); and other (2).The average time spent at each elective CS by the pediatrician was 37 minutes. For low-risk CS, the same medical attendance (i.e. a midwife) as for an uncomplicated NVD would be appropriate; this can free a doctor for other duties, and assist in de-medicalising a low-risk procedure.


3D texture analysis of MR images to improve classification of paediatric brain tumours: a preliminary study.
Brain and central nervous system (CNS) tumours form the second most common group of cancers in children in the UK, accounting for 27% of all childhood cancers. Initial assessment of tumours from MRI scans is usually performed qualitatively, via radiologists' visual inspection. However, different brain tumours do not always demonstrate clear differences in physical appearance, so a diagnosis is usually made via histopathological examination of biopsy samples taken through surgery. This gives rise to the need for accurate, yet non-invasive diagnostic aids. In a previous study, we demonstrated the potential of MRI texture analysis in capturing quantitative information about paediatric brain tumours. In this work, we carry out a preliminary investigation on the use of 3D (volumetric) texture analysis of T1 and T2-weighted MR images in order to classify paediatric brain tumours. We then compare its performance with the traditional 2D texture analysis approach. Our preliminary findings are very encouraging and show that 3D textural features are capable of capturing more discriminative information about the tumours than the traditional 2D approach. However, it remains necessary to expand the work further to include larger cohorts and additional modalities.


The influence of text messages and anxiety on pain perception and its impact on orthodontic patients routine.
This prospective study aimed at assessing the effects of anxiety and a follow-up text message on pain perception after the installation of fixed orthodontic appliances and its impact on the patients' routine. The sample of this study consisted of 103 orthodontic patients, 40 males and 63 females (mean age 20.5 years), distributed in two groups: G1 (n=51), including control patients that did not receive any post-procedure communication; and G2 (n=52), including patients that received a structured text message. In baseline phase, the patients completed a questionnaire to assess their level of anxiety prior to treatment. Pain was assessed by using 100-mm visual analog scale (VAS) in baseline and ten times prospectively in predetermined time points. VAS was also applied to assess the patient's routine alterations caused by the pain. All data were analyzed using ANOVA, Tukey, Mann-Whitney, t-test, chi-square and Spearman's correlation tests. All statistical tests were performed with significance level of 5%. Low-level and high-level anxiety was observed in 42.7% and 7.8% of the patients, respectively. Statistically significant correlation was observed between anxiety and pain (p< 0.05). Maximum mean pain intensity was detected in the second treatment day (G1=36.9mm and G2=26.2mm) and was significantly higher in G1. Nearly 53% of the patients in G1 reported alterations in the routine (18.8mm), while in G2 the percentage rate reached 28.8% (9.9mm) (p=0.013). Anxious patients report more pain after the installation of orthodontic appliances. Text messages were effective to reduce pain levels and to decrease the negative effects on patients' daily routine.


Characterization of the spectrum of Korean inflammatory demyelinating diseases according to the diagnostic criteria and AQP4-Ab status.
The relative frequencies of demyelinating diseases among Korean patients with idiopathic inflammatory demyelinating disease of the central nervous system (IIDD) have not been sufficiently studied. We therefore describe a cohort of 203 patients with IIDD from three centers in Korea whose syndromes were identified precisely according to international clinical criteria and autoantibody to aquaporin 4 (AQP4-Ab) status. In total, 260 consecutive patients were screened and 203 were included from three hospitals in Korea. All were tested for AQP4-Ab by using a cell-based assay. Patients who met the criteria for definite neuromyelitis optica (NMO) or had a positive AQP4-Ab test result were defined as the NMO group. Among the others, patients were assessed if they had acute disseminated encephalomyelitis, multiple sclerosis (MS), acute transverse myelitis, optic neuritis, or other demyelinating disease as a clinically isolated syndrome of the brain. Eighteen percent of patients were classified as the NMO group, 2% as acute disseminated encephalomyelitis, 18% as MS, 41% as acute transverse myelitis, 11% as optic neuritis, and 8% as other clinically isolated syndrome of the brain. AQP4-Ab was positive in 18% of patients and the relative frequency of NMO to MS (NMO/MS ratio) was 1.06. The mean duration of follow up in our patients was 64 months. Among Korean patients with idiopathic inflammatory demyelinating diseases, the incidence of NMO may be similar to that of MS, and the overall positivity of AQP4-Ab could be lower than previously reported. In addition, acute transverse myelitis that is not associated with MS or NMO can be relatively common in these patients. Further population-based studies with AQP4-Ab are needed to determine the exact incidence of NMO and other idiopathic inflammatory demyelinating diseases in Korea.


Intravenous Amiodarone and Sotalol Impair Contractility and Cardiac Output, but Procainamide Does Not: A Langendorff Study.
Direct comparison of the effects of antiarrhythmic agents on myocardial performance may be useful in choosing between medications in critically ill patients. Studies directly comparing multiple antiarrhythmic medications are lacking. The use of an experimental heart preparation permits examination of myocardial performance under constant loading conditions. Hearts of Sprague Dawley rats (n = 35, 402-507 g) were explanted and cannulated in working heart model with fixed preload and afterload. Each heart was then exposed to a 3-hour infusion of procainamide (20 µg/kg/min), esmolol (100 or 200 µg/kg/min), amiodarone (10 or 20 mg/kg/d), sotalol (80 mg/m2/d), or placebo infusions (n = 5 per dose). Cardiac output, contractility (dP/dTmax), diastolic performance (dP/dTmin), and heart rate were compared between groups over time by linear mixed modeling. Compared with placebo, sotalol decreased contractility by an average of 24% ( P < .001) over the infusion period, as did amiodarone (low dose by 13%, P = .029; high dose by 14%, P = .013). Compared with placebo, mean cardiac output was significantly lower in animals treated with sotalol (by 22%, P = .016) and esmolol 200 μg/kg/min (by 23%, P = .012). Over time, amiodarone decreased cardiac output (20 mg/kg/d, β = -89 [-144, -33] μL/min2 decrease, P = .002) and also worsened diastolic function, decreasing dP/dTmin by ∼18% and 22% ( P = .032 and P = .011, low and high doses, respectively). Procainamide did not have a significant effect on any measures of systolic or diastolic performance. In isolated hearts, amiodarone and sotalol depressed myocardial contractility, cardiac output, and diastolic function. However, procainamide did not negatively affect myocardial performance and represents a favorable agent in settings of therapeutic equivalence.


Somatic hypermutation of the AID transgene in B and non-B cells.
Somatic hypermutation (SHM) of the Ig genes is required for affinity maturation of the humoral response to foreign antigens. Activation-induced cytidine deaminase (AID), which is specifically expressed in germinal center centroblasts, is indispensable for this process. Expression of AID is sufficient to activate SHM in hybridomas, non-B cells, and Escherichia coli, suggesting that it initiates the mutational process by deaminating DNA. However, the cis-acting sequences that are responsible for targeting AID activity to the variable (V) region of Ig genes are unknown. Here we show that expression of AID in B cell lines (i.e., Burkitt's lymphoma Ramos and hybridoma P1-5) not only causes hypermutation of Ig sequences, but also of the AID transgene itself. Because it is possible that B cell-specific transacting factors bind to and recruit the "mutator" to the AID transgene, we tested whether the AID transgene can mutate in non-B cells. Indeed, we show that expression of AID in Chinese hamster ovary cells causes SHM of both the Ig and AID transgenes. These data suggest that high transcription rates alone may predispose any gene to mutation by AID but do not preclude that there are specific B cell factors that account for the extremely high rate of V mutation in vivo and its targeting to the V region.


