Heterogeneity of neoplastic cells in B-cell chronic lymphoproliferative disorders: biclonality versus intraclonal evolution of a single tumor cell clone.
B-cell chronic lymphoproliferative disorders (B-CLPD) are usually monoclonal expansions of a single B-cell clone. However in some cases, two unrelated B-cell clones co-exist. Additionally, cases with two B-cell subpopulations displaying a similar phenotype but distinct DNA contents exist, the exact nature of these cases remaining unknown. In order to gain insight into the characteristics of these complex B-CLPD we examined two cohorts of patients. One cohort had two phenotypically distinct B-cell populations (group A; n= 9) and the other, two B-cell subsets showing different DNA contents and/or light scatter properties, but a similar immunophenotype (group B; n= 7). Fluorescent in situ hybridization studies revealed the presence of genetic abnormalities in six cases from group A, either in one (n=5) or the two co-existing B-cell populations (n=1); in all these cases the two B-cell populations showed unrelated IgH gene rearrangements. In all seven cases from group B, the B-cell population showing higher DNA contents had additional chromosomal abnormalities as compared to the other subset; molecular analysis confirmed the monoclonal nature of these cases. In summary, we show that in group A, two phenotypically/cytogenetically distinct, unrelated B-cell clones co-exist, while the two B-cell populations from group B appear to represent different stages of evolution of a single clone.


Duration of U.S. stay and body mass index among Latino and Asian immigrants: A test of theoretical pathways.
Studies find that longer-term immigrants have higher body mass index (BMI) than their more recently arrived counterparts. Most interpretations of these health patterns by duration of U.S. residence rely on theories of immigrant integration; they posit that with increasing time in the United States, immigrants incorporate economically, socially, and culturally into aspects of U.S. society, and that these changes impact health. Few studies empirically examine whether these aspects of integration are indeed mediators of the association between duration of U.S. stay and BMI, and if their patterns differ across immigrant subgroups. This study examines data from the National Latino and Asian American Survey, using path analytic methods to simultaneously test six hypothesized mediators between duration and BMI: household income, English language ability, ethnic identity, family cohesion, acculturative stress and discrimination for both Latino and Asian immigrants, stratified by gender. We find little evidence for an association between duration and BMI for either Latino or Asian men. For women, duration and BMI have a significant and positive relationship, although the pathways differ between the two ethnic groups. For Latina women, household income and acculturative stress are significant indirect pathways, although they work in opposing directions. For Asian women, English proficiency and discrimination are significant indirect pathways. Our findings reveal complex pathways between duration and BMI that vary by ethnicity and gender and highlight limitations in the negative acculturation theory, which suggests that exposure to the United States should have a net negative impact on health. In contrast, our findings suggest that not all groups show declining health with longer duration, as measured by BMI, and that integration processes do not always translate into health differences in the expected directions. Future research on duration patterns may need to consider alternative explanations beyond incorporation-based processes, such as cross-national health theories or age, period, cohort effects.


Case report of complicated epidermoid cyst of the floor of the mouth: Radiology-histopathology correlation.
Epidermoid cysts, true dermoid cysts and teratoid cysts compose the spectrum of cystic teratomas, which are defined as neoplasms whose tissue are derivatives of more than one germ layer, foreign to that part of the body from which the tumor arises. Epidermoid cysts of the floor of the mouth are rare lesions and are much less common than dermoid cysts in the head and neck. This case reports a 43-year-old male patient who presented with a longstanding midline swelling in the submental region. Initial imaging was done using ultrasound followed by computed tomography (CT) scan. Biopsy was taken and revealed a cyst wall lined with epidermal squamous epithelium along with areas of focal ulceration suggesting chronic inflammatory changes of the wall of the epidermoid cyst. There are characteristic and even pathognomonic imaging features of epidermoid cysts at the floor of the mouth in ultrasound and CT scan. Imaging has an important role in the surgical management plan according to the size and location of the cyst in relation to geniohyoid and mylohyoid muscles.


The effects of yoga on psychosocial variables and exercise adherence: a randomized, controlled pilot study.
Physical inactivity is a serious issue for the American public. Because of conditions that result from inactivity, individuals incur close to $1 trillion USD in health-care costs, and approximately 250 000 premature deaths occur per year. Researchers have linked engaging in yoga to improved overall fitness, including improved muscular strength, muscular endurance, flexibility, and balance. Researchers have not yet investigated the impact of yoga on exercise adherence. The research team assessed the effects of 10 weeks of yoga classes held twice a week on exercise adherence in previously sedentary adults. The research team designed a randomized controlled pilot trial. The team collected data from the intervention (yoga) and control groups at baseline, midpoint, and posttest (posttest 1) and also collected data pertaining to exercise adherence for the yoga group at 5 weeks posttest (posttest 2). The pilot took place in a yoga studio in central New Jersey in the United States. The pretesting occurred at the yoga studio for all participants. Midpoint testing and posttesting occurred at the studio for the yoga group and by mail for the control group. Participants were 27 adults (mean age 51 y) who had been physically inactive for a period of at least 6 months prior to the study. Interventions The intervention group (yoga group) received hour-long hatha yoga classes that met twice a week for 10 weeks. The control group did not participate in classes during the research study; however, they were offered complimentary post research classes. Outcome Measures The study's primary outcome measure was exercise adherence as measured by the 7-day Physical Activity Recall. The secondary measures included (1) exercise self-efficacy as measured by the Multidimensional Self-Efficacy for Exercise Scale, (2) general well-being as measured by the General Well-Being Schedule, (3) exercise-group cohesion as measured by the Group Environment Questionnaire (GEQ), (4) acute feeling response as measured by the Exercise-induced Feeling Inventory (EFI), and (5) two open-ended questions coded for emerging themes and subcategories. The analysis revealed that the yoga group's mean hours of physical activity at 10 weeks reflected a significant increase in exercise adherence from baseline (P < .012) and a significant difference from the control group (P < .004). At 5 weeks post-intervention, no significant change had occurred in the yoga group's exercise adherence (P = .906). Exercise self-efficacy changed significantly from baseline to midpoint (P < .029). The general wellbeing data demonstrated a significant interaction effect (P < .001), resulting from an increase in general well-being in the intervention group and a decrease in general well-being in the control group. In addition, the yoga group's cohesion score was consistent with the norms on two constructs of the GEQ: Attraction to Group Task and Group Integration Task. The EFI revealed that the yoga participants "felt strongly" that their experiences in yoga were peaceful, happy, upbeat, and enthusiastic and that they felt revived following the yoga classes. Qualitative analysis of data revealed self-reported improvements in exercise behaviors, stress management, and eating habits. Ten weeks of yoga classes twice a week significantly increased previously inactive participants' adherence to physical activity. Additionally, the findings suggest that a mind-body exercise program may be an effective intervention in the fight against physical inactivity.


Systemic mastocytosis: bone marrow pathology, classification, and current therapies.
Mast cell disease (MCD) is characterized by the abnormal growth and accumulation of neoplastic mast cells (MC) in one or more organs. The diagnosis of systemic MCD is most commonly established by a thorough histological and immunohistochemical examination of a bone marrow (BM) trephine specimen. In cases with pathognomonic perivascular and -trabecular aggregates of morphologically atypical MC and significant BM involvement, the diagnosis may be relatively straightforward. In contrast, when a sparse, loose pattern of MC infiltration predominates, or when MCs are obscured by an associated non-MC hematological neoplasm, a high index of suspicion and use of adjunctive tests, including special stains, such as tryptase and CD25, may be necessary to reach a diagnosis. The updated classification for MCD clarifies the clinical and pathological criteria for categorizing patients into relatively discrete subgroups. Some cases, however, such those with Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA)(+) clonal eosinophilia associated with elevated serum tryptase levels, with features that overlap MCD and chronic eosinophilic leukemia, may not be easy to categorize on the basis of this classification. There is no standard therapy for MCD and treatment has to be tailored to the needs of the individual patient. MC-cytoreductive therapies, such as interferon-alpha and chemotherapy, are generally reserved for patients with progressive disease and organopathy. A subset of MCD patients with associated eosinophilia who carry the FIP1L1-PDGFRA oncogene will achieve complete clinical, histological, and molecular remissions with imatinib mesylate therapy, in contrast to those with c-kit D816V mutations. The BM pathology, consensus classification, and current therapies for MCD are further discussed in this article.


What children see affects how they spell.
The authors predicted that children who have experienced frequent visual confusion of text during their development because of unstable binocular control may be prevented from discovering the rules and patterns of English orthography. The authors compared the spelling errors made by children who had unstable binocular vision with those of children who had stable binocular vision and the same spelling ability. The subjects were drawn from a clinical population of children referred because of suspected reading difficulties; though they were of mixed abilities, they were generally poor spellers and readers. Children with unstable binocular control made spelling errors which were more phonologically plausible than those made by the control group with normal binocular vision.


Intravenous thrombolysis in nonagenarians with ischemic stroke.
Demographic changes will result in a rapid increase of patients age ≥90 years (nonagenarians), but little is known about outcomes in these patients after intravenous thrombolysis (IVT) for acute ischemic stroke. We aimed to assess safety and functional outcome in nonagenarians treated with IVT and to compare the outcomes with those of patients age 80 to 89 years (octogenarians). We analyzed prospectively collected data of 284 consecutive stroke patients age ≥80 years treated with IVT in 7 Swiss stroke units. Presenting characteristics, favorable outcome (modified Rankin scale [mRS] 0 or 1), mortality at 3 months, and symptomatic intracranial hemorrhage (SICH) using the National Institute of Neurological Disorders and Stroke (NINDS) and Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria were compared between nonagenarians and octogenarians. As compared with octogenarians (n=238; mean age, 83 years), nonagenarians (n=46; mean age, 92 years) were more often women (70% versus 54%; P=0.046) and had lower systolic blood pressure (161 mm Hg versus 172 mm Hg; P=0.035). Patients age ≥90 years less often had a favorable outcome and had a higher incidence of mortality than did patients age 80 to 89 years (14.3% versus 30.2%; P=0.034; and 45.2% versus 22.1%; P=0.002; respectively), while more nonagenarians than octogenarians experienced a SICH (SICH(NINDS), 13.3% versus 5.9%; P=0.106; SICH(SITS-MOST), 13.3% versus 4.7%; P=0.037). Multivariate adjustment identified age ≥90 years as an independent predictor of mortality (P=0.017). Our study suggests less favorable outcomes in nonagenarians as compared with octogenarians after IVT for ischemic stroke, and it demands a careful selection for treatment, unless randomized controlled trials yield more evidence for IVT in very old stroke patients.


