Epidemiology of coronary artery disease and stroke and associated risk factors in Gaza community -Palestine.
To determine the prevalence of cardiovascular disease and associated risk factors in the population of Gaza strip in Palestine. A cross-sectional stratified cluster sample design was applied in this study. A sample of 2240 participant (1121 males and 1119 females) aged ≥25 years participated in the study. For each individual, trained staff administered a questionnaire, where all variables of interest followed WHO's STEP wise approach to surveillance chronic disease risk factors (STEPS) (WHO, 2001). Sociodemographic data, anthropometric measure (body mass index, blood pressure), and biochemical test (blood sugar and lipids profiles) were measured. Short International Physical Activity (IPAQ) questionnaire form was used. Bivariate analysis and logistic regression were used with SPSS (version 22.0) to analyze the data. The most common condition was coronary artery disease (8.3%), followed by stroke events (3%). The associated risk factors were obesity (47.8%), hypertension (28.4%), current smoking account for (23.2%), diabetes mellitus (19.1%), high cholesterol level (8.8%), and high triglycerides level (40.2%). Additionally, the proportion of being physical active was found to be low (48.3%); particularly with increasing age. More than 30% of the population has less than 4 days of consumption of fruit and vegetables per week and 65.9% has less than 2 servings per day. The burden of CVDs and their associated risk factors is considerable in Gaza and represents a major public health concern. Effective strategies in management, education and healthcare centers are required for an accurate management and implementation of preventive measure in this area.


[Prevalence of hypertension in the population of Castile-Leon (Spain)].
Cardiovascular disease causes one out of 3 deaths in Spain. Hypertension is involved in ischemic heart disease and in other diseases provoking high morbidity and mortality. The aim of the present study was to describe the prevalence of hypertension and other indicators of this disorder in Castile-Leon in 2004. We performed a cross-sectional study in a random sample of 4,012 persons aged 15 years old or above, extracted through a two-stage, stratified design. Systolic and diastolic blood pressure was measured, a history was taken and clinical records were reviewed. A person was considered to be hypertensive when there was known hypertension (hyper-tension was recorded in the clinical records or the person was receiving treatment for hypertension) or when systolic blood pressure was 140 mmHg or more and diastolic blood pressure was 90 mmHg or more. The prevalence of hypertension in the population was 38.7% (95%CI: 36.5-40.9). The prevalence was higher in men (40.4% [95%CI: 37.4-43.4]) than in women (37.4% [95%CI: 34.7-40]). Hypertension was already known in 22.2%, representing 57.4% of all hypertensive individuals. In the remainder of the sample, 44% had prehypertension, 17.5% had stage 1 hypertension and 4% had stage II hypertension, according to the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The prevalence of hypertension in the population studied was consistent with that reported in other Spanish studies. A substantial proportion of hypertensive individuals were unaware of their status as such. Equally, a large proportion had prehypertension, which carries a high risk of cardiovascular disease.


Is the cerebellum a smith predictor?
The motor system may use internal predictive models of the motor apparatus to achieve better control than would be possible by negative feedback. Several theories have proposed that the cerebellum may form these predictive representations. In this article, we review these theories and try to unify them by reference to an engineering control model known as a Smith Predictor. We suggest that the cerebellum forms two types of internal model. One model is a forward predictive model of the motor apparatus (e.g., limb and muscle), providing a rapid prediction of the sensory consequences of each movement. The second model is of the time delays in the control loop (due to receptor and effector delays, axonal conductances, and cognitive processing delays). This model delays a copy of the rapid prediction so that it can be compared in temporal register with actual sensory feedback from the movement. The result of this comparison is used both to correct for errors in performance and as a training signal to learn the first model. We discuss evidence that the cerebellum could form both of these models and suggest that the cerebellum may hold at least two separate Smith Predictors. One, in the lateral cerebellum, would predict the movement outcome in visual, egocentric, or peripersonal coordinates. Another, in the intermediate cerebellum, would predict the consequences in motor coordinates. Generalization of the Smith Predictor theory is discussed in light of cerebellar involvement in nonmotor control systems, including autonomic functions and cognition.


[Long-term prognosis of manic-depressive psychosis].
Two groups of patients with a favourable and unfavourable prolonged course of manic-depressive psychosis (161 patients) were compared using computerized selection of the relevant sings and prognostically significant combinations of the signs. Out of the 39 clinical signs characteristic of the initial period of the disease, prognostically significant were the recurrence of psychotic attacks, severity of affective pathology, presence of cyclothymic states and their nature, manifestations of affective pathology (depressive or other) at the beginning of the first phase of psychosis and the severity of somato-vegetative disorders in this pathology. Additionally, the prognostic signs were identified in relation to sex. Combinations of these signs do not determine prognosis in all cases but make it far more probable.


Effect of daily fiber intake on reproductive function: the BioCycle Study.
High-fiber diets have been associated with decreased breast cancer risk, likely mediated by the effect of fiber on lowering circulating estrogen concentrations. The influence of fiber on aspects of reproduction, which include ovulation, has not been well studied in premenopausal women. The objective was to determine if fiber consumption is associated with hormone concentrations and incident anovulation in healthy, regularly menstruating women. The BioCycle Study was a prospective cohort study conducted from 2004 to 2006 that followed 250 women aged 18-44 y for 2 cycles. Dietary fiber consumption was assessed < or =4 times/cycle by using 24-h recall. Outcomes included concentrations of estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which were measured < or =8 times/cycle, and incident anovulation. Dietary fiber consumption was inversely associated with hormone concentrations (estradiol, progesterone, LH, and FSH; P < 0.05) and positively associated with the risk of anovulation (P = 0.003) by using random-effects models with adjustment for total calories, age, race, and vitamin E intake. Each 5-g/d increase in total fiber intake was associated with a 1.78-fold increased risk (95% CI: 1.11, 2.84) of an anovulatory cycle. The adjusted odds ratio of 5 g fruit fiber/d was 3.05 (95% CI: 1.07, 8.71). These findings suggest that a diet high in fiber is significantly associated with decreased hormone concentrations and a higher probability of anovulation. Further study of the effect of fiber on reproductive health and of the effect of these intakes in reproductive-aged women is warranted.


Cortical plasticity induced by inhibitory neuron transplantation.
Critical periods are times of pronounced brain plasticity. During a critical period in the postnatal development of the visual cortex, the occlusion of one eye triggers a rapid reorganization of neuronal responses, a process known as ocular dominance plasticity. We have shown that the transplantation of inhibitory neurons induces ocular dominance plasticity after the critical period. Transplanted inhibitory neurons receive excitatory synapses, make inhibitory synapses onto host cortical neurons, and promote plasticity when they reach a cellular age equivalent to that of endogenous inhibitory neurons during the normal critical period. These findings suggest that ocular dominance plasticity is regulated by the execution of a maturational program intrinsic to inhibitory neurons. By inducing plasticity, inhibitory neuron transplantation may facilitate brain repair.