Subwavelength electromagnetic near-field imaging of point dipole with metamaterial nanoslab.
We investigate near-field imaging of a point dipole by a lossy, nanoscale metamaterial slab. Making use of the electromagnetic angular-spectrum representation, we derive the Green tensor for the field transmission through the metamaterial slab, duly considering multiple reflections, polarizations, and wave-vector signs. With this general formalism, we calculate the point-spread function of the imaging system, which enables us to assess, for instance, resolution and image brightness. Our results demonstrate that with the metamaterial-slab lens one achieves resolution beyond the conventional diffraction limit of half the wavelength. In general, the resolution and image brightness are degraded when the slab thickness and absorption increase, but we show that in some cases the resolution is rather insensitive to the magnitude of the losses in the metamaterial.


The Escherichia coli primosomal DnaT protein exists in solution as a monomer-trimer equilibrium system.
The oligomerization reaction of the Escherichia coli DnaT protein has been quantitatively examined using fluorescence anisotropy and analytical ultracentrifugation methods. In solution, DnaT exists as a monomer-trimer equilibrium system. At the estimated concentration in the E. coli cell, DnaT forms a mixture of the monomer and trimer states with a 3:1 molar ratio. In spite of the modest affinity, the trimerization is a highly cooperative process, without the detectable presence of the intervening dimer. The DnaT monomer consists of a large N-terminal core domain and a small C-terminal region. The removal of the C-terminal region dramatically affects the oligomerization process. The isolated N-terminal domain forms a dimer instead of the trimer. These results indicate that the DnaT monomer possesses two structurally different, interacting sites. One site is located on the N-terminal domain, and two monomers, in the trimer, are associated through their binding sites located on that domain. The C-terminal region forms the other interacting site. The third monomer is engaged through the C-terminal regions. Surprisingly, the high affinity of the N-terminal domain dimer indicates that the DnaT monomer undergoes a conformational transition upon oligomerization, involving the C-terminal region. These data and the high specificity of the trimerization reaction, i.e., lack of any oligomers higher than a trimer, indicate that each monomer in the trimer is in contact with the two remaining monomers. A model of the global structure of the DnaT trimer based on the thermodynamic and hydrodynamic data is discussed.


Legal, social, and biological definitions of pedophilia.
Although there is substantial evidence in the historical and anthropological record of the sexual use of children by adults, surprisingly little is known about the etiology of pedophilia or its relation to other forms of sexual aggression. After briefly reviewing the research on pedophilia, we argue that one major difficulty in conducting or interpreting such research lies in the different definitions "pedophilia" has received. Most important, much of the research has accepted a legal definition of pedophilia, treating all offenders convicted of "child molestation" as pedophiles, regardless of the age or appearance of the victim. We argue that a distinction should be made between biological children and sociolegal children. Laws governing child molestation reflect sociolegal childhood, regardless of its discrepancy with biological childhood. "True" pedophiles should be identified by their preference for biological children. By using legal classifications, researchers may well be confusing two distinct types of offenders, child molesters and rapists, and confounding attempts to understand pedophilia.


Short Cationic Antimicrobial Peptides Display Superior Antifungal Activities toward Candidiasis and Onychomycosis in Comparison with Terbinafine and Amorolfine.
Novel antifungals are in high demand due to the challenges associated with resistant, persistent, and systemic fungal infections. Synthetic mimics of antimicrobial peptides are emerging as a promising class of compounds for antifungal treatment. In the current study, five synthetic cationic antimicrobial tripeptides were evaluated as antifungal therapeutics against 24 pathogenic strains of fungi. Three of the peptides displayed strong general antifungal properties at low micromolar inhibitory concentrations. The most promising peptide, compound 5, was selected and evaluated as an antifungal remedy for Candida albicans candidiasis in a human skin model and for the treatment of Trichophyton rubrum induced onychomycosis in an infected human nail model. Compound 5 was shown to display antifungal properties and a rapid mode of action superior to those of both the commercial comparators Loceryl and Lamisil. Compound 5 was also active against a clinical isolate of Candida albicans with acquired fluconazole resistance.


Self-Seeding Procedure for Obtaining Stacked Block Copolymer Lamellar Crystals in Solution.
We examined the formation of self-seeded platelet-like crystals from polystyrene-block-polyethylene oxide (PS-b-PEO) diblock copolymers in toluene as a function of polymer concentration (c), crystallization temperature (TC), and self-seeding temperature (TSS). We showed that the number (N) of platelet-like crystals and their mean lateral size (L) can be controlled through a self-seeding procedure. As (homogeneous) nucleation was circumvented by the self-seeding procedure, N did not depend on TC. N increased linearly with c and decayed exponentially with TSS but was not affected significantly by the time the sample was kept at TSS. The solubility limit of PS-b-PEO in toluene (c*), which was derived from the linear extrapolation of Nc→ 0 and from the total deposited mass of the platelets per area (MCc→0), depended on TC. We have also demonstrated that at low N, stacks consisting of a (large) number (η) of uniquely oriented lamellae can be achieved. At a given TC, L was controlled by N and η as well as by ∆c=c-c∗. Thus, besides being able to predict size and number of platelet-like crystals, the self-seeding procedure also allowed control of the number of stacked lamellae in these crystals.


Cytomegalovirus infection with MRI signal abnormalities affecting the optic nerves, optic chiasm, and optic tracts.
A 49-year-old woman who had been immunosuppressed after a renal transplant developed bilateral severe visual loss. Visual acuities were finger counting and hand movements in the two eyes. Both optic nerves were pale. There were no other ophthalmic abnormalities. Brain MRI disclosed marked signal abnormalities involving the optic nerves, optic chiasm, and optic tracts. Cerebrospinal fluid polymerase chain reaction (PCR) was positive for cytomegalovirus. Treatment did not restore vision. Such extensive clinical and imaging involvement of the anterior visual pathway, which has been previously reported with other herpes viruses, illustrates the propensity for this family of viruses to track along axons.


Enthalpy-entropy compensation in DNA melting thermodynamics.
We investigate enthalpy-entropy compensation for melting of nearest-neighbor doublets in DNA. Based on data for 10 normal doublets and for doublets containing a mispaired or analog base, the correlation of delta Szero with delta Hzero follows a rectangular hyperbola. Doublet melting temperature relates linearly to delta Hzero by Tm = T(o) + delta Hzero/a, where T(o) = 273 K and a = 80 cal/mol-K. Thus Tm is proportional to delta Hzero + aTo rather than to delta Hzero alone as previously thought by assuming delta Szero to be constant. The term aTo = 21.8 kcal/mol may reflect a constant enthalpy change in solvent accompanying the DNA enthalpy change for doublet melting and is roughly equivalent to breaking four H-bonds between water molecules for each melted doublet. The solvent entropy change (aTo/Tm) declines with increasing Tm, while the DNA entropy change (delta Hzero/Tm) rises, so the combined DNA + solvent entropy change stays constant at 80 cal/K/mol of doublet. If such constancy in DNA + solvent entropy changes also holds for enzyme clefts as "solvent," then free energy differences for competing correct and incorrect base pairs in polymerase clefts may be as large as enthalpy differences and possibly sufficient to account for DNA polymerase accuracy. The hyperbolic relationship between delta Szero and delta Hzero observed in 1 M salt can be used to evaluate delta Hzero and delta Szero from Tm at lower, physiologically relevant, salt concentrations.