Facile synthesis of AsP3.
The elements phosphorus and arsenic form tetrahedral P4 and As4 molecules, of which the former is a commodity chemical and the latter unstable. Previously, information on molecules of intermediate composition was limited to a spectroscopic study involving hot gas-phase mixtures of phosphorus and arsenic. The AsP3 molecule has yielded to chemical synthesis and was isolated in solid form as a pure substance with a melting point from 71 degrees to 73 degrees C. Physical properties and spectroscopic characterization data for AsP3 are described, and its structure was determined as a ligand in a coordination complex. Soluble in organic solvents, AsP3 represents an attractive starting point for any synthesis in which the target molecule or material contains an exact 1:3 ratio of arsenic to phosphorus.


Development of a screening tool for identifying women with menorrhagia for hemostatic evaluation.
A study was conducted to develop a short, easy to administer screening tool useful for stratifying women with unexplained menorrhagia for hemostatic testing for underlying bleeding disorders. One hundred forty-six women with a physician diagnosis of menorrhagia underwent comprehensive hemostatic testing for the diagnosis of bleeding disorders, including von Willebrand disease, platelet dysfunction, and coagulation factor deficiencies. A 12 page questionnaire of bleeding symptoms was administered. Bleeding symptoms with high predictive values for laboratory hemostatic abnormalities were combined and used as single variables to calculate sensitivity, specificity, and positive and negative predictive values in order to develop a short screening tool to identify females for testing and evaluation. A combination of 8 questions in 4 categories resulted in a sensitivity of 82% (95%CI 75-90) for bleeding disorders. Adding a pictorial blood assessment chart score > 100 increased the sensitivity of the screening tool to 95% (95%CI 91-99). These results demonstrate the feasibility of a simple questionnaire based screening tool to identify females for testing and evaluation for bleeding disorders.


Mouse models of aneuploidy to understand chromosome disorders.
An organism or cell carrying a number of chromosomes that is not a multiple of the haploid count is in a state of aneuploidy. This condition results in significant changes in the level of expression of genes that are gained or lost from the aneuploid chromosome(s) and most cases in humans are not compatible with life. However, a few aneuploidies can lead to live births, typically associated with deleterious phenotypes. We do not understand why phenotypes arise from aneuploid syndromes in humans. Animal models have the potential to provide great insight, but less than a handful of mouse models of aneuploidy have been made, and no ideal system exists in which to study the effects of aneuploidy per se versus those of raised gene dosage. Here, we give an overview of human aneuploid syndromes, the effects on physiology of having an altered number of chromosomes and we present the currently available mouse models of aneuploidy, focusing on models of trisomy 21 (which causes Down syndrome) because this is the most common, and therefore, the most studied autosomal aneuploidy. Finally, we discuss the potential role of carrying an extra chromosome on aneuploid phenotypes, independent of changes in gene dosage, and methods by which this could be investigated further.


Psychological correlates of frequency and type of drug use among jail inmates.
The comorbidity of drug abuse and various forms of psychopathology is pervasive and well documented. In particular, the incidence of depression, anxiety, and antisocial personality disorder is high among substance abusers relative to non-drug abusers. Offender populations have a high rate of substance abuse, and some studies suggest that the incidence of psychopathology may be even greater than in other drug using groups. In order to identify specific types of psychopathology as they relate to drug preferences and frequency of use among drug-using offenders, arrestees at the Baltimore City Detention Center were examined. During extensive interviews, drug-abusing arrestees provided information pertaining to their backgrounds, childhood histories, biological relatives, present behaviors, and criminal and drug histories. Additionally, several psychological inventories were administered to evaluate the presence of depression, anxiety, psychopathy, and impulsivity. Results indicate that the frequency with which subjects reported using specific drugs and drug of choice were significantly associated with particular measures of psychopathology. A composite measure of psychopathy was especially related to the frequency of alcohol, marijuana, and cocaine use. Subjects who reported using cocaine on a frequent basis scored high on measures of hostility and reported committing more property crimes, while violent crimes were more likely to be reported by subjects scoring high on the measure of psychopathy. Other noteworthy findings will be discussed along with the limitations of this study.


Evacuating damaged and destroyed buildings on 9/11: behavioral and structural barriers.
Evacuation of the World Trade Center (WTC) twin towers and surrounding buildings damaged in the September 11, 2001 attacks provides a unique opportunity to study factors that affect emergency evacuation of high rise buildings. Problem The goal of this study is to understand the extent to which structural and behavioral barriers and limitations of personal mobility affected evacuation by occupants of affected buildings on September 11, 2001. This analysis included 5,023 civilian, adult enrollees within the World Trade Center Health Registry who evacuated the two World Trade Center towers and over 30 other Lower Manhattan buildings that were damaged or destroyed on September 11, 2001. Multinomial logistic regression was used to predict total evacuation time (<30 to ≤60 minutes, >1 hour to <2 hours relative to ≤30 minutes) in relation to number of infrastructure barriers and number of behavioral barriers, adjusted for demographic and other factors. A higher percentage of evacuees reported encountering at least one behavioral barrier (84.9%) than reported at least one infrastructure barrier (51.9%). This pattern was consistent in all buildings except WTC 1, the first building attacked, where >90% of evacuees reported encountering both types of barriers. Smoke and poor lighting were the most frequently-reported structural barriers. Extreme crowding, lack of communication with officials, and being surrounded by panicked crowds were the most frequently-reported behavioral barriers. Multivariate analyses showed evacuation time to be independently associated with the number of each type of barrier as well as gender (longer times for women), but not with the floor from which evacuation began. After adjustment, personal mobility impairment was not associated with increased evacuation time. Because most high-rise buildings have unique designs, infrastructure factors tend to be less predictable than behavioral factors, but both need to be considered in developing emergency evacuation plans in order to decrease evacuation time and, consequently, risk of injury and death during an emergency evacuation.


Random Tactile Noise Stimulation Reveals Beta-Rhythmic Impulse Response Function of the Somatosensory System.
Both passive tactile stimulation and motor actions result in dynamic changes in beta band (15-30 Hz Hz) oscillations over somatosensory cortex. Similar to alpha band (8-12 Hz) power decrease in the visual system, beta band power also decreases following stimulation of the somatosensory system. This relative suppression of α and β oscillations is generally interpreted as an increase in cortical excitability. Here, next to traditional single-pulse stimuli, we used a random intensity continuous right index finger tactile stimulation (white noise), which enabled us to uncover an impulse response function of the somatosensory system. Contrary to previous findings, we demonstrate a burst-like initial increase rather than decrease of beta activity following white noise stimulation (human participants, N = 18, 8 female). These β bursts, on average, lasted for 3 cycles, and their frequency was correlated with resonant frequency of somatosensory cortex, as measured by a multifrequency steady-state somatosensory evoked potential paradigm. Furthermore, beta band bursts shared spectro-temporal characteristics with evoked and resting-state β oscillations. Together, our findings not only reveal a novel oscillatory signature of somatosensory processing that mimics the previously reported visual impulse response functions, but also point to a common oscillatory generator underlying spontaneous β bursts in the absence of tactile stimulation and phase-locked β bursts following stimulation, the frequency of which is determined by the resonance properties of the somatosensory system.SIGNIFICANCE STATEMENT The investigation of the transient nature of oscillations has gained great popularity in recent years. The findings of bursting activity, rather than sustained oscillations in the beta band, have provided important insights into its role in movement planning, working memory, inhibition, and reactivation of neural ensembles. In this study, we show that also in response to tactile stimulation the somatosensory system responds with ∼3 cycle oscillatory beta band bursts, whose spectro-temporal characteristics are shared with evoked and resting-state beta band oscillatory signatures of the somatosensory system. As similar bursts have been observed in the visual domain, these oscillatory signatures might reflect an important supramodal mechanism in sensory processing.


Dietary animal and plant protein intakes and their associations with obesity and cardio-metabolic indicators in European adolescents: the HELENA cross-sectional study.
Previous studies suggest that dietary protein might play a beneficial role in combating obesity and its related chronic diseases. Total, animal and plant protein intakes and their associations with anthropometry and serum biomarkers in European adolescents using one standardised methodology across European countries are not well documented. To evaluate total, animal and plant protein intakes in European adolescents stratified by gender and age, and to investigate their associations with cardio-metabolic indicators (anthropometry and biomarkers). The current analysis included 1804 randomly selected adolescents participating in the HELENA study (conducted in 2006-2007) aged 12.5-17.5 y (47% males) who completed two non-consecutive computerised 24-h dietary recalls. Associations between animal and plant protein intakes, and anthropometry and serum biomarkers were examined with General linear Model multivariate analysis. Average total protein intake exceeded the recommendations of World Health Organization and European Food Safety Authority. Mean total protein intake was 96 g/d (59% derived from animal protein). Total, animal and plant protein intakes (g/d) were significantly lower in females than in males and total and plant protein intakes were lower in younger participants (12.5-14.9 y). Protein intake was significantly lower in underweight subjects and higher in obese ones; the direction of the relationship was reversed after adjustments for body weight (g/(kg.d)). The inverse association of plant protein intakes was stronger with BMI z-score and body fat percentage (BF%) compared to animal protein intakes. Additionally, BMI and BF% were positively associated with energy percentage of animal protein. This sample of European adolescents appeared to have adequate total protein intake. Our findings suggest that plant protein intakes may play a role in preventing obesity among European adolescents. Further longitudinal studies are needed to investigate the potential beneficial effects observed in this study in the prevention of obesity and related chronic diseases.