Changes in coordination and its variability with an increase in running cadence.
Alterations in joint mechanics have been associated with common overuse injuries. An increase in running cadence in healthy runners has been shown to improve several parameters that have been tied to injury, but the reorganisation of motion that produces these changes has not been examined. The purpose of this study was to determine if runners change their segment coordination and coordination variability with an acute increase in cadence. Data were collected as ten uninjured runners ran overground at their preferred cadence as well as a cadence 10% higher than preferred. Segment coordination and coordination variability were calculated for select thigh-shank and shank-foot couples and selected knee mechanics were also calculated. Paired t-tests were used to examine differences between the preferred and increased cadence conditions. With increased cadence, there was a decrease in peak knee flexion and a later occurrence of peak knee flexion and internal rotation and shank internal rotation. Segment coordination was altered with most changes occurring in mid-late stance. Coordination variability decreased with an increase in cadence across all couples and phases of gait. These results suggest examination of coordination and its variability could give insight into the risk of intervention-induced injury.


The MAPK pathway as an apoptosis enhancer in melanoma.
Inhibition of RAF/MEK/ERK signaling is beneficial for many patients with BRAF(V600E)-mutated melanoma. However, primary and secondary resistances restrict long-lasting therapy success. Combination therapies are therefore urgently needed. Here, we evaluate the cellular effect of combining a MEK inhibitor with a genotoxic apoptosis inducer. Strikingly, we observed that an activated MAPK pathway promotes in several melanoma cell lines the pro-apoptotic response to genotoxic stress, and MEK inhibition reduces intrinsic apoptosis. This goes along with MEK inhibitor induced increased RAS and P-AKT levels. The protective effect of the MEK inhibitor depends on PI3K signaling, which prevents the induction of pro-apoptotic PUMA that mediates apoptosis after DNA damage. We could show that the MEK inhibitor dependent feedback loop is enabled by several factors, including EGF receptor and members of the SPRED family. The simultaneous knockdown of SPRED1 and SPRED2 mimicked the effects of MEK inhibitor such as PUMA repression and protection from apoptosis. Our data demonstrate that MEK inhibition of BRAF(V600E)-positive melanoma cells can protect from genotoxic stress, thereby achieving the opposite of the intended anti-tumorigenic effect of the combination of MEK inhibitor with inducers of intrinsic apoptosis.


Use of clinical judgement to guide administration of blood transfusions in Malawi.
The aim of this study was to investigate whether clinicians in Malawi could use clinical judgement alone to administer blood transfusions in accordance with guidelines. Clinicians at a district hospital did not use the Lovibond Comparator haemoglobin results provided by their laboratory as they felt them to be unreliable, preferring instead to rely on their clinical judgement alone to guide transfusion practice. Their transfusion practice and the Lovibond haemoglobin results were monitored against the World Health Organization recommended haemiglobincyanide method for haemoglobin measurement without the clinicians having access to this result. The Lovibond Comparator method was shown to have a sensitivity of only 21% to detect trigger haemoglobin values for transfusion published in local guidelines. Without access to a useful haemoglobin result, clinicians gave 67% of transfusions in accordance with the haemoglobin trigger values in the guidelines. This study shows that clinical features alone can provide a reasonable guide about the need for transfusion, and that poor quality laboratory tests limit the effectiveness of transfusion guidelines.


Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3' enhancer.
Production of the glycoprotein hormone erythropoietin (Epo) in response to hypoxic stimuli is almost entirely restricted to particular cells within liver and kidney, yet the transcriptional enhancer lying 3' to the Epo gene shows activity inducible by hypoxia after transfection into a wide variety of cultured cells. The implication of this finding is that many cells which do not produce Epo contain a similar, if not identical, oxygen-regulated control system, suggesting that the same system is involved in the regulation of other genes. We report that the human phosphoglycerate kinase 1 and mouse lactate dehydrogenase A genes are induced by hypoxia with characteristics which resemble induction of the Epo gene. In each case expression is induced by cobalt, but not by cyanide, and hypoxic induction is blocked by the protein-synthesis inhibitor cycloheximide. We show that the relevant cis-acting control sequences are located in the 5' flanking regions of the two genes, and we define an 18-bp element in the 5' flanking sequence of the phosphoglycerate kinase 1 gene which is both necessary and sufficient for the hypoxic response, and which has sequence and protein-binding similarities to the hypoxia-inducible factor 1 binding site within the Epo 3' enhancer.


Social brain volume is associated with in-degree social network size among older adults.
The social brain hypothesis proposes that large neocortex size evolved to support cognitively demanding social interactions. Accordingly, previous studies have observed that larger orbitofrontal and amygdala structures predict the size of an individual's social network. However, it remains uncertain how an individual's social connectedness reported by other people is associated with the social brain volume. In this study, we found that a greater in-degree network size, a measure of social ties identified by a subject's social connections rather than by the subject, significantly correlated with a larger regional volume of the orbitofrontal cortex, dorsomedial prefrontal cortex and lingual gyrus. By contrast, out-degree size, which is based on an individual's self-perceived connectedness, showed no associations. Meta-analytic reverse inference further revealed that regional volume pattern of in-degree size was specifically involved in social inference ability. These findings were possible because our dataset contained the social networks of an entire village, i.e. a global network. The results suggest that the in-degree aspect of social network size not only confirms the previously reported brain correlates of the social network but also shows an association in brain regions involved in the ability to infer other people's minds. This study provides insight into understanding how the social brain is uniquely associated with sociocentric measures derived from a global network.


Acute hypoxia and osteoclast activity: a balance between enhanced resorption and increased apoptosis.
Osteoclasts are the primary mediators of pathological bone resorption in many conditions in which micro-environmental hypoxia is associated with disease progression. However, effects of hypoxia on human osteoclast activity have not been reported. Mature human osteoclasts were differentiated from peripheral blood or obtained from giant cell tumour of bone. Osteoclasts were exposed to a constant hypoxic environment and then assessed for parameters including resorption (toluidine blue staining of dentine slices), membrane integrity (trypan blue exclusion), apoptosis (TUNEL, DAPI), and osteolysis-associated enzyme activity (TRAP, cathepsin K). 24 h exposure to 2% O(2) produced a 2.5-fold increase in resorption associated with increased TRAP and cathepsin K enzyme activity. Hypoxia-Inducible Factor-1alpha (HIF-1alpha) siRNA completely ablated the hypoxic increase in osteoclast resorption. 24 h at 2% O(2) also increased the number of osteoclasts with compromised membrane integrity from 6% to 21%, with no change in the total osteoclast number or the proportion of late-stage apoptotic cells. Transient reoxygenation returned the percentage of trypan blue-positive cells to normoxic levels, suggesting that osteoclasts can recover from the early stages of cell death. Repeated over an extended period, hypoxia/reoxygenation enhanced osteoclast differentiation at this pO(2). These data suggest that in diseased bone, where the pO(2) may fall to <or=2% O(2), a delicate balance between hypoxia-induced osteoclast activation and hypoxia-induced osteoclast apoptosis mediates pathological bone resorption.