Outcomes of outborn extremely preterm neonates admitted to a NICU with respiratory distress.
To compare the risk of mortality and morbidity between outborn and propensity score-matched inborn extremely preterm neonates. Multiple neonatal intensive care units (NICU) across the USA. Singleton neonates born at 22-29 weeks' gestation with no major anomalies who were admitted to a NICU and discharged between 2000 and 2014. Outborn neonates were restricted to those who transferred into a NICU on the day of birth. The association between inborn-outborn status and the time-to-event outcomes of in-hospital mortality and necrotising enterocolitis (NEC) were assessed using Cox proportional hazards regression. Logistic regression was used to assess the remaining secondary outcomes: retinopathy of prematurity requiring treatment (tROP), chronic lung disease (CLD), periventricular leucomalacia (PVL) and severe intraventricular haemorrhage (IVH). Since outborn status was not random, we used 1:1 propensity score matching to reduce the imbalance in illness severity. There were 59 942 neonates (7991 outborn) included in the study. Outborn neonates had poorer survival than inborns and higher rates of NEC, severe IVH, tROP and PVL. Inborn-outborn disparities in mortality were reduced over the study period. When analysing the matched cohort (6524 matched pairs), outborns were less likely to die in-hospital compared with inborns (HR 0.84, 95% CI 0.77 to 0.91). However, outborns experienced higher rates of NEC (HR 1.14, 95% CI 1.04 to 1.25), severe IVH (OR 1.52, 95% CI 1.38 to 1.68), tROP (OR 1.45, 95% CI 1.25 to 1.69) and CLD (OR 1.12, 95% CI 1.01 to 1.24). Additional research is needed to understand the contributors to increased morbidity for outborn extremely preterm neonates and identify interventions that mitigate this risk.


An alternative HER-2/neu transcript of 8 kb has an extended 3'UTR and displays increased stability in SKOV-3 ovarian carcinoma cells.
HER-2/neu is a potent oncogene that predicts poor outcome when overexpressed in ovarian cancer. The SKOV-3 ovarian carcinoma cell line, one of the only models for HER2-driven ovarian cancer, expresses a major uncharacterized 8-kb alternative HER-2 transcript. The aim of this study was to characterize the structure and determine the origin of the alternative sequence and examine the possible role of the 8-kb alternative transcript in overexpression of the HER-2 gene. The structure of the 8-kb transcript was investigated using polymerase chain reaction (PCR) and nucleotide sequencing of cDNA clones. PCR analysis of genomic DNA was used to assess the origin of the 8-kb transcript. The stability of the 8-kb mRNA was assessed by Northern blot analysis of RNA extracted from cells treated with transcriptional inhibitors. Similar 5'UTR and coding sequence but an extended 3'UTR were contained in the 8-kb compared to the well-characterized 4.5-kb HER-2 transcript. Genomic DNA had continuity between the novel 3'UTR sequence from the 8-kb transcript and adjacent HER-2 terminal exon sequence. The 8-kb transcript had a half-life of 13 h compared to 5.5 h for the 4.5-kb transcript (P<0.01). The 8-kb transcript is generated from alternative polyadenylation site usage rather than gene rearrangement. Since the 8-kb transcript contains alternative sequence found at the 3' end of the normal HER-2 gene, it could be expressed in other cells. Increased stability of the 8-kb transcript may confer a selective advantage for SKOV-3 cells by providing enhanced HER-2 expression.


Associations between asymmetric dimethylarginine, homocysteine, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in rheumatoid arthritis.
The aim of our study was to determine whether asymmetric dimethylarginine (ADMA) levels are associated with homocysteine (Hcy) and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) gene variants in patients with rheumatoid arthritis (RA). Serum ADMA and Hcy levels were measured in 201 RA individuals [155 (77.1%) females, median age 67 years (interquartile range 59-73)]. The MTHFR C677T polymorphism was assessed by using the LightCyclerTM System. Initially, ADMA was compared across the categories of MTHFR using a one-way analysis of variance (ANOVA), followed by a multivariate model, which accounted for Hcy, age, erythrocyte sedimentation rate (ESR), and homeostatic model assessment (HOMA). In univariable analysis, ADMA differed significantly across the categories of MTHFR (p = 0.037). Patients with the MTHFR 677TT genotype had the highest ADMA levels, with a mean of 0.62 (SE = 0.03), significantly higher than either those patients carrying the MTHFR 677CT (0.55, SE = 0.01) or the MTHFR 677CC (0.55, SE = 0.01) genotype (p = 0.042) in both cases. In the multivariable model, Hcy (p = 0.022) and ESR (p < 0.001) were found to have significant positive associations with ADMA but the relationship between MTHFR gene variants and ADMA was found to be non-significant (p = 0.102). Hcy and ADMA are significantly associated in RA. It is plausible that abnormal Hcy metabolism plays an important role in premature atherosclerosis in RA by promoting ADMA accumulation and leading to the derangement of vascular haemostasis.


Effects of the BDNF Val66Met Polymorphism on Gray Matter Volume in Typically Developing Children and Adolescents.
The Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) is associated with psychiatric disorders and regional gray matter volume (rGMV) in adults. However, the relationship between BDNF and rGMV in children has not been clarified. In this 3-year cross-sectional/longitudinal (2 time points) study, we investigated the effects of BDNF genotypes on rGMV in 185 healthy Japanese children aged 5.7-18.4 using magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) analyses. We found that the volume of the right cuneus in Met homozygotes (Met/Met) was greater than in Val homozygotes (Val/Val) in both exams, and the left insula and left ventromedial prefrontal cortex volumes were greater in Val homozygotes versus Met homozygotes in Exam l. In addition, Met homozygous subjects exhibited higher processing speed in intelligence indices than Val homozygotes and Val/Met heterozygotes at both time points. Longitudinal analysis showed that the left temporoparietal junction volume of Val/Met heterozygotes increased more substantially over the 3-year study period than in Val homozygotes, and age-related changes were observed for the Val/Met genotype. Our findings suggest that the presence of 2 Met alleles may have a positive effect on rGMV at the developmental stages analyzed in this study.


Generalised peripheral nerve dysfunction in acromegaly: a study by conventional and novel neurophysiological techniques.
Twenty four patients with clinical, radiological and biochemical evidence of acromegaly were investigated by a number of independent neurophysiological tests. Two-thirds of the patients showed evidence of generalised peripheral nerve dysfunction. A significant correlation was found between total exchangeable body sodium, an indicator of disease activity, and the severity of the neuropathy. The generalised peripheral nerve abnormality was found to occur independently of the associated carbohydrate intolerance human growth hormone levels and other endocrinological dysfunction in this disorder.


Can videoconferencing affect older people's engagement and perception of their social support in long-term conditions management: a social network analysis from the Telehealth Literacy Project.
Social support is a key component in managing long-term conditions. As people age in their homes, there is a greater risk of social isolation, which can be ameliorated by informal support networks. This study examined the relationship between changes in social support networks for older people living in a regional area following weekly videoconference groups delivered to the home. Between February and June 2014, we delivered 44 weekly group meetings via videoconference to participants in a regional town in Australia. The meetings provided participants with education and an opportunity to discuss health issues and connect with others in similar circumstances. An uncontrolled, pre-post-test methodology was employed. A social network tool was completed by 45 (87%) participants either pre- or post-intervention, of which 24 (46%) participants completed the tool pre- and post-intervention. In addition, 14 semi-structured interviews and 4 focus groups were conducted. Following the intervention, participants identified increased membership of their social networks, although they did not identify individuals from the weekly videoconference groups. The most important social support networks remained the same pre- and post-intervention namely, health professionals, close family and partners. However, post-intervention participants identified friends and wider family as more important to managing their chronic condition compared to pre-intervention. Participants derived social support, in particular, companionship, emotional and informational support as well as feeling more engaged with life, from the weekly videoconference meetings. Videoconference education groups delivered into the home can provide social support and enhance self-management for older people with chronic conditions. They provide the opportunity to develop a virtual social support network containing new and diverse social connections.