How long does it take to coil an intracranial aneurysm?
The change in the treatment of choice for intracranial aneurysms from clipping to coiling has been associated with an important change in logistics. The time needed for coiling is variable and depends on many factors. In this study, we assessed the procedural time for the coiling of 642 aneurysms and tried to identify predictors of a long procedural time. The procedural time for coiling was defined as the number of minutes between the first diagnostic angiographic run and the last angiographic run after embolization. Thus, induction of general anesthesia and catheterization of the first vessel were not included in the procedural time. A long procedural time was defined as the upper quartile of procedural times (70-158 min). Logistic regression analysis was performed for several variables. The mean procedural time was 57.3 min (median 52 min, range 15-158 min). More than half of the coiling procedures lasted between 30 and 60 min. Multiple logistic regression analysis identified the use of a supportive device (OR 5.4), procedural morbidity (OR 4.5) and large aneurysm size (OR 3.0) as independent predictors of a long procedural time. A poor clinical condition of the patient, the rupture status of the aneurysm, gender, the occurrence of procedural rupture, and aneurysm location were not related to a long procedural time. The mean time for the first 321 coiling procedures was not statistically significantly different from mean time for the last 321 procedures. With optimal logistics, coiling of most intracranial aneurysms can be performed in one to two hours, including patient handling before and after the actual coiling procedure.


Lentivirus-mediated gene transfer of gp91phox corrects chronic granulomatous disease (CGD) phenotype in human X-CGD cells.
Chronic granulomatous diseases (CGD) are caused by impaired antimicrobial activity in phagocytes, due to the absence or malfunction of the respiratory burst NADPH oxidase. Two-thirds of the patients have mutations in their X-linked CGD gene encoding gp91phox, the largest subunit of the NADPH oxidase. Aimed at gene therapy of X-CGD already at the level of resting pluripotent hematopoietic stem cells, we generated an advanced HIV-1-based vector with self-inactivating (SIN2) features containing the therapeutic gp91phox gene. In this vector an internal cytomegalovirus (CMV) promoter exclusively drives transgene expression. The green fluorescent protein (GFP) served as reporter for evaluation of gene transfer and expression in the human myeloid PLB985 X-CGD cell line. The X-CGD cells were efficiently transduced by the VSV-G pseudotyped lentivirus constructs (up to 74% GFP+ cells at 3 days post-transduction). CMV-driven GFP-expression was stable for at least 3 weeks after transduction and persisted after granulocytic differentiation of the target cells. Using the lentivector with the gp91phox transgene, 26% and 48% of the X-CGD cells expressed gp91phox at Days 2 and 20 after co-culture with 293T producer cells, respectively. Upon granulocytic differentiation of the transduced X-CGD cells with dimethylformamide (DMF), up to 63% (mean 49%, n = 7) of the cells were found to be functionally reconstituted with mean levels of superoxide production of 31% (n = 7) compared to wild-type PLB985 cells. Lentivirus vectors expressing gp91phox are able to at least partially correct human myeloid X-CGD cells.


Hornets can fly at night without obvious adaptations of eyes and ocelli.
Hornets, the largest social wasps, have a reputation of being facultatively nocturnal. Here we confirm flight activity of hornet workers in dim twilight. We studied the eyes and ocelli of European hornets (Vespa crabro) and common wasps (Vespula vulgaris) with the goal to find the optical and anatomical adaptations that enable them to fly in dim light. Adaptations described for obligately nocturnal hymenoptera such as the bees Xylocopa tranquebarica and Megalopta genalis and the wasp Apoica pallens include large ocelli and compound eyes with wide rhabdoms and large facet lenses. Interestingly, we did not find any such adaptations in hornet eyes or ocelli. On the contrary, their eyes are even less sensitive than those of the obligately diurnal common wasps. Therefore we conclude that hornets, like several facultatively nocturnal bee species such as Apis mellifera adansonii, A. dorsata and X. tenuiscapa are capable of seeing in dim light simply due to the large body and thus eye size. We propose that neural pooling strategies and behavioural adaptations precede anatomical adaptations in the eyes and ocelli when insects with apposition compound eyes turn to dim light activity.


Bilingual performance on nonword repetition in Spanish and English.
Nonword repetition (NWR) involves the ability to perceive, store, recall and reproduce phonological sequences. These same abilities play a role in word and morpheme learning. Cross-linguistic studies of performance on NWR tasks, word learning, and morpheme learning yield patterns of increased performance on all three tasks as a function of age and language experience. These results are consistent with the idea that there may be universal information-processing mechanisms supporting language learning. Because bilingual children's language experience is divided across two languages, studying performance in two languages on NWR could inform one's understanding of the relationship between information processing and language learning. The primary aims of this study were to compare bilingual language learners' recall of Spanish-like and English-like items on NWR tasks and to assess the relationships between performance on NWR, semantics, and morphology tasks. Sixty-two Hispanic children exposed to English and Spanish were recruited from schools in central Texas, USA. Their parents reported on the children's input and output in both languages. The children completed NWR tasks and short tests of semantics and morphosyntax in both languages. Mixed-model analysis of variance was used to explore direct effects and interactions between the variables of nonword length, language experience, language outcome measures, and cumulative exposure on NWR performance. Children produced the Spanish-like nonwords more accurately than the English-like nonwords. NWR performance was significantly correlated to cumulative language experience in both English and Spanish. There were also significant correlations between NWR and morphosyntax but not semantics. Language knowledge appears to play a role in the task of NWR. The relationship between performance on morphosyntax and NWR tasks indicates children rely on similar language-learning mechanisms to mediate these tasks. More exposure to Spanish may increase abilities to repeat longer nonwords. This knowledge may shift across levels of bilingualism. Further research is needed to understand this relationship, as it is likely to have implications for language teaching or intervention for children with language impairments.


Phenylketonuria in Hong Kong Chinese: a call for hyperphenylalaninemia newborn screening in the Special Administrative Region, China.
Hyperphenylalaninemia is one of the commonest inborn errors of metabolism affecting approximately 1 in 15,000 livebirths. Among Chinese, BH4 deficiency leading to hyperphenylalaninemia is much commoner than in Caucasians. Exact diagnosis is important for the treatment and genetic counseling. In 2000, newborn screening for phenylketonuria is mandatory by law in China throughout the whole country. However, it is not yet included in the newborn screening program of the Hong Kong Special Administrative Region, China. Published data on hyperphenylalaninemia among HongKong Chinese are largely lacking. We report a 1-year-old Hong Kong Chinese girl with severe 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. The patient presented with infantile hypotonia and was misdiagnosed as cerebral palsy. She had very mild hyperphenylalaninemia (95 μmol/L), significantly high phenylalnine-to-tyrosine ratio (3.1), and elevated prolactin of 1109 mIU/L. Genetic analysis confirmed a homozygous known disease-causing mutation PTS NM_000317.1:c.259C>T; NP_000308.1: p.P87S in the proband. In our local experience, while the estimated prevalence of hyperphenylalaninemia due to PTPS deficiency was reported to be 1 in 29,542 live births, not a single case of phenylalanine hydroxylase deficiency has been reported. Furthermore, there is a general lack of awareness of inherited metabolic diseases in the community as well as among the medical professionals. Very often, a low index of clinical suspicion will lead to delay in diagnosis, multiple unnecessary and costly investigations, prolonged morbidity and anxiety to the family affected. We strongly recommend that expanded newborn screening for hyperphenylalaninemia should be implemented for every baby born in the Hong Kong Special Administrative Region, China.


Understanding Factors Associated With Psychomotor Subtypes of Delirium in Older Inpatients With Dementia.
Few studies have analyzed factors associated with delirium subtypes. In this study, we investigate factors associated with subtypes of delirium only in patients with dementia to provide insights on the possible prevention and treatments. This is a cross-sectional study nested in the "Delirium Day" study, a nationwide Italian point-prevalence study. Older patients admitted to 205 acute and 92 rehabilitation hospital wards. Delirium was evaluated with the 4-AT and the motor subtypes with the Delirium Motor Subtype Scale. Dementia was defined by the presence of a documented diagnosis in the medical records and/or prescription of acetylcholinesterase inhibitors or memantine prior to admission. Of the 1057 patients with dementia, 35% had delirium, with 25.6% hyperactive, 33.1% hypoactive, 34.5% mixed, and 6.7% nonmotor subtype. There were higher odds of having venous catheters in the hypoactive (OR 1.82, 95% CI 1.18-2.81) and mixed type of delirium (OR 2.23, CI 1.43-3.46), whereas higher odds of urinary catheters in the hypoactive (OR 2.91, CI 1.92-4.39), hyperactive (OR 1.99, CI 1.23-3.21), and mixed types of delirium (OR 2.05, CI 1.36-3.07). We found higher odds of antipsychotics both in the hyperactive (OR 2.87, CI 1.81-4.54) and mixed subtype (OR 1.84, CI 1.24-2.75), whereas higher odds of antibiotics was present only in the mixed subtype (OR 1.91, CI 1.26-2.87). In patients with dementia, the mixed delirium subtype is the most prevalent followed by the hypoactive, hyperactive, and nonmotor subtype. Motor subtypes of delirium may be triggered by clinical factors, including the use of venous and urinary catheters, and the use of antipsychotics. Future studies are necessary to provide further insights on the possible pathophysiology of delirium in patients with dementia and to address the optimization of the management of potential risk factors.


Insulin gene therapy from design to beta cell generation.
Despite the fact that insulin injection can protect diabetic patients from developing diabetes-related complications, recent meta-analyses indicate that rapid and long-acting insulin analogues only provide a limited benefit compared with conventional insulin regarding glycemic control. As insulin deficiency is the main sequel of type-1 diabetes (T1D), transfer of the insulin gene-by-gene therapy is becoming an attractive treatment modality even though T1D is not caused by a single genetic defect. In contrast to human insulin and insulin analogues, insulin gene therapy targets to supplement patients not only with insulin but also with C-peptide. So far, insulin gene therapy has had limited success because of delayed and/or transient gene expression. Sustained insulin gene expression is now feasible using current gene-therapy vectors providing patients with basal insulin coverage, but management of postprandial hyperglycaemia is still difficult to accomplish because of the inability to properly control insulin secretion. Enteroendocrine cells of the gastrointestinal track (K cells and L cells) may be ideal targets for insulin gene therapy, but cell-targeting difficulties have limited practical implementation of insulin gene therapy for diabetes treatment. Therefore, recent gene transfer technologies developed to generate authentic beta cells through transdifferentiation are also highlighted in this review.