The impact of preoperative patient characteristics on health states after total hip replacement and related satisfaction thresholds: a cohort study.
The aim of the study was to analyze the effect of preoperative patient characteristics on health outcomes 6 months after total hip replacement (THR), to support patient's decision making in daily practice with predicted health states and satisfaction thresholds. By giving incremental effects for different patient subgroups, we support comparative effectiveness research (CER) on osteoarthritis interventions. In 2012, 321 patients participated in health state evaluation before and 6 months after THR. Health-related quality of life (HRQoL) was measured with the EQ-5D questionnaire. Hip-specific pain, function, and mobility were measured with the WOMAC in a prospective observation of a cohort. The predictive capability of preoperative patient characteristics - classified according to socio-demographic factors, medical factors, and health state variables - for changes in health outcomes is tested by correlation analysis and multivariate linear regressions. Related satisfaction thresholds were calculated with the patient acceptable symptom state (PASS) concept. The mean WOMAC and EQ-5D scores before operation were 52 and 60 respectively (0 worst, 100 best). At the 6-month follow-up, scores improved by 35 and 19 units. On average, patients reported satisfaction with the operation if postoperative (change) WOMAC scores were higher than 85 (32) and postoperative (change) EQ-5D scores were higher than 79 (14). Changes in WOMAC and EQ-5D scores can mainly be explained by preoperative scores. The lower the preoperative WOMAC or EQ-5D scores, the higher the change in the scores. Very good or very poor preoperative scores lower the probability of patient satisfaction with THR. Shared decision making using a personalized risk assessment approach provides predicted health states and satisfaction thresholds.


Flow cytometry of spinach chloroplasts : determination of intactness and lectin-binding properties of the envelope and the thylakoid membranes.
Intact spinach (Spinacia oleracea) chloroplasts, thylakoid membranes, and inside-out or right-side-out thylakoid vesicles have been characterized by flow cytometry with respect to forward angle light scatter, right angle light scatter, and chlorophyll fluorescence. Analysis of intact chloroplasts with respect to forward light scatter and the chlorophyll fluorescence parameter revealed the presence of truly "intact" and "disrupted" chloroplasts. The forward light scatter parameter, normally considered to reflect object size, was instead found to reflect the particle density. One essential advantage of flow cytometry is that additional parameters such as Ricinus communis agglutinin (linked to fluorescein isothiocyanate) fluorescence can be determined through logical conditions placed on bit-maps, amounting to an analytical purification procedure. In the present case, chloroplast subpopulations with fully preserved envelopes, thylakoid membrane, and inside-out or right-side-out thylakoid membranes vesicles can be distinguished. Flow cytometry is also a useful tool to address the question of availability of glycosyl moities on the membrane surfaces if one keeps in mind that organelle-to-organelle interactions could be partially mediated through a recognition process. A high specific binding of R. communis agglutinin and peanut lectin to the chloroplast envelope was detected. This showed that galactose residues were exposed and accessible to specific lectins on the chloroplast surface. No exposed glucose, fucose, or mannose residues could be detected by the appropriate lectins. Ricin binding to the intact chloroplasts caused a strong aggregation. Disruption of these aggregates by resuspension or during passage in the flow cytometer induced partial breakage of the chloroplasts. Only minor binding of R. communis agglutinin and peanut lectin to the purified thylakoid membranes was detected; the binding was found to be low for both inside-out and right-side-out vesicles of the thylakoid membranes.


[Relationship between regional mast cell activity and peripheral nerve discharges during manual acupuncture stimulation of "Zusanli" (ST 36)].
To observe changes of discharges of the sciatic nerve branch and mast cell activities and collagen fibers in the acupoint area during manual acupuncture stimulation of "Zusanli"(ST 36), so as to reveal the relationship between peripheral nerve and mast cell activities. A total of 30 male SD rats were divided into normal, acupuncture control (an acupuncture neidle was inserted into ST 36 without manipulation), manual acupuncture (MA), disodium cromoglycate (DSCG, suppressing mast cell activity) plus acupuncture (MA + DSCG) and col lagenase (dissolving the collagen fibers) plus acupuncture (MA+ collagenase) groups (6 rats/group). After dissection of a branch of the sciatic nerve innervating ST 36 region in the left hind-limb under anesthesia, the ipsilateral ST 36 was stimulated by manipulating the acupuncture needle for 20 min. Discharges of the sciatic nerve branch were recorded by using a pair of metal electrodes and data acquisition system (Power Lab). Skin and muscle tissues of ST 36 area were sampled, sliced and stained with Toluidine Blue for detecting the number of degranulated mast cells. Compared with the control group, the mean power spectrum of d ischarges of the sciatic nerve and the mean rates of the degranulated mast cells in "Zusanli" (ST 36) area in the MA group were significantly increased (P<0.01). Whereas the mean power spectrum of discharges of the sciatic nerve and the mean degranulation rates of mast cells were considerably lower in the MA + DSCG group and MA+ collagenase group than in the MA group (P<0.01). No significant differences were found between the normal and control groups, and between the MA+NDSCG and MA+collagenase groups in the mean power density and degranulation rates of mast cells (P>0.05). Manual acupuncture stimulation of Zuai"ST 36 can significantly potentiate the discharge activity of the sciatic nerve and induce degranulation of mast cells at the same time, suggesting an involvement of mast cells in initiating acupuncture signals by peripheral sensory nerve.


Brain structure and aging in chronic temporal lobe epilepsy.
To characterize differences in brain structure and their patterns of age-related change in individuals with chronic childhood/adolescent onset temporal lobe epilepsy compared with healthy controls. Subjects included participants with chronic temporal lobe epilepsy (n = 55) of mean childhood/adolescent onset and healthy controls (n = 53), age 14-60 years. Brain magnetic resonance imaging (MRI) studies (1.5 T) were processed using FreeSurfer to obtain measures of lobar thickness, area, and volume as well as volumes of diverse subcortical structures and cerebellum. Group differences were explored followed by cross-sectional lifespan modeling as a function of age. Anatomic abnormalities were extensive in participants with chronic temporal lobe epilepsy including distributed subcortical structures (hippocampus, thalamus, caudate, and pallidum), cerebellar gray and white matter, total cerebral gray and white matter; and measures of cortical gray matter thickness, area, or volume in temporal (medial, lateral) and extratemporal lobes (frontal, parietal). Increasing chronologic age was associated with progressive changes in diverse cortical, subcortical, and cerebellar regions for both participants with epilepsy and controls. Age-accelerated changes in epilepsy participants were seen in selected areas (third and lateral ventricles), with largely comparable patterns of age-related change across other regions of interest. Extensive cortical, subcortical, and cerebellar abnormalities are present in participants with mean chronic childhood/adolescent onset temporal lobe epilepsy implicating a significant neurodevelopmental impact on brain structure. With increasing chronologic age, the brain changes occurring in epilepsy appear to proceed in a largely age-appropriate fashion compared to healthy controls, the primary exception being age-accelerated ventricular expansion (lateral and third ventricles). These cumulative structural abnormalities appear to represent a significant anatomic burden for persons with epilepsy, the consequences of which remain to be determined as they progress into elder years.