VEGF incorporated into calcium phosphate ceramics promotes vascularisation and bone formation in vivo.
Bone formation and osseointegration of biomaterials are dependent on angiogenesis and vascularization. Angiogenic growth factors such as vascular endothelial growth factor (VEGF) were shown to promote biomaterial vascularization and enhance bone formation. However, high local concentrations of VEGF induce the formation of malformed, nonfunctional vessels. We hypothesized that a continuous delivery of low concentrations of VEGF from calcium phosphate ceramics may increase the efficacy of VEGF administration.VEGF was co-precipitated onto biphasic calcium phosphate (BCP) ceramics to achieve a sustained release of the growth factor. The co-precipitation efficacy and the release kinetics of the protein were investigated in vitro. For in vivo investigations BCP ceramics were implanted into critical size cranial defects in Balb/c mice. Angiogenesis and microvascularization were investigated over 28 days by means of intravital microscopy. The formation of new bone was determined histomorphometrically. Co-precipitation reduced the burst release of VEGF. Furthermore, a sustained, cell-mediated release of low concentrations of VEGF from BCP ceramics was mediated by resorbing osteoclasts. In vivo, sustained delivery of VEGF achieved by protein co-precipitation promoted biomaterial vascularization, osseointegration, and bone formation. Short-term release of VEGF following superficial adsorption resulted in a temporally restricted promotion of angiogenesis and did not enhance bone formation. The release kinetics of VEGF appears to be an important factor in the promotion of biomaterial vascularization and bone formation. Sustained release of VEGF increased the efficacy of VEGF delivery demonstrating that a prolonged bioavailability of low concentrations of VEGF is beneficial for bone regeneration.


Effects of feeding diets containing distillers' dried grains with solubles and wheat middlings with equal predicted dietary net energy on growth performance and carcass composition of growing-finishing pigs.
This experiment evaluated the effects of feeding distillers' dried grains with solubles (DDGS) and wheat middlings (WM) in diets with similar estimated NE content on growth performance and carcass characteristics of growing-finishing pigs. Pigs ( = 384; 29.1 ± 3.6 kg initial BW) were blocked by initial BW, and within blocks, pens were randomly allotted to 1 of 4 dietary treatments (8 pigs/pen and 12 replicates/treatment) in a 4-phase feeding program (29 to 50, 50 to 75, 75 to 100, and 100 to 120 kg BW). Dietary treatments were arranged in a 2 × 2 factorial design and formulated to consist of: 1) corn and soybean meal (CON), 2) CON with 30% DDGS, 3) CON with 15% WM, and 4) CON with 30% DDGS and 15% WM. Diets met or exceeded nutrient requirements published by the and were formulated to contain the same concentrations of standardized ileal digestible (SID) Lys and meet or exceed minimum SID AA to Lys ratios within phases. No significant interactions for DDGS × WM × phase or DDGS × WM were observed for all growth performance criteria. Pigs fed diets containing 30% DDGS had reduced ( < 0.05) ADFI (1.76 vs. 1.86 kg/d) and ADG (0.85 vs. 0.91 kg/d) compared with pigs fed diets with no DDGS in phase 1 but not in other phases. The G:F of pigs fed diets containing DDGS was not different during phase 1 to 3 but was greater ( < 0.01) in phase 4 (0.313 vs. 0.291) compared with that of pigs fed diets with no DDGS. Pigs fed diets containing 15% WM had similar ADFI and G:F but reduced ( < 0.05) ADG (0.86 vs. 0.90 kg/d) compared with pigs fed diets without WM in phase 1, but no difference in ADG was observed in phases 2 to 4. No DDGS × WM interaction was observed for carcass traits. Pigs fed diets containing 30% DDGS had reduced ( < 0.01) HCW (86.5 vs. 89.9 kg), carcass yield (72.3 vs. 73.6%), LM area (45.0 vs. 47.9 cm), and percentage of carcass fat-free lean (52.1 vs. 53.4%), but backfat depth was not affected compared with pigs fed diets with no DDGS. Pigs fed diets containing 15% WM had lower carcass yield (72.7 vs. 73.1%; < 0.05) and HCW (87.7 vs. 88.7 kg; < 0.10) than pigs fed diets with no addition of WM, but other carcass traits were not affected. In conclusion, overall ADG and G:F were not affected by feeding 30% DDGS or 15% WM when diets were formulated on the NE basis, but more accurate and dynamic estimation of NE content for DDGS sources is needed to optimize caloric efficiency at different physiological ages of pigs.


Propensity Score Methods: Theory and Practice for Anesthesia Research.
Observational data are often readily available or less costly to obtain than conducting a randomized controlled trial. With observational data, investigators may statistically evaluate the relationship between a treatment or therapy and outcomes. However, inherent in observational data is the potential for confounding arising from the nonrandom assignment of treatment. In this statistical grand rounds, we describe the use of propensity score methods (ie, using the probability of receiving treatment given covariates) to reduce bias due to measured confounders in anesthesia and perioperative medicine research. We provide a description of the theory and background appropriate for the anesthesia researcher and describe statistical assumptions that should be assessed in the course of a research study using the propensity score. We further describe 2 propensity score methods for evaluating the association of treatment or therapy with outcomes, propensity score matching and inverse probability of treatment weighting, and compare to covariate-adjusted regression analysis. We distinguish several estimators of treatment effect available with propensity score methods, including the average treatment effect, the average treatment effect for the treated, and average treatment effect for the controls or untreated, and compare to the conditional treatment effect in covariate-adjusted regression. We highlight the relative advantages of the various methods and estimators, describe analysis assumptions and how to critically evaluate them, and demonstrate methods in an analysis of thoracic epidural analgesia and new-onset atrial arrhythmias after pulmonary resection.


Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results.
The introduction in 1998 of imatinib mesylate (IM) revolutionized management of patients with chronic myeloid leukemia (CML) and the second generation of tyrosine kinase inhibitors may prove superior to IM. Real-time quantitative polymerase chain reaction (RQ-PCR) provides an accurate measure of the total leukemiacell mass and the degree to which BCR-ABL transcripts are reduced by therapy correlates with progression-free survival. Because a rising level of BCR-ABL is an early indication of loss of response and thus the need to reassess therapeutic strategy, regular molecular monitoring of individual patients is clearly desirable. Here we summarize the results of a consensus meeting that took place at the National Institutes of Health (NIH) in Bethesda in October 2005. We make suggestions for (1) harmonizing the differing methodologies for measuring BCR-ABL transcripts in patients with CML undergoing treatment and using a conversion factor whereby individual laboratories can express BCR-ABL transcript levels on an internationally agreed scale; (2) using serial RQ-PCR results rather than bone marrow cytogenetics or fluorescence in situ hybridization (FISH) for the BCR-ABL gene to monitor individual patients responding to treatment; and (3) detecting and reporting Philadelphia (Ph) chromosome-positive subpopulations bearing BCR-ABL kinase domain mutations. We recognize that our recommendations are provisional and will require revision as new evidence emerges.