Resorbable versus titanium plates for facial fractures.
Rigid internal fixation of the jaw bones is a routine procedure for the management of facial fractures. Titanium plates and screws are routinely used for this purpose. The limitations of this system has led to the development of plates manufactured from bioresorbable materials which, in some cases, omits the necessity for the second surgery. However, concerns remain about the stability of fixation and the length of time required for their degradation and the possibility of foreign body reactions. To compare the effectiveness of bioresorbable fixation systems with titanium systems for the management of facial fractures. We searched the following databases: The Cochrane Oral Health Group's Trials Register (to 20th August 2008), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE (1950 to 20th August 2008), EMBASE (from 1980 to 20th August 2008), http://www.clinicaltrials.gov/ and http://www.controlled-trials.com (to 20th August 2008). Randomised controlled trials comparing resorbable versus titanium fixation systems used for facial fractures. Retrieved studies were independently screened by two review authors. Results were to be expressed as random-effects models using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals. Heterogeneity was to be investigated including both clinical and methodological factors. The search strategy retrieved 53 potentially eligible studies. None of the retrieved studies met our inclusion criteria and all were excluded from this review. One study is awaiting classification as we failed to obtain the full text copy. Three ongoing trials were retrieved, two of which were stopped before recruiting the planned number of participants. In one study, the excess complications in the resorbable arm was declared as the reason for stopping the trial. This review illustrates that there are no published randomised controlled clinical trials relevant to this review question. There is currently insufficient evidence for the effectiveness of resorbable fixation systems compared with conventional titanium systems for facial fractures. The findings of this review, based on the results of the aborted trials, do not suggest that resorbable plates are as effective as titanium plates. In future, the results of ongoing clinical trials may provide high level reliable evidence for assisting clinicians and patients for decision making. Trialists should design their studies accurately and comprehensively to meet the aims and objectives defined for the study.


MicroRNA regulation of the synaptic plasticity-related gene Arc.
Expression of activity-regulated cytoskeleton associated protein (Arc) is crucial for diverse types of experience-dependent synaptic plasticity and long-term memory in mammals. However, the mechanisms governing Arc-specific translation are little understood. Here, we asked whether Arc translation is regulated by microRNAs. Bioinformatic analysis predicted numerous candidate miRNA binding sites within the Arc 3'-untranslated region (UTR). Transfection of the corresponding microRNAs in human embryonic kidney cells inhibited expression of an Arc 3'UTR luciferase reporter from between 10 to 70% across 16 microRNAs tested. Point mutation and deletion of the microRNA-binding seed-region for miR-34a, miR-326, and miR-19a partially or fully rescued reporter expression. In addition, expression of specific microRNA pairs synergistically modulated Arc reporter expression. In primary rat hippocampal neuronal cultures, ectopic expression of miR-34a, miR-193a, or miR-326, downregulated endogenous Arc protein expression in response to BDNF treatment. Conversely, treatment of neurons with cell-penetrating, peptide nucleic acid (PNA) inhibitors of miR-326 enhanced Arc mRNA expression. BDNF dramatically upregulated neuronal expression of Arc mRNA and miR-132, a known BDNF-induced miRNA, without affecting expression of Arc-targeting miRNAs. Developmentally, miR-132 was upregulated at day 10 in vitro whereas Arc-targeting miRNAs were downregulated. In the adult brain, LTP induction in the dentate gyrus triggered massive upregulation of Arc and upregulation of miR-132 without affecting levels of mature Arc-targeting miRNAs. Turning to examine miRNA localization, qPCR analysis of dentate gyrus synaptoneurosome and total lysates fractions demonstrated synaptic enrichment relative to small nucleolar RNA. In conclusion, we find that Arc is regulated by multiple miRNAs and modulated by specific miRNA pairs in vitro. Furthermore, we show that, in contrast to miR-132, steady state levels of Arc-targeting miRNAs do not change in response to activity-dependent expression of Arc in hippocampal neurons in vitro or during LTP in vivo.


A comprehensive HADHA c.1528G>C frequency study reveals high prevalence of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in Poland.
Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is associated with c.1528G>C substitution in the HADHA gene, since most patients have the prevalent mutation on at least one allele. As it is known that the disease is relatively frequent in Europe, especially around the Baltic Sea, and that the majority of Polish LCHADD patients originate from the coastal Pomeranian province, partly inhabited by an ancient ethnic group, the Kashubians, we aimed to determine the carrier frequency of the prevalent HADHA mutation in various districts of Poland with special focus on the Kashubian district. A total of 6,854 neonatal dried blood samples from the entire country, including 2,976 Pomeranian neonates of Kashubian origin, were c.1528G>C genotyped. Fifty-nine heterozygous carriers for the prevalent c.1528G>C substitution (41 Pomeranian children) were detected in the studied group. Our data reveal a geographically skewed distribution of the c.1528C allele in the Polish population; in the northern Pomeranian province the carrier frequency is 1:73, which is the highest frequency ever reported, whereas in the remaining regions it is 1:217. Hence, the incidence of LCHADD in Poland is predicted to be 1:118,336 versus 1:16,900 in the Pomeranian district. Despite the relative rarity of the disease, screening for LCHADD in neonates born in the northern part of Poland, especially those of Kashubian origin, is justified. Our data allow us to suggest a probable Kashubian origin of the prevalent c.1528G>C mutation.


Human cyclophilin 40 is a heat shock protein that exhibits altered intracellular localization following heat shock.
The unactivated steroid receptors are chaperoned into a conformation that is optimal for binding hormone by a number of heat shock proteins, including Hsp90, Hsp70, Hsp40, and the immunophilin, FKBP52 (Hsp56). Together with its partner cochaperones, cyclophilin 40 (CyP40) and FKBP51, FKBP52 belongs to a distinct group of structurally related immunophilins that modulate steroid receptor function through their association with Hsp90. Due to the structural similarity between the component immunophilins, FKBP52 and cyclophilin 40, we decided to investigate whether CyP40 is also a heat shock protein. Exposure of MCF-7 breast cancer cells to elevated temperatures (42 degrees C for 3 hours) resulted in a 75-fold increase in CyP40 mRNA levels, but no corresponding increase in CyP40 protein expression, even after 7 hours of heat stress. The use of cycloheximide to inhibit protein synthesis revealed that in comparison to MCF-7 cells cultured at 37 degrees C, those exposed to heat stress (42 degrees C for 3 hours) displayed an elevated rate of degradation of both CyP40 and FKBP52 proteins. Concomitantly, the half-life of the CyP40 protein was reduced from more than 24 hours to just over 8 hours following heat shock. As no alteration in CyP40 protein levels occurred in cells exposed to heat shock, an elevated rate of degradation would imply that CyP40 protein was synthesized at an increased rate, hence the designation of human CyP40 as a heat shock protein. Application of heat stress elicited a marked redistribution of CyP40 protein in MCF-7 cells from a predominantly nucleolar localization, with some nuclear and cytoplasmic staining, to a pattern characterized by a pronounced nuclear accumulation of CyP40, with no distinguishable nucleolar staining. This increase in nuclear CyP40 possibly resulted from a redistribution of cytoplasmic and nucleolar CyP40, as no net increase in CyP40 expression levels occurred in response to stress. Exposure of MCF-7 cells to actinomycin D for 4 hours resulted in the translocation of the nucleolar marker protein, B23, from the nucleolus, with only a small reduction in nucleolar CyP40 levels. Under normal growth conditions, MCF-7 cells exhibited an apparent colocalization of CyP40 and FKBP52 within the nucleolus.


M1.3--a small scaffold for DNA origami .
The DNA origami method produces programmable nanoscale objects that form when one long scaffold strand hybridizes to numerous oligonucleotide staple strands. One scaffold strand is dominating the field: M13mp18, a bacteriophage-derived vector 7249 nucleotides in length. The full-length M13 is typically folded by using over 200 staple oligonucleotides. Here we report the convenient preparation of a 704 nt fragment dubbed "M1.3" as a linear or cyclic scaffold and the assembly of small origami structures with just 15-24 staple strands. A typical M1.3 origami is large enough to be visualized by TEM, but small enough to show a cooperativity in its assembly and thermal denaturation that is reminiscent of oligonucleotide duplexes. Due to its medium size, M1.3 origami with globally modified staples is affordable. As a proof of principle, two origami structures with globally 5'-capped staples were prepared and were shown to give higher UV-melting points than the corresponding assembly with unmodified DNA. M1.3 has the size of a gene, not a genome, and may function as a model for gene-based nanostructures. Small origami with M1.3 as a scaffold may serve as a workbench for chemical, physical, and biological experiments.


Using the Integrative Model to explain how exposure to sexual media content influences adolescent sexual behavior.
Published research demonstrates an association between exposure to media sexual content and a variety of sex-related outcomes for adolescents. What is not known is the mechanism through which sexual content produces this "media effect" on adolescent beliefs, attitudes, and behavior. Using the Integrative Model of Behavioral Prediction, this article uses data from a longitudinal study of adolescents ages 16 to 18 (N = 460) to determine how exposure to sexual media content influences sexual behavior. Path analysis and structural equation modeling demonstrated that intention to engage in sexual intercourse is determined by a combination of attitudes, normative pressure, and self-efficacy but that exposure to sexual media content only affects normative pressure beliefs. By applying the Integrative Model, we are able to identify which beliefs are influenced by exposure to media sex and improve the ability of health educators, researchers, and others to design effective messages for health communication campaigns and messages pertaining to adolescents' engaging in sexual intercourse.