External validation of mathematical models to distinguish between benign and malignant adnexal tumors: a multicenter study by the International Ovarian Tumor Analysis Group.
Several scoring systems have been developed to distinguish between benign and malignant adnexal tumors. However, few of them have been externally validated in new populations. Our aim was to compare their performance on a prospectively collected large multicenter data set. In phase I of the International Ovarian Tumor Analysis multicenter study, patients with a persistent adnexal mass were examined with transvaginal ultrasound and color Doppler imaging. More than 50 end point variables were prospectively recorded for analysis. The outcome measure was the histologic classification of excised tissue as malignant or benign. We used the International Ovarian Tumor Analysis data to test the accuracy of previously published scoring systems. Receiver operating characteristic curves were constructed to compare the performance of the models. Data from 1,066 patients were included; 800 patients (75%) had benign tumors and 266 patients (25%) had malignant tumors. The morphologic scoring system used by Lerner gave an area under the receiver operating characteristic curve (AUC) of 0.68, whereas the multimodal risk of malignancy index used by Jacobs gave an AUC of 0.88. The corresponding values for logistic regression and artificial neural network models varied between 0.76 and 0.91 and between 0.87 and 0.90, respectively. Advanced kernel-based classifiers gave an AUC of up to 0.92. The performance of the risk of malignancy index was similar to that of most logistic regression and artificial neural network models. The best result was obtained with a relevance vector machine with radial basis function kernel. Because the models were tested on a large multicenter data set, results are likely to be generally applicable.


Technique analysis in elite athletes using principal component analysis.
The aim of this study was to advance current movement analysis methodology to enable a technique analysis in sports facilitating (1) concurrent comparison of the techniques between several athletes; (2) identification of potentially beneficial technique modifications and (3) a visual representation of the findings for feedback to the athletes. Six elite cross-country skiers, three world cup winners and three national elite, roller ski skated using the V2 technique on a treadmill while their movement patterns were recorded using 41 reflective markers. A principal component analysis performed on the marker positions resulted in multi-segmental "principal" movement components (PMs). A novel normalisation facilitated comparability of the PMs between athletes. Additionally, centre of mass (COM) trajectories were modelled. We found correlations between the athletes' performance levels (judged from race points) and specific features in the PMs and in the COM trajectories. Plausible links between COM trajectories and PMs were observed, suggesting that better performing skiers exhibited a different, possibly more efficient use of their body mass for propulsion. The analysis presented in the current study revealed specific technique features that appeared to relate to the skiers' performance levels. How changing these features would affect an individual athlete's technique was visualised with animated stick figures.


Prenatal and Postpartum Evening Salivary Cortisol Levels in Association with Peripartum Depressive Symptoms.
The biology of peripartum depression remains unclear, with altered stress and the Hypothalamus-Pituitary-Adrenal axis response having been implicated in its pathophysiology. The current study was undertaken as a part of the BASIC project (Biology, Affect, Stress, Imaging, Cognition), a population-based longitudinal study of psychological wellbeing during pregnancy and the postpartum period in Uppsala County, Sweden, in order to assess the association between evening salivary cortisol levels and depressive symptoms in the peripartum period. Three hundred and sixty-five pregnant women from the BASIC cohort were recruited at pregnancy week 18 and instructed to complete a Swedish validated version of the Edinburgh Postnatal Depression Scale at the 36th week of pregnancy as well as the sixth week after delivery. At both times, they were also asked to provide evening salivary samples for cortisol analysis. A comprehensive review of the relevant literature is also provided. Women with postpartum EPDS score ≥ 10 had higher salivary evening cortisol at six weeks postpartum compared to healthy controls (median cortisol 1.19 vs 0.89 nmol/L). A logistic regression model showed a positive association between cortisol levels and depressive symptoms postpartum (OR = 4.1; 95% CI 1.7-9.7). This association remained significant even after controlling for history of depression, use of tobacco, partner support, breastfeeding, stressful life events, and sleep problems, as possible confounders (aOR = 4.5; 95% CI 1.5-14.1). Additionally, women with postpartum depressive symptoms had higher postpartum cortisol levels compared to both women with depressive symptoms antenatally and controls (p = 0.019 and p = 0.004, respectively). Women with depressive symptoms postpartum had higher postpartum cortisol levels, indicating an altered response of the HPA-axis in postpartum depression.


Taspase1: a threonine aspartase required for cleavage of MLL and proper HOX gene expression.
The Mixed-Lineage Leukemia gene (MLL/HRX/ALL1) encodes a large nuclear protein homologous to Drosophila trithorax that is required for the maintenance of HOX gene expression. MLL is cleaved at two conserved sites generating N320 and C180 fragments, which heterodimerize to stabilize the complex and confer its subnuclear destination. Here, we purify and clone the protease responsible for cleaving MLL. We entitle it Taspase1 as it initiates a class of endopeptidases that utilize an N-terminal threonine as the active site nucleophile to proteolyze polypeptide substrates following aspartate. Taspase1 proenzyme is intramolecularly proteolyzed generating an active 28 kDa alpha/22 kDa beta heterodimer. RNAi-mediated knockdown of Taspase1 results in the appearance of unprocessed MLL and the loss of proper HOX gene expression. Taspase1 coevolved with MLL/trithorax as Arthropoda and Chordata emerged from Metazoa suggesting that Taspase1 originated to regulate complex segmental body plans in higher organisms.


Chromosome arm-specific BAC end sequences permit comparative analysis of homoeologous chromosomes and genomes of polyploid wheat.
Bread wheat, one of the world's staple food crops, has the largest, highly repetitive and polyploid genome among the cereal crops. The wheat genome holds the key to crop genetic improvement against challenges such as climate change, environmental degradation, and water scarcity. To unravel the complex wheat genome, the International Wheat Genome Sequencing Consortium (IWGSC) is pursuing a chromosome- and chromosome arm-based approach to physical mapping and sequencing. Here we report on the use of a BAC library made from flow-sorted telosomic chromosome 3A short arm (t3AS) for marker development and analysis of sequence composition and comparative evolution of homoeologous genomes of hexaploid wheat. The end-sequencing of 9,984 random BACs from a chromosome arm 3AS-specific library (TaaCsp3AShA) generated 11,014,359 bp of high quality sequence from 17,591 BAC-ends with an average length of 626 bp. The sequence represents 3.2% of t3AS with an average DNA sequence read every 19 kb. Overall, 79% of the sequence consisted of repetitive elements, 1.38% as coding regions (estimated 2,850 genes) and another 19% of unknown origin. Comparative sequence analysis suggested that 70-77% of the genes present in both 3A and 3B were syntenic with model species. Among the transposable elements, gypsy/sabrina (12.4%) was the most abundant repeat and was significantly more frequent in 3A compared to homoeologous chromosome 3B. Twenty novel repetitive sequences were also identified using de novo repeat identification. BESs were screened to identify simple sequence repeats (SSR) and transposable element junctions. A total of 1,057 SSRs were identified with a density of one per 10.4 kb, and 7,928 junctions between transposable elements (TE) and other sequences were identified with a density of one per 1.39 kb. With the objective of enhancing the marker density of chromosome 3AS, oligonucleotide primers were successfully designed from 758 SSRs and 695 Insertion Site Based Polymorphisms (ISBPs). Of the 96 ISBP primer pairs tested, 28 (29%) were 3A-specific and compared to 17 (18%) for 96 SSRs. This work reports on the use of wheat chromosome arm 3AS-specific BAC library for the targeted generation of sequence data from a particular region of the huge genome of wheat. A large quantity of sequences were generated from the A genome of hexaploid wheat for comparative genome analysis with homoeologous B and D genomes and other model grass genomes. Hundreds of molecular markers were developed from the 3AS arm-specific sequences; these and other sequences will be useful in gene discovery and physical mapping.