Vagal and cardiac reactivity to psychological stressors in trained and untrained men.
The aim of this study was to determine whether higher aerobic fitness is associated with enhanced vagal influences on the myocardium, resulting in moderation of chronotropic cardiac activity during psychological stress and recovery. Heart period (HP) and respiratory sinus arrhythmia (RSA) were obtained from 10 aerobically trained (AT) and 10 untrained (UT) college-aged men at rest and during three contiguous psychological challenges and 3 min of recovery. Ratings of perceived stress were obtained at the end of the rest period, at the midpoint of each stressor, and at 30 s into recovery. Time series methods were used to quantify RSA from the beat-to-beat HP series. Responsivity was assessed both in terms of absolute levels of activity and phasic changes in activity (task or recovery minus baseline). Both groups reported similar levels of subjective stress throughout the experiment. The AT exhibited longer HP at rest and during psychological stress and recovery than did the UT. However, the groups did not differ on RSA at rest or during psychological stress and recovery, nor did they differ on phasic changes in RSA or HP during stress or recovery. Additionally, aerobic capacity was not correlated with absolute levels or phasic changes in RSA during psychological challenge for either group and, except in Min 2 for the UT, similar results were obtained for recovery. The results supported the hypothesis that, among young men, higher aerobic fitness is associated with longer HP at rest and during psychological stress and recovery. However, the lower cardiac chronotropic activation observed among the AT relative to the UT was not paralleled by a group difference in the amplitude of RSA. These results suggest that the group difference in HP was not mediated directly by the vagal mechanisms manifested in the amplitude of RSA.


The central role of Sertoli cells in spermatogenesis.
Sertoli cells are the somatic cells of the testis that are essential for testis formation and spermatogenesis. Sertoli cells facilitate the progression of germ cells to spermatozoa via direct contact and by controlling the environment milieu within the seminiferous tubules. The regulation of spermatogenesis by FSH and testosterone occurs by the action of these hormones on the Sertoli cells. While the action of testosterone is necessary for spermatogenesis, the action of FSH minimally serves to promote spermatogenic output by increasing the number of Sertoli cells.


Morphologic and molecular characterization of seven species of the remarkably diverse and widely distributed metopid genus Urostomides Jankowski, 1964 (Armophorea, Ciliophora).
The free-living ciliates of the order Metopida Jankowski, 1980 are pivotal players in the microbial food web of the sulfuretum, acting as hosts to prokaryotic endo- and ectosymbionts. They are also of interest in the study of the function and evolution of their mitochondrion-related organelle, the hydrogenosome. The taxonomy and phylogeny of this group remains confused, due, in large part, to the fact that most of its taxa have not been characterized by modern methods including molecular sequencing. In this report we provide morphologic and molecular characterization of seven taxa from the poorly-known resurrected genus Urostomides obtained in the course of broad geographic sampling. Foissner (2016) established the family Apometopidae to include Apometopus (a junior synonym of Urostomides) and Cirranter Jankowski, 1964. These two genera differ from all other metopid genera in having a four-rowed perizonal ciliary stripe, the only currently recognizable morphologic synapomorphy for the family. The members of Urostomides show remarkable morphologic diversity. The genus has a broad geographic distribution, occurring on six continents. Urostomides species form a strongly supported clade in phylogenetic analyses. Relationships within the genus itself are less clearly resolved. The diagnoses of Apometopidae and Urostomides are emended.


Caspase 8 inhibits programmed necrosis by processing CYLD.
Caspase 8 initiates apoptosis downstream of TNF death receptors by undergoing autocleavage and processing the executioner caspase 3 (ref. 1). However, the dominant function of caspase 8 is to transmit a pro-survival signal that suppresses programmed necrosis (or necroptosis) mediated by RIPK1 and RIPK3 (refs 2-6) during embryogenesis and haematopoiesis(7-9). Suppression of necrotic cell death by caspase 8 requires its catalytic activity but not the autocleavage essential for apoptosis(10); however, the key substrate processed by caspase 8 to block necrosis has been elusive. A key substrate must meet three criteria: it must be essential for programmed necrosis; it must be cleaved by caspase 8 in situations where caspase 8 is blocking necrosis; and mutation of the caspase 8 processing site on the substrate should convert a pro-survival response to necrotic death without the need for caspase 8 inhibition. We now identify CYLD as a substrate for caspase 8 that satisfies these criteria. Following TNF stimulation, caspase 8 cleaves CYLD to generate a survival signal. In contrast, loss of caspase 8 prevented CYLD degradation, resulting in necrotic death. A CYLD substitution mutation at Asp 215 that cannot be cleaved by caspase 8 switches cell survival to necrotic cell death in response to TNF.


Associations between socio-demographic characteristics and healthy lifestyles in Korean Adults: the result of the 2010 Community Health Survey.
Several previous studies have found that healthy behaviors substantially reduce non-communicable disease incidence and mortality. The present study was performed to estimate the prevalence of four modifiable healthy behaviors and a healthy lifestyle among Korean adults according to socio-demographic and regional factors. We analyzed data from 199 400 Korean adults aged 19 years and older who participated in the 2010 Korean Community Health Survey. We defined a healthy lifestyle as a combination of four modifiable healthy behaviors: non-smoking, moderate alcohol consumption, regular walking, and a healthy weight. We calculated the prevalence rates and odds ratios of each healthy behavior and healthy lifestyle according to socio-demographic and regional characteristics. The prevalence rates were as follows: non-smoking, 75.0% (53.7% in men, 96.6% in women); moderate alcohol consumption, 88.2% (79.7% in men, 96.9% in women); regular walking, 45.0% (46.2% in men, 43.8% in women); healthy weight, 77.4% (71.3% in men, 73.6% in women); and a healthy lifestyle, 25.5% (16.4% in men, 34.6% in women). The characteristics associated with a low prevalence of healthy lifestyle were male gender, younger age (19 to 44 years of age), low educational attainment, married, living in a rural area, living in the Chungcheong, Youngnam, or Gwangwon-Jeju region, and poorer self-rated health. Further research should be implemented to explore the explainable factors of disparities for socio-demographic and regional characteristics to engage in the healthy lifestyle among adults.


Protein degradation corrects for imbalanced subunit stoichiometry in OST complex assembly.
Protein degradation is essential for cellular homeostasis. We developed a sensitive approach to examining protein degradation rates in Saccharomyces cerevisiae by coupling a SILAC approach to selected reaction monitoring (SRM) mass spectrometry. Combined with genetic tools, this analysis made it possible to study the assembly of the oligosaccharyl transferase complex. The ER-associated degradation machinery compensated for disturbed homeostasis of complex components by degradation of subunits in excess. On a larger scale, protein degradation in the ER was found to be a minor factor in the regulation of protein homeostasis in exponentially growing cells, but ERAD became relevant when the gene dosage was affected, as demonstrated in heterozygous diploid cells. Hence the alleviation of fitness defects due to abnormal gene copy numbers might be an important function of protein degradation.


Hospital pharmacists' participation in audit in the United Kingdom.
To investigate systematically participation in audit of NHS hospital pharmacists in the United Kingdom. Questionnaire census survey. All NHS hospital pharmacies in the UK providing clinical pharmacy services. 462 hospital pharmacies. Extent and nature of participation in medical, clinical, and pharmacy audits according to hospital management and teaching status, educational level and specialisation of pharmacists, and perceived availability of resources. 416 questionnaires were returned (response rate 90%). Pharmacists contributed to medical audit in 50% (204/410) of hospitals, pharmacy audit in 27% (108/404), and clinical audit in only 7% (29/404). Many pharmacies (59% (235/399)) were involved in one or more types of audit but few (4%, (15/399)) in all three. Participation increased in medical and pharmacy audits with trust status (medical audit: 57% (65/115) trust hospital v 47% (132/281) non-trust hospital; pharmacy audit: 34% (39/114) v 24% (65/276)) and teaching status (medical audit: 58% (60/104) teaching hospital v 47% (130/279) non-teaching hospital; pharmacy audit 30% (31/104) v 25% (68/273)) and similarly for highly qualified pharmacists (MPhil or PhD, MSc, diplomas) (medical audit: 54% (163/302) with these qualifications v 38% (39/103) without; pharmacy audit: 32% (95/298) v 13% (13/102)) and specialists pharmacists (medical audit: 61% (112/184) specialist v 41% (90/221) non-specialist; pharmacy audit: 37% (67/182) v 19% (41/218)). Pharmacies contributing to medical audit commonly provided financial information on drug use (86% 169/197). Pharmacy audits often concentrated on audit of clinical pharmacy services. Pharmacists are beginning to participate in the critical evaluation of health care, mainly in medical audit.


Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis.
We examined the receptor subtypes and signal transduction mechanisms contributing to the estrogenic modulation of cannabinoid-induced changes in energy balance. Food intake and, in some cases, O2 consumption, CO2 production and the respiratory exchange ratio were evaluated in ovariectomized female guinea pigs treated s.c. with the cannabinoid receptor agonist WIN 55,212-2 or its cremephor/ethanol/0.9% saline vehicle, and either with estradiol benzoate (EB), the estrogen receptor (ER) α agonist PPT, the ERβ agonist DPN, the Gq-coupled membrane ER agonist STX, the GPR30 agonist G-1 or their respective vehicles. Patch-clamp recordings were performed in hypothalamic slices. EB, STX, PPT and G-1 decreased daily food intake. Of these, EB, STX and PPT blocked the WIN 55,212-2-induced increase in food intake within 1-4 h. The estrogenic diminution of cannabinoid-induced hyperphagia correlated with a rapid (within 15 min) attenuation of cannabinoid-mediated decreases in glutamatergic synaptic input onto arcuate neurons, which was completely blocked by inhibition of protein kinase C (PKC) and attenuated by inhibition of protein kinase A (PKA). STX, but not PPT, mimicked this rapid estrogenic effect. However, PPT abolished the cannabinoid-induced inhibition of glutamatergic neurotransmission in cells from animals treated 24 h prior. The estrogenic antagonism of this presynaptic inhibition was observed in anorexigenic proopiomelanocortin neurons. These data reveal that estrogens negatively modulate cannabinoid-induced changes in energy balance via Gq-coupled membrane ER- and ERα-mediated mechanisms involving activation of PKC and PKA. As such, they further our understanding of the pathways through which estrogens act to temper cannabinoid sensitivity in regulating energy homeostasis in females.


Cobalt 60 versus 15 MeV photons during total body irradiation: doses in the critical organs and complexicity of the procedure.
The aim of this work was to compare the doses in critical organs, treatment duration, patient comfort and personnel workload during total body irradiation carried out alternatively with a Cobalt 60 and with 15 MeV photons at linear accelerator. Twenty consecutive patients irradiated with a Cobalt unit and twenty irradiated with 15 MeV photons in a linear accelerator were used for comparison of the dose delivered. Each irradiation was repeated eight times during four consecutive days up to a total dose of 12.6 Gy in the whole body (below 10 Gy in the lungs). Lateral fields were used in six fractions, and anterior-posterior fields in two fractions. An electron boost to the thorax wall was added. Doses were calculated and measured in-vivo in ten transverse sections. For the patient taken as an example doses in the middle of the lungs were 10.7 Gy for Co-60 and 11.2 Gy for 15 MeV photons without compensators and 9.6 Gy, 9.6 Gy respectively when compensators were applied. Mean doses in the lungs in the group were 9.5 Gy for Co-60 and 9.7 Gy for X 15 MeV, respectively. Duration of the treatment was shorter with the use of the 15 MeV than that with Co-60 by about 20%. Repositioning of the patient during two fractions with the use of X 15 MeV could be eliminated and therefore the patient's comfort increased.


Incorporation of a Physical Education and Nutrition Program Into Neurosurgery: A Proof of Concept Pilot Program.
Balancing the demands of a busy medical career with personal wellness can be daunting, and there is little education on these principles available to physicians in training. To implement a voluntary wellness initiative in our neurosurgery department to promote healthy lifestyle choices. This report details the baseline data collected as part of this quality improvement initiative. The wellness initiative was implemented in July 2015 and available to all faculty and resident physicians in the Department of Neurological Surgery in collaboration with the Medical University of South Carolina Wellness Center. All participants were provided a Fitbit Surge HR wrist monitor (Fitbit, Boston, Massachusetts) and underwent baseline physical and psychological testing. Six faculty physicians and 9 residents participated. Overall physical fitness levels varied widely between subjects. Health screening demonstrated abnormalities in 80% of participants (elevated systolic blood pressure in 60%, elevated diastolic in 47%, elevated serum low-density lipoprotein in 53%). Body composition analysis demonstrated body weight higher than ideal in 69% (47% overweight; 13% obese). Recommended average body fat mass reduction was 25.4 pounds. Seventy-nine percent reported below-average quality of life compared with the average healthy adult. All subjects reported wanting more time for personal health. Baseline health and psychological screenings in our department demonstrated alarmingly prevalent, previously undiagnosed abnormalities on cardiovascular and body weight screenings. Obstacles to leading a healthier lifestyle have been identified and solutions have been incorporated into the program. This quality improvement initiative may serve as a template for other programs seeking to improve physician physical and mental well-being. BMI, body mass indexESS, Epworth Sleepiness ScaleHR, heart rate.


Analysis of human immunodeficiency virus type 1 (HIV-1) variants and levels of infection in dendritic and T cells from symptomatic HIV-1-infected patients.
Dendritic cells (DC) are required to initiate primary cellular immune responses. Human immunodeficiency virus type 1 (HIV-1) infection of DC may be central to transmission and persistence of virus and in the pathogenesis of AIDS. In symptomatic HIV-1-infected patients the proportion of DC in the mononuclear cell population was reduced. Provirus load in the T cells was 3-100 times higher than in DC and there was no correlation between the levels of infection in the two cell types. Phylogenetic analysis of amino acids in the V3 loop and flanking regions indicated intermingling of sequences and thus provides the first evidence for transfer of virus between DC and T cells in vivo. In one of three patients analysed there were significant differences in amino acid residues in the V3 region. This may reflect reduced interactions between DC and T cells in infected individuals and for the existence of variants with a stronger tropism for DC, which could play a role in transmission by initiating infection in mucosal DC.


Strategy and management of severe hemorrhage complicating pancreatitis and post-pancreatectomy.
Transcatheter arterial embolization (TAE) is increasingly used as the first-line treatment for hemorrhage complicating pancreatitis and post-pancreatectomy. However, the optimal therapeutic strategy remains unclear. Among 1924 consecutive patients, 40 patients with severe pancreatic hemorrhage in Xuanwu Hospital were enrolled between 2005 and 2017. Patients underwent angiography and direct TAE for primary diagnosis and treatment of bleeding. Repeat TAE, watch and wait, and laparotomy were used as the other therapeutic options. Patient data, technical success, and 90-day survival were identified. Pancreatic diseases underlying hemorrhage included acute pancreatitis (n=19, 47.5%), chronic pancreatitis (n=12, 30%), and pancreatic cancer (n=9, 22.5%). A history of percutaneous catheter drainage or pancreatic surgery was seen in 29 patients (72.5%). There were 48 angiographies, 31 embolizations, and 5 laparotomies performed. Rebleeding occurred in 8 patients (20%); 4 of whom underwent re-embolization, 3 had laparotomy, and 1 had conservative treatment. Successful clinical hemostasis was achieved in 37 patients. Complications were observed in only 2 patients with renal failure and 1 patient with hepatic insufficiency. In total, 25 patients (62.5%) were alive at the 90-day follow-up. Endovascular management is effective for achieving hemostasis in severe pancreatic hemorrhage with a high success rate and low recurrence, and laparotomy is not suitable for rebleeding cases.