Disparities in outcomes of patients admitted with diabetic foot infections.
The purpose of this study was to evaluate the disparities in the outcomes of White, African American (AA) and non-AA minority (Hispanics and Native Americans (NA)), patients admitted in the hospitals with diabetic foot infections (DFIs). The HCUP-Nationwide Inpatient Sample (2002 to 2015) was queried to identify patients who were admitted to the hospital for management of DFI using ICD-9 codes. Outcomes evaluated included minor and major amputations, open or endovascular revascularization, and hospital length of stay (LOS). Incidence for amputation and open or endovascular revascularization were evaluated over the study period. Multivariable regression analyses were performed to assess the association between race/ethnicity and outcomes. There were 150,701 admissions for DFI, including 98,361 Whites, 24,583 AAs, 24,472 Hispanics, and 1,654 Native Americans (NAs) in the study cohort. Overall, 45,278 (30%) underwent a minor amputation, 9,039 (6%) underwent a major amputation, 3,151 underwent an open bypass, and 8,689 had an endovascular procedure. There was a decreasing incidence in major amputations and an increasing incidence of minor amputations over the study period (P < .05). The risks for major amputation were significantly higher (all p<0.05) for AA (OR 1.4, 95%CI 1.4,1.5), Hispanic (OR 1.3, 95%CI 1.3,1.4), and NA (OR 1.5, 95%CI 1.2,1.8) patients with DFIs compared to White patients. Hispanics (OR 1.3, 95%CI 1.2,1.5) and AAs (OR 1.2, 95%CI 1.1,1.4) were more likely to receive endovascular intervention or open bypass than Whites (all p<0.05). NA patients with DFI were less likely to receive a revascularization procedure (OR 0.6, 95%CI 0.3, 0.9, p = 0.03) than Whites. The mean hospital length of stay (LOS) was significantly longer for AAs (9.2 days) and Hispanics (8.6 days) with DFIs compared to Whites (8.1 days, p<0.001). Despite a consistent incidence reduction of amputation over the past decade, racial and ethnic minorities including African American, Hispanic, and Native American patients admitted to hospitals with DFIs have a consistently significantly higher risk of major amputation and longer hospital length of stay than their White counterparts. Native Americans were less likely to receive revascularization procedures compared to other minorities despite exhibiting an elevated risk of an amputation. Further study is required to address and limit racial and ethnic disparities and to further promote equity in the treatment and outcomes of these at-risk patients.


The Potential Role of Gut-Derived Inflammation in Multiple System Atrophy.
Recent evidence suggests that Parkinson's disease (PD) is associated with intestinal microbiota dysbiosis, abnormal intestinal permeability, and intestinal inflammation. Our study aimed to determine if these gut abnormalities are present in another synucleinopathy, multiple system atrophy (MSA). In six MSA and 11 healthy control subjects, we performed immunohistochemistry studies of colonic sigmoid mucosa to evaluate the intestinal barrier marker Zonula Occludens-1 and the endotoxin-related inflammation marker Toll-like-receptor-4 expression. We also assessed colonic sigmoid mucosal and fecal microbiota compositions using high-throughput 16S ribosomal RNA gene amplicon sequencing. MSA subjects showed disrupted tight junction protein Zonula Occludens-1 structure in sigmoid mucosa tissue suggesting intestinal barrier dysfunction. The lipopolysaccharide specific inflammatory receptor Toll-like-receptor-4 was significantly higher in the colonic sigmoid mucosa in MSA relative to healthy controls. Microbiota analysis suggested high relative abundance of gram-negative, putative "pro-inflammatory" bacteria in various family and genus level taxa, from the phylum Bacteroidetes and Proteobacteria, in MSA feces and mucosa. At the taxonomic level of genus, putative "anti-inflammatory" butyrate-producing bacteria were less abundant in MSA feces. Predictive functional analysis indicated that the relative abundance of a number of genes involved in metabolism were lower in MSA feces, whereas the relative abundance of genes involved in lipopolysaccharide biosynthesis were higher in both MSA feces and mucosa compared to healthy controls. This proof-of-concept study provides preliminary evidence that like PD, MSA subjects display evidence of disrupted intestinal barrier integrity, increased marker of endotoxin-related intestinal inflammation, and pro-inflammatory colonic microbiota.


CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia.
The pathological hallmarks of bronchopulmonary dysplasia (BPD), one of the most common long-term pulmonary complications associated with preterm birth, include arrested alveolarization, abnormal vascular growth, and variable interstitial fibrosis. Severe BPD is often complicated by pulmonary hypertension characterized by excessive pulmonary vascular remodeling and right ventricular hypertrophy that significantly contributes to the mortality and morbidity of these infants. Connective tissue growth factor (CTGF) is a multifunctional protein that coordinates complex biological processes during tissue development and remodeling. We have previously shown that conditional overexpression of CTGF in airway epithelium under the control of the Clara cell secretory protein promoter results in BPD-like architecture in neonatal mice. In this study, we have generated a doxycycline-inducible double transgenic mouse model with overexpression of CTGF in alveolar type II epithelial (AT II) cells under the control of the surfactant protein C promoter. Overexpression of CTGF in neonatal mice caused dramatic macrophage and neutrophil infiltration in alveolar air spaces and perivascular regions. Overexpression of CTGF also significantly decreased alveolarization and vascular development. Furthermore, overexpression of CTGF induced pulmonary vascular remodeling and pulmonary hypertension. Most importantly, we have also demonstrated that these pathological changes are associated with activation of integrin-linked kinase (ILK)/glucose synthesis kinase-3β (GSK-3β)/β-catenin signaling. These data indicate that overexpression of CTGF in AT II cells results in lung pathology similar to those observed in infants with severe BPD and that ILK/GSK-3β/β-catenin signaling may play an important role in the pathogenesis of severe BPD.


"APRIL hath put a spring of youth in everything": Relevance of APRIL for survival.
A proliferation inducing ligand (APRIL or TALL-2 and TRDL-1) was first discovered as a cytokine over-expressed in many transformed cells and with the capacity to stimulate proliferation. APRIL was shown to bind two different receptors of the TNF receptor superfamily: B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), as well as heparan sulphate proteoglycans (HSPGs). APRIL has since been shown to play a physiological role in B cell biology, in particular the survival of plasma B cells in a specialized APRIL-rich niche. However, aberrant expression of APRIL and the subsequent activation of pro-survival pathways, is potentially the driving force for the survival of several B cell malignancies. APRIL has therefore become an important therapeutic target, but many questions regarding its mechanism of action still remain. It is for instance unclear what the exact physiological implications of the APRIL-HSPG interaction could be. Neither do we know the precise signals elicited by APRIL in normal or in malignant cells, and whether blocking these effects could provide real therapeutic gain in cancer patients. In this review we discuss the specific relevance of APRIL for cell survival, in terms of both its physiological role and its role in tumor biology, and highlight some of the key questions that will undoubtedly form the basis of future research in this field.


Cancer testis antigen expression in gastrointestinal stromal tumors: new markers for early recurrence.
Cancer testis antigens (CTAs) are expressed in a variety of malignant tumors but not in any normal adult tissues except germ cells and occasionally placenta. Because of this tumor-associated pattern of expression, CTAs are regarded as potential vaccine targets. The expression of CTAs in gastrointestinal stromal tumors (GIST) has not been analyzed systematically previously. The present study was performed to analyze the expression of CTA in GIST and to determine if CTA expression correlates with prognosis. Thirty-five GIST patients were retrospectively analyzed for their expression of CTAs by immunohistochemistry using the following monoclonal antibodies (mAb/antigen): MA454/MAGE-A1, M3H67/MAGE-A3, 57B/MAGE-A4, CT7-33/MAGE-C1 and E978/NY-ESO-1. Fourteen tumors (40%) expressed 1 or more of the 5 CTAs tested. Fourteen percent (n = 5/35) were positive for MAGE-A1, MAGE-A3 or MAGE-A4, respectively. Twenty-six percent (n = 9/35) stained positive for MAGE-C1 and 20% (n = 7/35) for NY-ESO-1. A highly significant correlation between CTA expression and tumor recurrence risk was observed (71% vs. 29%; p = 0.027). In our study population, the high-risk GIST expressed CTAs more frequently than low-risk GIST (p = 0.012). High-risk GISTs which stained positive for at least 1 CTA, recurred in 100% (n = 25) of the cases. This is the first study analyzing CTA expression in GIST and its prognostic value for recurrence. The CTA staining could add information to the individual patient prognosis and represent an interesting target for future treatment strategies.


Cost and utilization outcomes of opioid-dependence treatments.
To evaluate the healthcare costs associated with treatment of opioid-dependence disorder with medications versus no medication, and with the 4 agents approved by the US Food and Drug Administration (FDA). Retrospective claims database analysis. Eligible adults with opioid dependence were identified from a large US health plan and the PharMetrics Integrated Database. Data included all medical and pharmacy claims at all available healthcare sites. Case-mix adjustment was applied using baseline demographic, clinical, and healthcare utilization variables for 13,316 patients; half of these patients used an FDA-approved medication for opioid dependence. A similar comparison was performed among 10,513 patients treated with extended-release naltrexone (NTX-XR) (n = 156) prior to FDA approval for opioid dependence or with a medication approved at the time: oral naltrexone (NTX) (n = 845), buprenorphine (n = 7596), or methadone (n = 1916). Analyses calculated 6-month persistence, utilization, and paid claims for opioid-dependence medications, detoxification and rehabilitation, opioid-related and non-related inpatient admissions, outpatient services, and total costs. Medication was associated with fewer inpatient admissions of all types. Despite higher costs for medications, total healthcare costs, including inpatient, outpatient, and pharmacy costs, were 29% lower for patients who received a medication for opioid dependence versus patients treated without medication. Patients given XR-NTX had fewer opioid-related and non-opioid-related hospitalizations than patients receiving oral medications. Despite higher costs for XR-NTX, total healthcare costs were not significantly different from those for oral NTX or buprenorphine, and were 49% lower than those for methadone. Patients with opioid dependence who received medication for this disorder had lower hospital utilization and total costs than patients who did not receive pharmacologic therapy. Patients who received XR-NTX had lower inpatient healthcare utilization at comparable or lower total costs than those receiving oral medications.