High accuracy dosimetry with small pieces of Gafchromic films.
To investigate the influence of several factors on the accuracy of dose measurements and feasibility of application of small Gafchromic detectors for postal audit. Our experience showed that precision of dose measurements with small pieces of Gafchromic films may be significantly improved. Gafchromic films with dimensions of 1 × 1, 2 × 2 and 3 × 3 cm2 were exposed to 6 MV X-rays at dose levels of 50 cGy-210 cGy. The single- and multichannel methods (MM) were used for dose measurements. Detectors were scanned with an Epson V750PRO flatbed colour scanner. For 1 × 1 and larger detector sizes, separate calibration curves were established. The influence of the following factors was investigated: the heterogeneity of Gafchromic detectors group for single- and MM, ambient thermal detector conditions, the dose delivered on the measurement accuracy, application of two separate calibration curves for the smallest and larger pieces of films. The MM improves significantly the precision of dose measurement. The uncertainty attributed to detector active layer differences and scanner instabilities was about 1 cGy (1 StDev) regardless of dose and detector size. The ambient temperature of the environment in which films were stored after irradiation influenced the dose reading. Significant difference of transmission for detectors sized 1 × 1 and 2 × 2cm2 was observed. The maximal difference between applied dose and dose reading performed was 1.1%. The MM with a scaling protocol leads to a very high precision of dose measurements. The ambient thermal detector environment causes significant changes of measured signal. The detector size has relevant impact on dose reading.


A Phytophthora infestans cystatin-like protein targets a novel tomato papain-like apoplastic protease.
There is emerging evidence that the proteolytic machinery of plants plays important roles in defense against pathogens. The oomycete pathogen Phytophthora infestans, the agent of the devastating late blight disease of tomato (Lycopersicon esculentum) and potato (Solanum tuberosum), has evolved an arsenal of protease inhibitors to overcome the action of host proteases. Previously, we described a family of 14 Kazal-like extracellular serine protease inhibitors from P. infestans. Among these, EPI1 and EPI10 bind and inhibit the pathogenesis-related (PR) P69B subtilisin-like serine protease of tomato. Here, we describe EPIC1 to EPIC4, a new family of P. infestans secreted proteins with similarity to cystatin-like protease inhibitor domains. Among these, the epiC1 and epiC2 genes lacked orthologs in Phytophthora sojae and Phytophthora ramorum, were relatively fast-evolving within P. infestans, and were up-regulated during infection of tomato, suggesting a role during P. infestans-host interactions. Biochemical functional analyses revealed that EPIC2B interacts with and inhibits a novel papain-like extracellular cysteine protease, termed Phytophthora Inhibited Protease 1 (PIP1). Characterization of PIP1 revealed that it is a PR protein closely related to Rcr3, a tomato apoplastic cysteine protease that functions in fungal resistance. Altogether, this and earlier studies suggest that interplay between host proteases of diverse catalytic families and pathogen inhibitors is a general defense-counterdefense process in plant-pathogen interactions.


SQUAMOUS CARCINOMA OF THE LUNG WITH OSTEOCARTILAGINOUS STROMA.
An instance of a squamous carcinoma of the lung with osteocartilaginous metaplasia in the stroma is reported. This unusual stromal response is similar to extraskeletal osteocartilaginous metaplasia in any other site, and is a change which occasionally is produced by a variety of pathological and experimental conditions, including gastrointestinal adenocarcinoma and urinary tract epithelial carcinoma. This stromal response should be differentiated from a true sarcomatous participation in the tumour.


Strain Evolution in Cold-Warm Forged Steel Components Studied by Means of EBSD Technique.
Electron BackScatter Diffraction (EBSD) in conjunction with Field-Emission Environmental Scanning Electron Microscopy (FEG-ESEM) has been used to evaluate the microstructural and local plastic strain evolution in different alloys (AISI 1005, AISI 304L and Duplex 2205) deformed by a single-stage cold and warm forging process. The present work is aimed to describe the different behavior of the austenite and ferrite during plastic deformation as a function of different forging temperatures. Several topological EBSD maps have been measured on the deformed and undeformed states. Then, image quality factor, distributions of the grain size and misorientation have been analyzed in detail. In the austenitic stainless steel, the γ-phase has been found to harden more easily, then α-phase and γ-phase in AISI 1005 and in duplex stainless steel, sequentially. Compared to the high fraction of continuous dynamic recrystallized austenitic zones observed in stainless steels samples forged at low temperatures, the austenitic microstructure of samples forged at higher temperatures, 600-700 °C, has been found to be mainly characterized by large and elongated grains with some colonies of fine nearly-equiaxed grains attributed to discontinuous dynamic recrystallization.


When depression mediates the relationship between entity beliefs and performance.
The aim of this study was to determine whether depression can explain the negative relationship between academic performance and the belief that intelligence is a fixed trait, i.e., entity belief. A sample of 353 French volunteer adolescents (age 11-16) completed questionnaires assessing entity theory and depressive symptoms (Children Depression Inventory: CDI). Academic performance was assessed by math performance while controlling for baseline level of math ability. Results of this study revealed that entity theory is a significant negative predictor of academic performance and a significant positive predictor of depression. Importantly, our findings also show that depression plays a significant mediating role between entity theory and academic performance. Our findings indicate that individuals who consider their abilities to be non-malleable are more likely to develop depressive symptoms which, in turn, decrease academic performance. These findings contribute to tailoring specific prevention and treatment programs for childhood and adolescent depression.