Human mitochondrial thioredoxin. Involvement in mitochondrial membrane potential and cell death.
Thioredoxins (Trx) are a class of small multifunctional redox-active proteins found in all organisms. Recently, we reported the cloning of a mitochondrial thioredoxin, Trx2, from rat heart. To investigate the biological role of Trx2 we have isolated the human homologue, hTrx2, and generated HEK-293 cells overexpressing Trx2 (HEK-Trx2). Here, we show that HEK-Trx2 cells are more resistant toward etoposide. In addition, HEK-Trx2 are more sensitive toward rotenone, an inhibitor of complex I of the respiratory chain. Finally, overexpression of Trx2 confers an increase in mitochondrial membrane potential, DeltaPsi(m). Treatment with oligomycin could both reverse the effect of rotenone and decrease the membrane potential suggesting that Trx2 interferes with the activity of ATP synthase. Taken together, these results suggest that Trx2 interacts with specific components of the mitochondrial respiratory chain and plays an important role in the regulation of the mitochondrial membrane potential.


Establishment of a real-time RT-PCR for the determination of absolute amounts of IGF-I and IGF-II gene expression in liver and extrahepatic sites of the tilapia.
We developed a one-tube two-temperature real-time RT-PCR that allows to absolutely quantify the gene expression of hormones using the standard curve method. As our research focuses on the expression of the insulin-like growth factors (IGFs) in bony fish, we established the technique for IGF-I and IGF-II using the tilapia (Oreochromis niloticus) as model species. As approach, we used primer extension adding a T7 phage polymerase promoter (21 nt) to the 5' end of the antisense primers. This procedure avoids the disadvantages arising from plasmids. Total RNA extracted from liver was subjected to conventional RT-PCR to create templates for in vitro transcription of IGF-I and IGF-II cRNA. Correct template sizes including the T7 promoter were verified (IGF-I: 91 nt; IGF-II: 94 nt). The PCR products were used to create IGF-I and IGF-II cRNAs which were quantified in dot blot by comparison with defined amounts of standardised kanamycin mRNA. Standardised threshold cycle (Ct) values for IGF-I and IGF-II mRNA were achieved by real-time RT-PCR and used to create standard curves. To allow sample normalisation the standard curve was also established for beta-actin as internal calibrator (template: 86 nt), and validation experiments were performed demonstrating similar amplification efficiencies for target and reference genes. Based on the standard curves, the absolute amounts of IGF-I and IGF-II mRNA were determined for liver (IGF-I: 8.90+/-1.90 pg/microg total RNA, IGF-II: 3.59+/-0.98 pg/microg total RNA) and extrahepatic sites, such as heart, kidney, intestine, spleen, gills, gonad, and brain considering the different lengths of cRNAs and mRNAs by correction factors. The reliability of the method was confirmed in additional experiments. The amplification of descending dilutions of cRNA and total liver RNA resulted in parallel slopes of the amplification curves. Furthermore, amplification plots of the standard cRNA and the IGF-I and IGF-II mRNAs showed signals starting at the expected Ct values. Thus, the one-tube RT-PCR described here is highly sensitive (detection level approximately 2 pg/microg total RNA) and allows precise absolute quantification. The method is rapid as there are neither separate reverse transcriptions nor post-amplification steps, and can be executed with low risk of contamination. Therefore, it will be helpful when investigating gene expression in any species and tissue whenever absolute levels are of concern.


Reliability and Validity of the Musculoskeletal Tumor Society Scoring System for the Upper Extremity in Japanese Patients.
The Musculoskeletal Tumor Society (MSTS) scoring system developed in 1993 is a widely used disease-specific evaluation tool for assessment of physical function in patients with musculoskeletal tumors; however, only a few studies have confirmed its reliability and validity. The aim of this study was to validate the MSTS scoring system for the upper extremity (MSTS-UE) in Japanese patients with musculoskeletal tumors for use by others in research. Does the MSTS-UE have: (1) sufficient reliability and internal consistency; (2) adequate construct validity; and (3) reasonable criterion validity in comparison to the Toronto Extremity Salvage Score (TESS) or SF-36? Reliability was performed using test-retest analysis, and internal consistency was evaluated with Cronbach's alpha coefficient. Construct validity was evaluated using a scree plot to confirm the construct number and the Akaike information criterion network. Criterion validity was evaluated by comparing the MSTS-UE with the TESS and SF-36. The test-retest reliability with intraclass correlation coefficient (0.95; 95% CI, 0.91-0.97) was excellent, and internal consistency with Cronbach's α (0.7; 95% CI, 0.53-0.81) was acceptable. There were no ceiling and floor effects. The Akaike Information Criterion network showed that lifting ability, pain, and dexterity played central roles among the components. The MSTS-UE showed substantial correlation with the TESS scoring scale (r = 0.75; p < 0.001) and fair correlation with the SF-36 physical component summary (r = 0.37; p = 0.007). Although the MSTS-UE showed slight correlation with the SF-36 mental component summary, the emotional acceptance component of the MSTS-UE showed fair correlation (r = 0.29; p = 0.039). We can conclude that the MSTS is not an adequate measure of general health-related quality of life; however, this system was designed mainly to be a simple measure of function in a single extremity. To evaluate the mental state of patients with musculoskeletal tumors in the upper extremity, further study is needed.


The socioeconomic aspects of laser refractive surgery.
Excimer laser photorefractive keratectomy (PRK) has shown promising results in preliminary studies. However, even if long-term safety and efficacy are demonstrated, questions have been raised about its viability from a cost-effectiveness perspective. We analyzed the economic investment of elective excimer laser PRK both from the societal and individual perspectives. When the present value of likely expenses associated with excimer laser PRK and follow-up care are compared with those entailed in wearing soft contact lenses, PRK is roughly equivalent to daily wear soft contact lenses over a 10-year horizon and considerably less expensive than extended-wear soft contact lenses. When the analytic perspective is extended to 20 years, excimer laser PRK is a less expensive investment than both daily wear and extended-wear soft contact lenses.


Test-area simulation method for the direct determination of the interfacial tension of systems with continuous or discontinuous potentials.
A novel test-area (TA) technique for the direct simulation of the interfacial tension of systems interacting through arbitrary intermolecular potentials is presented in this paper. The most commonly used method invokes the mechanical relation for the interfacial tension in terms of the tangential and normal components of the pressure tensor relative to the interface (the relation of Kirkwood and Buff [J. Chem. Phys. 17, 338 (1949)]). For particles interacting through discontinuous intermolecular potentials (e.g., hard-core fluids) this involves the determination of delta functions which are impractical to evaluate, particularly in the case of nonspherical molecules. By contrast we employ a thermodynamic route to determine the surface tension from a free-energy perturbation due to a test change in the surface area. There are important distinctions between our test-area approach and the computation of a free-energy difference of two (or more) systems with different interfacial areas (the method of Bennett [J. Comput. Phys. 22, 245 (1976)]), which can also be used to determine the surface tension. In order to demonstrate the adequacy of the method, the surface tension computed from test-area Monte Carlo (TAMC) simulations are compared with the data obtained with other techniques (e.g., mechanical and free-energy differences) for the vapor-liquid interface of Lennard-Jones and square-well fluids; the latter corresponds to a discontinuous potential which is difficult to treat with standard methods. Our thermodynamic test-area approach offers advantages over existing techniques of computational efficiency, ease of implementation, and generality. The TA method can easily be implemented within either Monte Carlo (TAMC) or molecular-dynamics (TAMD) algorithms for different types of interfaces (vapor-liquid, liquid-liquid, fluid-solid, etc.) of pure systems and mixtures consisting of complex polyatomic molecules.