CADM1/TSLC1 Identifies HTLV-1-Infected Cells and Determines Their Susceptibility to CTL-Mediated Lysis.
Human T cell lymphotropic virus-1 (HTLV-1) primarily infects CD4+ T cells, causing inflammatory disorders or a T cell malignancy in 5% to 10% of carriers. The cytotoxic T lymphocyte (CTL) response is a key factor that controls the viral load and thus the risk of disease. The ability to detect the viral protein Tax in primary cells has made it possible to estimate the rate at which Tax-expressing infected cells are eliminated by CTLs in persistently infected people. However, most HTLV-1-infected cells are Tax-at a given time, and their immunophenotype is poorly defined. Here, we aimed to identify a cell-surface molecule expressed by both Tax+ and Tax-HTLV-1-infected cells and use it to analyse the CTL response in fresh peripheral blood mononuclear cells. Cell adhesion molecule 1 (CADM1/TSLC1) was the best single marker of HTLV-1 infection, identifying HTLV-1-infected cells with greater sensitivity and specificity than CD25, CCR4 or ICAM-1. CADM1+CD4+ T cells carried a median of 65% of proviral copies in peripheral blood. In a cohort of 23 individuals, we quantified the rate of CTL-mediated killing of Tax+ and Tax-CADM1+ cells. We show that CADM1 expression is associated with enhanced susceptibility of infected cells to CTL lysis: despite the immunodominance of Tax in the CTL response, Tax+CADM1- cells were inefficiently lysed by CTLs. Upregulation of the CADM1 ligand CRTAM on CD8+ T cells correlated with efficient lysis of infected cells. Tax-CADM1+ cells were lysed at a very low rate by autologous CTLs, however, were efficiently killed when loaded with exogenous peptide antigen. High expression of CADM1 on most HTLV-1-infected cells in the face of enhanced CTL counterselection implies that CADM1 confers a strong benefit on the virus.


Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau.
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.


Host response to Candida albicans bloodstream infection and sepsis.
Candida albicans is a major cause of bloodstream infection which may present as sepsis and septic shock - major causes of morbidity and mortality world-wide. After invasion of the pathogen, innate mechanisms govern the early response. Here, we outline the models used to study these mechanisms and summarize our current understanding of innate immune responses during Candida bloodstream infection. This includes protective immunity as well as harmful responses resulting in Candida induced sepsis. Neutrophilic granulocytes are considered principal effector cells conferring protection and recognize C. albicans mainly via complement receptor 3. They possess a range of effector mechanisms, contributing to elimination of the pathogen. Neutrophil activation is closely linked to complement and modulated by activated mononuclear cells. A thorough understanding of these mechanisms will help in creating an individualized approach to patients suffering from systemic candidiasis and aid in optimizing clinical management.


Hyperactivation of PARP triggers nonhomologous end-joining in repair-deficient mouse fibroblasts.
Regulation of poly(ADP-ribose) (PAR) synthesis and turnover is critical to determining cell fate after genotoxic stress. Hyperactivation of PAR synthesis by poly(ADP-ribose) polymerase-1 (PARP-1) occurs when cells deficient in DNA repair are exposed to genotoxic agents; however, the function of this hyperactivation has not been adequately explained. Here, we examine PAR synthesis in mouse fibroblasts deficient in the base excision repair enzyme DNA polymerase β (pol β). The extent and duration of PARP-1 activation was measured after exposure to either the DNA alkylating agent, methyl methanesulfonate (MMS), or to low energy laser-induced DNA damage. There was strong DNA damage-induced hyperactivation of PARP-1 in pol β nullcells, but not in wild-type cells. In the case of MMS treatment, PAR synthesis did not lead to cell death in the pol β null cells, but instead resulted in increased PARylation of the nonhomologous end-joining (NHEJ) protein Ku70 and increased association of Ku70 with PARP-1. Inhibition of the NHEJ factor DNA-PK, under conditions of MMS-induced PARP-1 hyperactivation, enhanced necrotic cell death. These data suggest that PARP-1 hyperactivation is a protective mechanism triggering the classical-NHEJ DNA repair pathway when the primary alkylated base damage repair pathway is compromised.


Selective expression of H-2 (i-region) loci controlling determinants on helper and suppressor T lymphocytes.
Data presented here show that locidentify in the I-region of the H-2 gene complex are selectively expressed in different functional T-cell subpopulations. These loci are closely linked (or possibly identical) to loci that control immune responses. They control surface determinants which identify helper and suppressor T lymphocytes. Determinants described here on allotype suppressor T cells (Ts) are found on normal (nonsuppressed) lymphoid cells, but are not found on helper T cells (Th). These determinants are controlled by a locus mapping in the I region of the H-2 complex. In an accompanying publication we show that this locus (Ia-4) marks a new I subregion (I-J) and is expressed only on T cells. Thus Ia-4 determinants idenfity a T-cell subpopulation which includes Ts but not Th. Th also carry identifying surface determinants controlled by loci that map to the H-2 complex, probably within the I region. These determinants are not found on Ts. Data presented also establish that loci in the I region control determinants on Th, but do not conclusively demonstrate that these are the determinants that distinguish Th from Ts. The selective expression of H-2-controlled determinants on Ts and Th suggests that these determinants are directly involved in immunoregulation.


Recruitment of HIV and its receptors to dendritic cell-T cell junctions.
Monocyte-derived dendritic cells (MDDCs) can efficiently bind and transfer HIV infectivity without themselves becoming infected. Using live-cell microscopy, we found that HIV was recruited to sites of cell contact in MDDCs. Analysis of conjugates between MDDCs and T cells revealed that, in the absence of antigen-specific signaling, the HIV receptors CD4, CCR5, and CXCR4 on the T cell were recruited to the interface while the MDDCs concentrated HIV to the same region. We propose that contact between dendritic cells and T cells facilitates transmission of HIV by locally concentrating virus, receptor, and coreceptor during the formation of an infectious synapse.


Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour.
Magnesium maintenance therapy is one of the types of tocolytic therapy used after an episode of threatened preterm labour (usually treated with an initial dose of tocolytic therapy) in an attempt to prevent the onset of further preterm contractions. To assess whether magnesium maintenance therapy is effective in preventing preterm birth after the initial threatened preterm labour is arrested. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (May 2010). Randomised controlled trials of magnesium therapy given to women after threatened preterm labour. The review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. We checked data entry. We included four trials, which recruited 422 women. Three trials had high risk of bias and none included any long-term follow up of infants. No differences in the incidence of preterm birth or perinatal mortality were seen when magnesium maintenance therapy was compared with placebo or no treatment; or alternative therapies (ritodrine or terbutaline). The risk ratio (RR) for preterm birth (less than 37 weeks) for magnesium compared with placebo or no treatment was 1.05, 95% confidence interval (CI) 0.80 to 1.40 (two trials, 99 women); and 0.99, 95% CI 0.57 to 1.72 (2 trials, 100 women) for magnesium compared with alternative therapies. The RR for perinatal mortality for magnesium compared with placebo or no treatment was 5.00, 95% CI 0.25 to 99.16 (one trial, 50 infants) and also compared with alternative treatments, was 5.00, 95% CI 0.25 to 99.16 (one trial, 50 infants). Women taking magnesium preparations were less likely to report palpitations or tachycardia than women receiving alternative therapies (RR 0.26, 95% CI 0.13 to 0.52, three trials, 237 women) but were much more likely to experience diarrhoea (RR 7.66, 95% CI 2.18 to 26.98, three trials, 237 women). There is not enough evidence to show any difference between magnesium maintenance therapy compared with either placebo or no treatment, or alternative therapies (ritodrine or terbutaline) in preventing preterm birth after an episode of threatened preterm labour.


Myxoid fibroadenomas differ from conventional fibroadenomas: a hypothesis-generating study.
Breast myxoid fibroadenomas (MFAs) are characterized by a distinctive hypocellular myxoid stroma, and occur sporadically or in the context of Carney complex, an inheritable condition caused by PRKAR1A-inactivating germline mutations. Conventional fibroadenomas (FAs) are underpinned by recurrent MED12 mutations in the stromal components of the lesions. The aim of this study was to investigate the genomic landscape of MFAs and compare it with that of conventional FAs. Eleven MFAs from patients without clinical and/or genetic evidence of Carney complex were retrieved. DNA samples of tumour and matching normal tissue were subjected to massively parallel sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay, an assay targeting 410 cancer genes. Genetic alterations detected by MSK-IMPACT were tested in samples in which the stromal and epithelial components were separately laser capture-microdissected. Sequencing revealed no germline PRKAR1A mutations and non-synonymous mutations in six MFAs. Interestingly, in three of the MFAs in which the stromal and epithelial components were separately microdissected, the mutations were found to be restricted to the epithelial rather than the stromal component. The sole exception was a lesion harbouring a somatic truncating PRKAR1A mutation. Upon histological re-review, this case was reclassified as a breast myxoma, consistent with the spectrum of tumous observed in Carney complex patients. In this case, the PRKAR1A somatic mutation was restricted to the stromal component. MFAs lack MED12 mutations, and their stromal components seem not to harbour mutations in the 410 cancer genes tested. Whole-exome and/or whole-genome analyses of MFAs are required to elucidate their genetic drivers.


Comprehensive analysis of differentially expressed rice actin depolymerizing factor gene family and heterologous overexpression of OsADF3 confers Arabidopsis Thaliana drought tolerance.
Actin depolymerizing factors (ADFs) are small actin-binding proteins. Many higher-plant ADFs has been known to involve in plant growth, development and pathogen defense. However, in rice the temporal and spatial expression of OsADF gene family and their relationship with abiotic stresses tolerance is still unknown. Here we reported the first comprehensive gene expression profile analysis of OsADF gene family. The OsADF genes showed distinct and overlapping gene expression patterns at different growth stages, tissues and abiotic stresses. We also demonstrated that both OsADF1 and OsADF3 proteins were localized in the nucleus. OsADF1 and OsADF3 were preferentially expressed in vascular tissues. Under ABA or abiotic stress treatments, OsADF3::GUS activity was enhanced in lateral roots and root tips. Ectopically overexpressed OsADF3 conferred the mannitol- and drought-stress tolerance of transgenic Arabidopsis seedlings by increasing germination rate, primary root length and survival. Several drought-tolerance responsive genes (RD22, ABF4, DREB2A, RD29A, PIP1; 4 and PIP2; 6) were upregulated in transgenic Arabidopsis under drought stress. These results suggested that OsADF gene family may participate in plant abiotic stresses response or tolerance and would facilitate functional validation of other OsADF genes.