Avoided and avoidable risks of cancer.
Despite the considerable efforts and funds devoted to cancer research over several decades, cancer still remains a mainly lethal disease. Cancer incidence and mortality have not declined at the same rate as other major causes of death, indicating that primary prevention remains a most valuable approach to decrease mortality. There is general agreement that environmental exposures are variously involved in the causation of the majority of cancer cases and that at least half of all cancers could be avoided by applying existing etiologic knowledge. There is disagreement, however, regarding the proportion of cancer risks attributable to specific etiological factors, including diet, occupation and pollution. Estimates of attributable risks are largely based today on unverified assumptions and the calculation of attributable risks involves taking very unequal evidence of various types of factors and treating them equally. Effective primary prevention resulting in a reduction of cancer risk can be obtained by: (i) a reduction in the number of carcinogens to which humans are exposed; or (ii) a reduction of the exposure levels to carcinogens. Exposure levels that could be seen as sufficiently low when based on single agents, may actually not be safe in the context of the many other concomitant carcinogenic and mutagenic exposures. The list of human carcinogens and of their target organs might be quite different if: (i) epidemiological data were available for a larger proportion of human exposures for which there is experimental evidence of carcinogenicity; (ii) more attention was paid to epidemiological evidence that is suggestive of an exposure-cancer association, but is less than sufficient, particularly in identifying target organs; and (iii) experimental evidence of carcinogenicity, supported by mechanistic considerations, were more fully accepted as predictions of human risk.


Companies' Health Technology Assessment Strategies and Practices in Australia, Canada, England, France, Germany, Italy and Spain: An Industry Metrics Study.
Background: Health technology assessment (HTA) has increased in importance in supporting payer decision making by assessing the relative effectiveness and cost effectiveness of new medicines. Thus, pharmaceutical companies need to address the HTA requirements early during development to improve reimbursement outcomes. Currently, there is a lack of research to assess the impact of HTA on development and jurisdictional outcome from companies' perspectives. This study aimed to assess companies' HTA strategy and characterise HTA practice in seven jurisdictions. Methods: A multi-year, annual study collected information for individual products, focusing on development activities regarding inclusion of HTA requirements and selection of global comparators. The generation of local contextual information, submission strategies and predictability of HTA outcomes was examined jurisdictionally in Australia, Canada, England, France, Germany, Italy and Spain. The study questionnaire was built into a secure online data collection platform and data were provided annually by participating companies. Results: Data for 169 compounds were provided by nine international companies between 2014 and 2018. HTA requirements were implemented in evidence generation plan for 63% of products during development. Global comparators were accepted by HTA bodies for more than half of studied products; Spain showed the highest acceptance rate (85%). Companies took advantages of parallel process in Australia and Canada to shorten product rollout time. Australia demonstrated general consistency in HTA review time, and England had the longest variation (interquartile range, 216 days). Requirements for additional information after submission occurred at all HTA bodies. Germany and Italy showed the highest percentage of products being reimbursed as per regulatory label (80 and 68%, respectively). Canada was the most predictable jurisdiction, with the highest proportion of review outcome (90%) that met companies' expectations. Conclusion: Companies are addressing HTA requirements during development for many products; however, they are challenged by varying requirements and practices and product success ultimately depends on how HTA organisations and payers assess added value in the context of the national healthcare systems. This ongoing study created a baseline to help capture fact-based changes for company HTA strategies and HTA body practices.


Treatment of refractory post-esophagectomy anastomotic esophageal strictures using temporary fully covered esophageal metal stenting compared to repeated bougie dilation: results of a randomized controlled trial.
Background and study aims Fully covered self-expanding metal stents (FCSEMS) provide an alternative to bougie dilation (BD) for refractory benign esophageal strictures. Controlled studies comparing temporary placement of FCSES to repeated BD are not available. Patients and methods Patients with refractory anastomotic esophageal strictures, dysphagia scores ≥ 2, and two to five prior BD were randomized to 8 weeks of FCSEMS or to repeated BD. The primary endpoint was the number of BD during the 12 months after baseline treatment. Results Eighteen patients were included (male 67 %, median age 66.5; 9 received metal stents, 9 received BD). Technical success rate of stent placement and stent removal was 100 %. Recurrent dysphagia occurred in 13 patients (72 %) during follow-up. No significant difference was found between the stent and BD groups for mean number of BD during follow-up (5.4 vs. 2.4, P = 0.159), time to recurrent dysphagia (median 36 days vs. 33 days, Kaplan-Meier: P = 0.576) and frequency of reinterventions per month (median 0.3 vs. 0.2, P = 0.283). Improvement in quality of life score was greater in the stent group compared to the BD group at month 12 (median 26 % vs. 4 %, P = 0.011). Conclusions The current data did not provide evidence for a statistically significant difference between the two groups in the number of BD during the 12 months after initial treatment. Metal stenting offers greater improvement in quality of life from baseline at 12 months compared to repeated BD for patients with refractory anastomotic esophageal strictures.


G1/S transcription factors assemble in increasing numbers of discrete clusters through G1 phase.
In budding yeast, the transcription factors SBF and MBF activate a large program of gene expression in late G1 phase that underlies commitment to cell division, termed Start. SBF/MBF are limiting with respect to target promoters in small G1 phase cells and accumulate as cells grow, raising the questions of how SBF/MBF are dynamically distributed across the G1/S regulon and how this impacts the Start transition. Super-resolution Photo-Activatable Localization Microscopy (PALM) mapping of the static positions of SBF/MBF subunits in fixed cells revealed each transcription factor was organized into discrete clusters containing approximately eight copies regardless of cell size and that the total number of clusters increased as cells grew through G1 phase. Stochastic modeling using reasonable biophysical parameters recapitulated growth-dependent SBF/MBF clustering and predicted TF dynamics that were confirmed in live cell PALM experiments. This spatio-temporal organization of SBF/MBF may help coordinate activation of G1/S regulon and the Start transition.


Effort-Reward Imbalance at Work and Incident Coronary Heart Disease: A Multicohort Study of 90,164 Individuals.
Epidemiologic evidence for work stress as a risk factor for coronary heart disease is mostly based on a single measure of stressful work known as job strain, a combination of high demands and low job control. We examined whether a complementary stress measure that assesses an imbalance between efforts spent at work and rewards received predicted coronary heart disease. This multicohort study (the "IPD-Work" consortium) was based on harmonized individual-level data from 11 European prospective cohort studies. Stressful work in 90,164 men and women without coronary heart disease at baseline was assessed by validated effort-reward imbalance and job strain questionnaires. We defined incident coronary heart disease as the first nonfatal myocardial infarction or coronary death. Study-specific estimates were pooled by random effects meta-analysis. At baseline, 31.7% of study members reported effort-reward imbalance at work and 15.9% reported job strain. During a mean follow-up of 9.8 years, 1,078 coronary events were recorded. After adjustment for potential confounders, a hazard ratio of 1.16 (95% confidence interval, 1.00-1.35) was observed for effort-reward imbalance compared with no imbalance. The hazard ratio was 1.16 (1.01-1.34) for having either effort-reward imbalance or job strain and 1.41 (1.12-1.76) for having both these stressors compared to having neither effort-reward imbalance nor job strain. Individuals with effort-reward imbalance at work have an increased risk of coronary heart disease, and this appears to be independent of job strain experienced. These findings support expanding focus beyond just job strain in future research on work stress.