Time-dependent neuronal changes associated with craving in opioid dependence: an fMRI study.
Relapse after initially successful treatment is a significant problem facing the treatment of opioid dependence. Evidence suggests craving elicited by re-exposure to drug cues may precipitate relapse. Attempts to identify neural biomarkers of cue-elicited craving have yielded inconsistent findings. We aimed to apply a novel continuous functional magnetic resonance imaging technique to follow the minute-to-minute evolution of brain responses, which correlate with the waxing and waning of craving. Newly detoxified male opioid-dependent patients and healthy control participants attended two separate, counterbalanced, functional magnetic resonance imaging scanning sessions during which they viewed a 10-minute video (drug cue or neutral cue) followed by 5 minutes of fixation. Participants rated the intensity of their craving throughout each session. We hypothesized that subcortical/ventral prefrontal cortex (PFC) regions and dorsal PFC regions would show different associations with craving reflecting their putative roles in appetitive processing versus cognitive control. Compared with controls, drug cue (minus neutral cue) video recruited the left amygdala and was temporally correlated with craving. In contrast, dorsal anterior cingulate blood-oxygen-level-dependent signal time course was higher than controls only during a period after cue exposure when craving levels were declining. Against expectations, neither the ventral striatum nor ventral PFC was significantly recruited by drug cue exposure. Findings suggest that the amygdala has a central role in craving, whereas the dorsal anterior cingulate may control craving in treatment-seeking patients. Time course analysis yielded new insights into the neural substrates of craving that could objectively validate development of psychological and pharmacological approaches to sustained abstinence.


Assessing adolescent mindfulness: validation of an adapted Mindful Attention Awareness Scale in adolescent normative and psychiatric populations.
Interest in mindfulness-based interventions for children and adolescents is burgeoning, bringing with it the need for validated instruments to assess mindfulness in youths. The present studies were designed to validate among adolescents a measure of mindfulness previously validated for adults (e.g., Brown & Ryan, 2003), which we herein call the Mindful Attention Awareness Scale-Adolescent (MAAS-A). In 2 large samples of healthy 14- to 18-year-olds (N = 595), Study 1 supported a single-factor MAAS-A structure, along with acceptably high internal consistency, test-retest reliability, and both concurrent and incremental validity. In Study 2, with a sample of 102 psychiatric outpatient adolescents age 14-18 years, participants randomized to a mindfulness-based stress reduction intervention showed significant increases in MAAS-A scores from baseline to 3-month follow-up, relative to nonsignificant score changes among treatment-as-usual participants. Increases in MAAS-A scores among mindfulness-based stress reduction participants were significantly related to beneficial changes in numerous mental health indicators. The findings support the reliability and validity of the MAAS-A in normative and mixed psychiatric adolescent populations and suggest that the MAAS-A has utility in mindfulness intervention research.


β-Lactoglobulin-linoleate complexes: In vitro digestion and the role of protein in fatty acid uptake.
The dairy protein β-lactoglobulin (BLG) is known to bind fatty acids such as the salt of the essential longchain fatty acid linoleic acid (cis,cis-9,12-octadecadienoic acid, n-6, 18:2). The aim of the current study was to investigate how bovine BLG-linoleate complexes, of various stoichiometry, affect the enzymatic digestion of BLG and the intracellular transport of linoleate into enterocyte-like monolayers. Duodenal and gastric digestions of the complexes indicated that BLG was hydrolyzed more rapidly when complexed with linoleate. Digested as well as undigested BLG-linoleate complexes reduced intracellular linoleate transport as compared with free linoleate. To investigate whether enteroendocrine cells perceive linoleate differently when part of a complex, the ability of linoleate to increase production or secretion of the enteroendocrine satiety hormone, cholecystokinin, was measured. Cholecystokinin mRNA levels were different when linoleate was presented to the cells alone or as part of a protein complex. In conclusion, understanding interactions between linoleate and BLG could help to formulate foods with targeted fatty acid bioaccessibility and, therefore, aid in the development of food matrices with optimal bioactive efficacy.


Basis for the control of purine biosynthesis by purine ribonucleotides.
An animal model was used to determine the basis for the increase in purine biosynthesis that results from hepatic depletion of purine nucleotides, such as seen in patients with type I glycogen storage disease or following fructose administration. Mice were injected intravenously with glucose or fructose, 2.5 mg/g of body weight, and the animals were killed at 0, 3, and 30 min following carbohydrate infusion. Fructose, but not glucose, administration led to a threefold increase in [14C]glycine incorporation into hepatic purine nucleotides documenting an increase in the rate of purine biosynthesis in the liver of fructose-treated animals. In the fructose, but not the glucose-treated animals, there was a reduction in the hepatic content of purine nucleotides that are inhibitory for amidophosphoribosyltransferase, the enzyme that catalyzes the first reaction unique to the pathway of purine biosynthesis. PP-ribose-P, an important metabolite in the control of purine biosynthesis, was increased 2,3-fold in liver following fructose, but not glucose administration. In conjunction with the decrease in inhibitory nucleotides and increase in PP-ribose-P 29% of amidophosphoribosyltransferase was shifted from the large inactive to the small active form of the enzyme. Results of these studies demonstrate that the end-products of the pathway, purine nucleotides, control the activity of the enzyme that catalyzes the first reaction leading to purine nucleotide synthesis either through a direct effect of purine nucleotides on the enzyme, through an indirect effect of the change in nucleotides on PP-ribose-P synthesis, or a combination of these effects. The resultant changes in amidophosphoribosyltransferase conformation and activity provide a basis for understanding the increase in purine biosynthesis that results from hepatic depletion of purine nucleotides.


Intraoperative monitoring of a patient with craniovertebral junction meningioma.
Intraoperative monitoring is considered as a useful tool to prevent neurological damage during different neurosurgical procedures. Somatosensory evoked potentials (SEP) allow simultaneous assessment of several cortical and sub cortical centers. In this case presentation, we report intraoperative monitoring of an elderly patient with craniovertebral junction meningioma. Tibial SEP responses were elicited by stimulation of the tibial nerve; the recordings were visually analyzed for the presence of the main peaks P40-N50, peak to peak amplitudes, peak latencies and compared to baseline recordings throughout the procedure. During decompression from the medial aspect of the medulla SEP responses were lost for a brief period of time. Surgeons achieved total tumor removal and the patient left the operating room without any neurological deficit.


Multireference adaptive noise canceling applied to the EEG.
The technique of multireference adaptive noise canceling (MRANC) is applied to enhance transient nonstationarities in the electroeancephalogram (EEG), with the adaptation implemented by means of a multilayer-perception artificial neural network (ANN). The method was applied to recorded EEG segments and the performance on documented nonstationarities recorded. The results show that the neural network (nonlinear) gives an improvement in performance (i.e., signal-to-noise ratio (SNR) of the nonstationarities) compared to a linear implementation of MRANC. In both cases an improvement in the SNR was obtained. The advantage of the spatial filtering aspect of MRANC is highlighted when the performance of MRANC is compared to that of the inverse auto-regressive filtering of the EEG, a purely temporal filter.