Color separating with integrated photonic bandgap optical diodes: a numerical study.
An optical diode (OD) and its application based on the photonic band-gap (PBG) property of chiral photonic crystals are presented. The OD is constructed from wave-plates and cholesteric liquid crystals with two different pitches. The component is polarization sensitive and exhibits passive anisotropic transmission analogous to the electronic diode. The non-reciprocal transmission of linearly polarized light at the different PBG regions is discussed. A new scheme of a color-separating system with the OD is proposed. The OD behavior constitutes the operational mechanism for a color splitter.


Combined Hyperbaric Oxygen Partial Pressure at 1.4 Bar with Infrared Radiation: A Useful Tool To Improve Tissue Hypoxemia?
Tissue hypoxia contributes to the pathogenesis of several acute and chronic diseases. Hyperbaric oxygen therapy (HBO) and whole-body warming using low-temperature infrared technology (LIT) are techniques that might improve hypoxemia. Combining HBO and LIT as hyperbaric oxygen therapy combined with low-temperature infrared radiation (HBOIR) might be an approach that results in positive synergistic effects on oxygenation. LIT increases blood flow and could reduce HBO-induced vasoconstriction, and hyperoxia could compensate for the increased metabolic oxygen requirements mediated by LIT. Both LIT and HBO increase the oxygen diffusion distance in the tissues. HBOIR at 0.5 bar has been shown to be safe and feasible. However, physiological responses and the safety of HBOIR at an increased oxygen (O2) partial pressure of 1.4 bar or 2.4 atmospheres absolute (ATA) still need to be determined. The hope is that should HBOIR at an increased oxygen partial pressure of 1.4 bar be safe, future studies to examine its efficacy in patients with clinical conditions, which include peripheral arterial disease (PAD) or wound healing disorders, will follow. The results of pilot studies have shown that HBOIR at an overload pressure is safe and well tolerated in healthy participants but can generate moderate cardiovascular changes and an increase in body temperature. From the findings of this pilot study, due to its potential synergistic effects, HBOIR could be a promising tool for the treatment of human diseases associated with hypoxemia.


Monitoring response to therapy with thallium-201 and technetium-99m-sestamibi SPECT in nasopharyngeal carcinoma.
This study prospectively assessed the value of 201Tl and 99mTc-sestamibi (MIBI) SPECT in monitoring disease regression/progression as compared with MRI findings in patients with nasopharyngeal carcinoma (NPC) having radiotherapy with or without chemotherapy. Eighteen patients (age range 15-78 yr, mean 45 yr) had consecutive SPECT imaging using a dual-head gamma camera after the injection of 111 MBq 201Tl and 555 MBq MIBI before therapy and at 3 mo and 6 mo after completion of therapy. A total of 106 SPECT studies was correlated with contemporaneous MRI studies. Tumor-to-background ratios were obtained on coronal slices. Visually detectable lesions in the region of the nasopharynx and cervical lymph nodes were considered positive for residual disease. The gold standard for the presence of disease was the combination of repeat MRI scans, endoscopic examination and clinical evaluation performed 12-15 mo after completion of therapy. MIBI-SPECT proved superior to both 201Tl SPECT and MRI after 3 or 6 mo follow-up in predicting complete response. Accuracy rates in the detection of residual disease in the nasopharynx are 39%, 72% and 89% for MRI, 201Tl and MIBI, respectively, for the 3-mo evaluation; 71%, 71% and 94% for MRI, 201Tl and MIBI, respectively, for the 6-mo evaluation. MIBI SPECT could be used as a screening test in predicting response to therapy in patients with NPC.


It takes two to tango: IκBs, the multifunctional partners of NF-κB.
The inhibitory IκB proteins have been discovered as fundamental regulators of the inducible transcription factor nuclear factor-κB (NF-κB). As a generally excepted model, stimulus-dependent destruction of inhibitory IκBs and processing of precursor molecules, both promoted by components of the signal integrating IκB kinase complex, are the key events for the release of various NF-κB/Rel dimers and subsequent transcriptional activation. Intense research of more than 20 years provides evidence that the extending family of IκBs act not simply as reversible inhibitors of NF-κB activation but rather as a complex regulatory module, which assures feedback regulation of the NF-κB system and either can inhibit or promote transcriptional activity in a stimulus-dependent manner. Thus, IκB and NF-κB/Rel family proteins establish a complex interrelationship that allows modulated NF-κB-dependent transcription, tailored to the physiological environment.


Racism and child health: a review of the literature and future directions.
Racism is a mechanism through which racial/ethnic disparities occur in child health. To assess the present state of research into the effects of racism on child health, a review of the literature was undertaken. A MEDLINE review of the literature was conducted between October and November 2007. Studies reporting on empirical research relating to racism or racial discrimination as a predictor or contributor to a child health outcome were included in this review. The definition of "child health" was broad and included behavioral, mental, and physical health. Forty articles describing empirical research on racism and child health were found. Most studies (65%) reported on research performed on behavioral and mental health outcomes. Other areas studied included birth outcomes, cardiovascular and metabolic diseases, and satisfaction with care. Most research has been conducted on African-American samples (70%), on adolescents and on older children, and without a uniformly standardized approach to measuring racism. Furthermore, many studies used measures that were created for adult populations. There are a limited number of studies evaluating the relationship between racism and child health. Most studies, to date, show relationships between perceived racism and behavioral and mental health. Future studies need to include more ethnically diverse minority groups and needs to consider studying the effects of racism in younger children. Instruments need to be developed that measure perceptions of racism in children and youth that take into account the unique contexts and developmental levels of children, as well as differences in the perception of racism in different ethnocultural groups. Furthermore, studies incorporating racism as a specific psychosocial stressor that can potentially have biophysiologic sequelae need to be conducted to understand the processes and mechanisms through which racism may contribute to child health disparities.


Self-assembly of colloidal particles in deformation landscapes of electrically driven layer undulations in cholesteric liquid crystals.
We study elastic interactions between colloidal particles and deformation landscapes of undulations in a cholesteric liquid crystal under an electric field applied normal to cholesteric layers. The onset of undulation instability is influenced by the presence of colloidal inclusions and, in turn, layers' undulations mediate the spatial patterning of particle locations. We find that the bending of cholesteric layers around a colloidal particle surface prompts the local nucleation of an undulations lattice at electric fields below the well-defined threshold known for liquid crystals without inclusions, and that the onset of the resulting lattice is locally influenced, both dimensionally and orientationally, by the initial arrangements of colloids defined using laser tweezers. Spherical particles tend to spatially localize in the regions of strong distortions of the cholesteric layers, while colloidal nanowires exhibit an additional preference for multistable alignment offset along various vectors of the undulations lattice. Magnetic rotation of superparamagnetic colloidal particles couples with the locally distorted helical axis and undulating cholesteric layers in a manner that allows for a controlled three-dimensional translation of these particles. These interaction modes lend insight into the physics of liquid crystal structure-colloid elastic interactions, as well as point the way towards guided self-assembly of reconfigurable colloidal composites with potential applications in diffraction optics and photonics.


PTH induction of transcriptional activity of the cAMP response element-binding protein requires the serine 129 site and glycogen synthase kinase-3 activity, but not casein kinase II sites.
We have previously shown that PTH induction of c-fos expression in the rat osteoblastic cell line UMR 106-01 requires the phosphorylation of cAMP response element-binding protein (CREB) at serine 133. Here we show that this event is not sufficient for induced transcriptional activity in UMR cells. Serine 129, but not the casein kinase II sites (serines 108, 111, 114, 117, and 121), also plays a role in the activation of CREB. First, by metabolically labeling an epitope-tagged CREB, we determined that, in addition to serine 133, other residues are phosphorylated in vivo. Using mutational analysis of a GAL4-CREB reporter system we demonstrate that serines 129 and 133 are both required for PTH-induced transcriptional activity, whereas the casein kinase II sites are not. Furthermore, PTH failed to induce transcriptional activity of GAL4-CREB in cells treated with genistein, a general tyrosine kinase inhibitor known to inhibit glycogen synthase kinase-3 (GSK-3) activity, or LiCl, the most specific GSK-3-inhibiting agent known, strongly implicating GSK-3beta in this process. Importantly, although genistein and LiCl each inhibit GSK-3beta activity, neither prevented the phosphorylation of serine 133 induced by PTH. Lastly, when serine 129 is replaced with a negatively charged aspartic acid, LiCl has no effect on the PTH-induced trans-activation of CREB. We propose that GSK-3beta phosphorylates CREB at serine 129 and thus is required for the increased transcriptional activity of CREB in response to PTH.


Characterization of the Mixed Radiation Field Produced by Carbon and Oxygen Ion Beams of Therapeutic Energy: A Monte Carlo Simulation Study.
The main advantages of charged particle radiotherapy compared to conventional X-ray external beam radiotherapy are a better tumor conformality coupled with the capability of treating deep-seated radio-resistant tumors. This work investigates the possibility to use oxygen beams for hadron therapy, as an alternative to carbon ions. Oxygen ions have the advantage of a higher relative biological effectiveness (RBE) and better conformality to the tumor target. This work describes the mixed radiation field produced by an oxygen beam in water and compares it to the one produced by a therapeutic carbon ion beam. The study has been performed using Geant4 simulations. The dose is calculated for incident carbon ions with energies of 162 MeV/u and 290 MeV/u, and oxygen ions with energies of 192 MeV/u and 245 MeV/u, and hence that the range of the primary oxygen ions projectiles in water was located at the same depth as the carbon ions. The results show that the benefits of oxygen ions are more pronounced when using lower energies because of a slightly higher peak-to-entrance ratio, which allows either providing higher dose in tumor target or reducing it in the surrounding healthy tissues. It is observed that, per incident particle, oxygen ions deliver higher doses than carbon ions. This result coupled with the higher RBE shows that it may be possible to use a lower fluence of oxygen ions to achieve the same therapeutic dose in the patient as that obtained with carbon ion therapy.