High-dose ibuprofen for reduction of striatal infarcts during middle cerebral artery occlusion in rats.
Ibuprofen is an antiinflammatory drug that disrupts leukocyte-endothelial cell interactions by limiting expression of endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), also known as CD54. The authors hypothesized that ibuprofen could reduce the size of the infarct associated with transient focal ischemia by inhibition of ICAM-1 expression, and they evaluated its effects in rats treated with middle cerebral artery (MCA) occlusion. Ibuprofen treatment was compared with mild systemic hypothermia, which is known to be neuroprotective and is commonly used during neurosurgical procedures. The maximum ibuprofen dose (240 mg/kg/day) that could be tolerated with no systemic toxicity was established in the initial experiments. In the efficacy experiment, rats were pretreated with vehicle, ibuprofen, or hypothermia (33 degrees C) prior to 2 hours of MCA occlusion; then their brains were harvested at 24 hours of reperfusion for histological studies. End-ischemic cerebral blood flow (CBF) was evaluated using [14C]iodoantipyrine autoradiography in additional cohorts. Expression of ICAM-1 within ischemic compared with nonischemic caudate nucleus and putamen (striatum) or cortex was evaluated using immunohistochemical studies. Compared with vehicle treatment, ibuprofen produced a 46.2% reduction (p = 0.01) in striatal infarcts, which was comparable to hypothermia (48.7% reduction, p = 0.02). Ibuprofen did not alter end-ischemic CBF in any region studied, and the ibuprofen treatment group had the lowest proportion of animals with marked ICAM-1 staining. Ibuprofen given in maximum tolerated doses reduces the striatal infarct size after focal cerebral ischemia. The neuroprotective mechanism does not work through preservation of intraischemic CBF and is consistent with inhibition of ICAM-1 expression; however, at the doses used in this study, other effects of ibuprofen on platelet and endothelial function are possible.


Myxobolus cerebralis internal transcribed spacer 1 (ITS-1) sequences support recent spread of the parasite to North America and within Europe.
Molecular approaches for resolving relationships among the Myxozoa have relied mainly on small subunit (SSU) ribosomal DNA (rDNA) sequence analysis. This region of the gene is generally used for higher phylogenetic studies, and the conservative nature of this gene may make it inadequate for intraspecific comparisons. Previous intraspecific studies of Myxobolus cerebralis based on molecular analyses reported that the sequence of SSU rDNA and the internal transcribed spacer (ITS) were highly conserved in representatives of the parasite from North America and Europe. Considering that the ITS is usually a more variable region than the SSU, we reanalyzed available sequences on GenBank and obtained sequences from other M. cerebralis representatives from the states of California and West Virginia in the USA and from Germany and Russia. With the exception of 7 base pairs, most of the sequence designated as ITS-1 in GenBank was a highly conserved portion of the rDNA near the 3-prime end of the SSU region. Nonetheless, the additional ITS-1 sequences obtained from the available geographic representatives were well conserved. It is unlikely that we would have observed virtually identical ITS-1 sequences between European and American M. cerebralis samples had it spread naturally over time, particularly when compared to the variation seen between isolates of another myxozoan (Kudoa thyrsites) that has most likely spread naturally. These data further support the hypothesis that the current distribution of M. cerebralis in North America is a result of recent introductions followed by dispersal via anthropogenic means, largely through the stocking of infected trout for sport fishing.


Pathological gambling. A comprehensive review.
Due to recent changes of gambling laws, accessibility to gambling has become more widespread and thus, there has also been an increase in the prevalence of pathological gambling (PG). The wide range of social, economic, and psychological problems associated with PG are well known. There is a need for better understanding of PG and this review attempts to do so. Literature searches using the Medline and PsycINFO databases were used. Critical examining of the literature showed that familial/genetic, sociological, and individual factors (e.g., an individual's personality, biochemistry, psychological states, and cognitions) are implicated in the development and maintenance of PG, yet at present, the evidences are not solid. Similarly, there have been a lot of theories for PG but again, none of them are solid enough to provide a clear understanding of PG. Recent psychological-based theories seem to provide some solid ground for further research. We highlight four areas for future consideration for research. (1) Most studies have generalized findings from one form of gambling to another. It is suggested that it is now not tenable to consider gambling as a single phenomenon that can explain all forms of gambling. (2) Almost all of the studies in the gambling literature are Western-based and the results are often generalized to other ethnic and cultural groups. There is now an urgent need to close this gap. (3) Future studies need to address methodological problems in the current gambling/PG literature. (4) Almost all of the gambling literature has focused on the issue of why people start gambling. It is suggested that looking at variables as to why people stop gambling in a single episode may be a more fruitful area of research then why people start gambling. This is because what motivates one to continue gambling, despite losses in a session and across sessions, is a characteristic that distinguishes nonproblem gamblers from problem gamblers and pathological gamblers (PGs).


Discrete solitons and scattering of lattice waves in guiding arrays with a nonlinear PT-symmetric defect.
Discrete fundamental and dipole solitons are constructed, in an exact analytical form, in an array of linear waveguides with an embedded PT-symmetric dimer, which is composed of two nonlinear waveguides carrying equal gain and loss. Fundamental solitons in tightly knit lattices, as well as all dipole modes, exist above a finite threshold value of the total power. However, the threshold vanishes for fundamental solitons in loosely knit lattices. The stability of the discrete solitons is investigated analytically by means of the Vakhitov-Kolokolov (VK) criterion, and, in the full form, via the computation of eigenvalues for perturbation modes. Fundamental and dipole solitons tend to be stable at smaller and larger values of the total power (norm), respectively. The increase of the strength of the coupling between the two defect-forming sites leads to strong expansion of the stability areas. The scattering problem for linear lattice waves impinging upon the defect is considered too.


[Rhino-cerebral fungal infection successfully treated with supplementary hyperbaric oxygen therapy].
Rhino-cerebral fungal infections are rare and difficult disorders to cure. We report the case of a woman presenting a left trigeminal neuralgia complicated by ophthalmoplegia and blindness. MRI demonstrated a lesion of the left orbital apex with extension into the cavernous sinus. Fungal infiltration (aspergillosis or mucormycosis), was seen on biopsy. High-dose liposomal Amphotericin B (5mg/kg/day) for six weeks was unsuccessful. Adjunctant hyperbaric oxygen therapy led to clinical and radiological improvement. Hyperbaric oxygen therapy is discussed in the medical management of rhino-cerebral yeast abscesses.


Not By Success Alone: Role Models Provide Pathways to Communal Opportunities in STEM.
Because of stereotypes that science, technology, engineering, and mathematics (STEM) fields do not fulfill communal goals, communally oriented individuals may select out of STEM. One potential route to engaging and promoting communally oriented individuals in STEM fields is through interactions with advisors or role models in STEM. We first demonstrate the perceived difficulty of finding role models who enact communal behaviors in STEM relative to other fields (Preliminary Study). Communally oriented students reported higher likelihood of observing admired others in math or science (i.e., investigative vicarious learning) over time (Study 1). Individuals preferred hypothetical STEM advisors who enacted communal workplace behaviors (Studies 2a-2b). Finally, individuals' communal orientation predicted how important they found the communal behaviors of actual role models (Studies 3a-3b). These findings provide further support for the goal congruity prediction that contexts-whether relational or occupational-that offer the pursuit of valued goals will be preferred.