Foods, macronutrients and breast cancer risk in postmenopausal women: a large UK cohort.
The role of diet in breast cancer aetiology is unclear; recent studies have suggested associations may differ by estrogen receptor status. Baseline diet was assessed in 2000-04 using a validated questionnaire in 691 571 postmenopausal UK women without previous cancer, who had not changed their diet recently. They were followed by record linkage to national cancer and death databases. Cox regression yielded adjusted relative risks for breast cancer for 10 food items and eight macronutrients, subdivided mostly into five categories of baseline intake. Trends in risk across the baseline categories were calculated, assigning re-measured intakes to allow for measurement error and changes in intake over time; P-values allowed for multiple testing. Women aged 59.9 (standard deviation (SD 4.9)) years at baseline were followed for 12 (SD 3) years; 29 005 were diagnosed with invasive breast cancer. Alcohol intake had the strongest association with breast cancer incidence: relative risk (RR) 1.08 [99% confidence interval (CI) 1.05-1.11] per 10 g/day higher intake, P = 5.8 × 10-14. There were inverse associations with fruit: RR 0.94 (99% CI 0.92-0.97) per 100 g/day higher intake, P = 1.1 × 10-6, and dietary fibre: RR 0.91 (99% CI 0.87-0.96) per 5 g/day increase, P = 1.1 × 10-4. Fruit and fibre intakes were correlated (ρ = 0.62) and were greater among women who were not overweight, so residual confounding cannot be excluded. There was no heterogeneity for any association by estrogen receptor status. By far the strongest association was between alcohol intake and an increased risk of breast cancer. Of the other 17 intakes examined, higher intakes of fruit and fibre were associated with lower risks of breast cancer, but it is unclear whether or not these associations are causal.


Detection and quantification of flow consistency in business process models.
Business process models abstract complex business processes by representing them as graphical models. Their layout, as determined by the modeler, may have an effect when these models are used. However, this effect is currently not fully understood. In order to systematically study this effect, a basic set of measurable key visual features is proposed, depicting the layout properties that are meaningful to the human user. The aim of this research is thus twofold: first, to empirically identify key visual features of business process models which are perceived as meaningful to the user and second, to show how such features can be quantified into computational metrics, which are applicable to business process models. We focus on one particular feature, consistency of flow direction, and show the challenges that arise when transforming it into a precise metric. We propose three different metrics addressing these challenges, each following a different view of flow consistency. We then report the results of an empirical evaluation, which indicates which metric is more effective in predicting the human perception of this feature. Moreover, two other automatic evaluations describing the performance and the computational capabilities of our metrics are reported as well.


Autophagy-Associated Protein SmATG12 Is Required for Fruiting-Body Formation in the Filamentous Ascomycete Sordaria macrospora.
In filamentous fungi, autophagy functions as a catabolic mechanism to overcome starvation and to control diverse developmental processes under normal nutritional conditions. Autophagy involves the formation of double-membrane vesicles, termed autophagosomes that engulf cellular components and bring about their degradation via fusion with vacuoles. Two ubiquitin-like (UBL) conjugation systems are essential for the expansion of the autophagosomal membrane: the UBL protein ATG8 is conjugated to the lipid phosphatidylethanolamine and the UBL protein ATG12 is coupled to ATG5. We recently showed that in the homothallic ascomycete Sordaria macrospora autophagy-related genes encoding components of the conjugation systems are required for fruiting-body development and/or are essential for viability. In the present work, we cloned and characterized the S. macrospora (Sm)atg12 gene. Two-hybrid analysis revealed that SmATG12 can interact with SmATG7 and SmATG3. To examine its role in S. macrospora, we replaced the open reading frame of Smatg12 with a hygromycin resistance cassette and generated a homokaryotic ΔSmatg12 knockout strain, which displayed slower vegetative growth under nutrient starvation conditions and was unable to form fruiting bodies. In the hyphae of S. macrospora EGFP-labeled SmATG12 was detected in the cytoplasm and as punctate structures presumed to be phagophores or phagophore assembly sites. Delivery of EGFP-labelled SmATG8 to the vacuole was entirely dependent on SmATG12.


Sex and ethnic-origin specific BMI cut points improve prediction of 40-year mortality: the Israel GOH study.
Although obesity has been associated with a higher risk for premature death, the sex and ethnic-origin specific body mass index (BMI) levels that are associated with increased mortality are controversial. We investigated the 40-year cumulative all-cause mortality, in relation to the BMI in adult life, among men and women originating from Yemen, Europe/America, Middle East and North Africa, using sex and ethnic-origin specific BMI cut points. A random stratified cohort (n = 5710) was sampled from the central population registry and followed since 1969 for vital status. Weight, height and blood pressure were measured, and smoking status was recorded at baseline. BMI was analysed according to conventional categories and according to sex and ethnic-origin specific quintiles. Elevated and significant mortality hazard ratios (HRs) of 1.21 [95% confidence interval (CI) 1.00-1.45] for women and 1.22 (95%CI 1.03-1.44) for men were found for the highest origin-specific BMI quintile. In men, the lowest ethnic-origin specific quintile was also significantly associated with increased mortality (HR of 1.22 95% CI 1.03-1.45), adjusting for age, smoking and blood pressure. Obesity was associated with mortality in non-smokers (HR = 1.29, 95% CI 1.04-1.61 in men and HR = 1.46, 95% CI 1.19-1.79 in women), whereas leanness was associated with mortality only among smoking men (HR = 1.39, 95% CI 1.09-1.77). Refinement of BMI categories using country of origin specific quintiles demonstrated significantly increased mortality in the upper quintile in both sexes, while according to the conventional values this association did not prevail in men. We propose the establishment of sex and origin-specific BMI categories when setting goals for disease prevention.


BMP4 inhibits breast cancer metastasis by blocking myeloid-derived suppressor cell activity.
The TGFβ growth factor family member BMP4 is a potent suppressor of breast cancer metastasis. In the mouse, the development of highly metastatic mammary tumors is associated with an accumulation of myeloid-derived suppressor cells (MDSC), the numbers of which are reduced by exogenous BMP4 expression. MDSCs are undetectable in naïve mice but can be induced by treatment with granulocyte colony-stimulating factor (G-CSF/Csf3) or by secretion of G-CSF from the tumor. Both tumor-induced and G-CSF-induced MDSCs effectively suppress T-cell activation and proliferation, leading to metastatic enhancement. BMP4 reduces the expression and secretion of G-CSF by inhibiting NF-κB (Nfkb1) activity in human and mouse tumor lines. Because MDSCs correlate with poor prognosis in patients with breast cancer, therapies based on activation of BMP4 signaling may offer a novel treatment strategy for breast cancer. Cancer Res; 74(18); 5091-102. ©2014 AACR.


FragViz: visualization of fragmented networks.
Researchers in systems biology use network visualization to summarize the results of their analysis. Such networks often include unconnected components, which popular network alignment algorithms place arbitrarily with respect to the rest of the network. This can lead to misinterpretations due to the proximity of otherwise unrelated elements. We propose a new network layout optimization technique called FragViz which can incorporate additional information on relations between unconnected network components. It uses a two-step approach by first arranging the nodes within each of the components and then placing the components so that their proximity in the network corresponds to their relatedness. In the experimental study with the leukemia gene networks we demonstrate that FragViz can obtain network layouts which are more interpretable and hold additional information that could not be exposed using classical network layout optimization algorithms. Network visualization relies on computational techniques for proper placement of objects under consideration. These algorithms need to be fast so that they can be incorporated in responsive interfaces required by the explorative data analysis environments. Our layout optimization technique FragViz meets these requirements and specifically addresses the visualization of fragmented networks, for which standard algorithms do not consider similarities between unconnected components. The experiments confirmed the claims on speed and accuracy of the proposed solution.


Participation in Peer-Play Activities Among Children With Specific Learning Disability: A Randomized Controlled Trial.
Children with a specific learning disability (SLD) have deficits in social and academic competence and executive function (EF). In this study, we used the Model of Human Occupation to investigate the effect of peer-play activities on occupational values and competence as well as EF skills (i.e., behavior regulation and metacognition) in children with SLD. Forty-nine children ages 7-11 yr with SLD were randomly assigned to the peer-play and control groups. Outcome measures were the Behavior Rating Inventory of Executive Function and the Child Occupational Self-Assessment (COSA). Data analysis showed that the effects of the intervention on EF skills were medium to large. The occupational values and competence did not change according to the COSA. Occupational therapy practitioners can use peer-play activities to enhance EF in children with SLD; however, perceived occupational values and competence may not show any changes with the peer-play intervention using a self-assessment instrument.


Transduction of bitter and sweet taste by gustducin.
Several lines of evidence suggest that both sweet and bitter tastes are transduced via receptors coupled to heterotrimeric guanine-nucleotide-binding proteins (G proteins). Gustducin is a taste receptor cell (TRC)-specific G protein that is closely related to the transducins. Gustducin and rod transducin, which is also expressed in TRCs, have been proposed to couple bitter-responsive receptors to TRC-specific phosphodiesterases to regulate intracellular cyclic nucleotides. Here we investigate gustducin's role in taste transduction by generating and characterizing mice deficient in the gustducin alpha-subunit (alpha-gustducin). As predicted, the mutant mice showed reduced behavioural and electrophysiological responses to bitter compounds, whereas they were indistinguishable from wild-type controls in their responses to salty and sour stimuli. Unexpectedly, mutant mice also exhibited reduced behavioural and electrophysiological responses to sweet compounds. Our results suggest that gustducin is a principal mediator of both bitter and sweet signal transduction.