Antibodies to colonic epithelial cells from the serum and colonic mucosal washings in ulcerative colitis.
It has been suggested that antibodies to a colonocyte protein of 40 kD (an intestinal isoform of tropomyosin) are specifically found in the serum and mucosa of patients with ulcerative colitis, which has important pathogenic implications. This study isolated and purified tropomyosin from the colonic mucosa, but no specific binding to this protein has been detected in serum samples or immunoglobulins isolated from mucosal washings of 20 ulcerative colitis (UC) patients by enzyme linked immunosorbent assay (ELISA) compared with 21 controls or 17 Crohn's disease (CD) patients. Samples from a further 12 patients with UC and primary sclerosing cholangitis (it is proposed that cross reactivity against the intestinal tropomyosin isoform accounts for the extraintestinal disease) also did not show binding to tropomyosin, whereas monoclonal antitropomyosin antisera bound both ELISAs and western blots. This study also examined the proteins in the normal colonic biopsy specimens on western blots that are bound by both serum samples and mucosal immunoglobulin preparations from these patients groups; there was no specific IgG or IgA binding to patients with UC or UC/primary sclerosing cholangitis, whereas binding to mitochondrial proteins of 70,000 and 45,000 was seen in samples from 12 primary biliary cirrhosis positive controls. This work does not support the hypothesis that autoimmune activity against the intestinal isoform or tropomyosin is important in the pathogenesis of ulcerative colitis.


Heart disease in patients with thyroid dysfunction: hyperthyroidism, hypothyroidism and beyond.
The thyroid and the cardiovascular system are closely related, both in physiological and pathological conditions. The adverse consequences on the heart of overt thyroid disease are well-known and even subclinical forms of both hyperthyroidism and hypothyroidism are associated with increased cardiovascular mortality. In recent years, attention has shifted towards milder forms of thyroid disease, such as the so-called "low T3 syndrome", which is characterized by an isolated reduction in circulating levels of the biologically active form of thyroid hormone, triiodothyronine (T3). Furthermore, variations of T3 within the physiological range have been linked to coronary artery disease, one of the leading causes of morbidity and mortality worldwide. The present manuscript provides an overview of thyroid physiology and pathophysiology, with a particular focus on cardiovascular disease in patients with milder forms of thyroid dysfunction.


Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity.
25-hydroxy-vitamin D (25-OH-D) insufficiency/deficiency is increasingly prevalent and has been associated with many chronic diseases, including rheumatoid arthritis (RA). Our purpose was to define the prevalence and associations of 25-OH-D insufficiency/deficiency in a cohort of US veterans with RA. vitamin D status (25-OH-D) was assessed in patients with RA using radioimmunoassay on banked plasma collected at enrollment. Insufficiency was defined as concentrations < 30 ng/ml and deficiency as < 20 ng/ml. Associations of 25-OH-D insufficiency/deficiency with patient characteristics obtained at enrollment were examined using multivariate logistic regression, adjusting for age, sex, season of enrollment, and race. patients (850 men, 76% Caucasian) had a mean (SD) age of 64 (SD 11.3) years. The prevalences of 25-OH-D insufficiency and deficiency were 84% and 43%, respectively. After multivariate adjustment, both insufficiency and deficiency were more common with anti-cyclic citrullinated peptide antibody positivity and non-Caucasian race, and in the absence of vitamin D supplementation. 25-OH-D deficiency, but not insufficiency, was independently associated with higher tender joint counts and highly sensitive C-reactive protein levels. in a predominantly elderly, male RA population, 25-OH-D insufficiency was highly prevalent. With the increasing adverse health outcomes associated with hypovitaminosis D, screening and supplementation, particularly among minority, seropositive patients with RA, should be performed routinely.


The trimer-of-hairpins motif in membrane fusion: Visna virus.
Structural studies of viral membrane fusion proteins suggest that a "trimer-of-hairpins" motif plays a critical role in the membrane fusion process of many enveloped viruses. In this motif, a coiled coil (formed by homotrimeric association of the N-terminal regions of the protein) is surrounded by three C-terminal regions that pack against the coiled coil in an oblique antiparallel manner. The resulting trimer-of-hairpins structure serves to bring the viral and cellular membranes together for fusion. learncoil-vmf, a computational program developed to recognize coiled coil-like regions that form the trimer-of-hairpins motif, predicts these regions in the membrane fusion protein of the Visna virus. Peptides corresponding to the computationally identified sequences were synthesized, and the soluble core of the Visna membrane fusion protein was reconstituted in solution. Its crystal structure at 1.5-A resolution demonstrates that a trimer-of-hairpins structure is formed. Remarkably, despite less than 23% sequence identity, the ectodomains in Visna and HIV-1 envelope glycoproteins show detailed structural conservation, especially within the area of a hydrophobic pocket in the central coiled coil currently being targeted for the development of new anti-HIV drugs.


The relationship between abstinence for one year following pretreatment assessment and alcohol use and other functioning at two years in individuals presenting for alcohol treatment.
The purpose of this study was to replicate and extend research that shows abstinence from alcohol during the first year following treatment predicts better longer term functioning in alcohol use and other areas. The subjects were 187 men and women who had participated in a clinical trial of the differential effectiveness of two behavioral treatments for alcohol problems as a function of subject characteristics. All subjects who participated in this phase of the study were classified as either abstinent from alcohol or not based on their drinking behavior during the first 12 months following treatment initiation. Subjects' alcohol use and other behaviors were evaluated for Months 13-24. The primary dependent variables of interest were alcohol use, self-efficacy, and psychological functioning. A comparison of the two abstinence groups showed that abstainers, compared to drinkers, had less alcohol use, higher self-efficacy, and better psychological functioning. CONCLUSIONS The results suggest the association is robust between abstinence during the first year following treatment initiation or cessation and later functioning, and extend this finding to include psychological functioning. Future research should focus on possible mediators of the abstinence correlations with later behavior that are of theoretical and practical importance, and on specifying gradients of duration of abstinence or other drinking patterns reflecting improvement and their relationship to longer term functioning.


Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness: Part 2.
We present a precision medical perspective to assist in the definition, diagnosis, and management of Post Treatment Lyme Disease Syndrome (PTLDS)/chronic Lyme disease. PTLDS represents a small subset of patients treated for an erythema migrans (EM) rash with persistent or recurrent symptoms and functional decline. The larger population with chronic Lyme disease is less understood and well defined. Multiple Systemic Infectious Disease Syndrome (MSIDS) is a multifactorial model for treating chronic disease(s), which identifies up to 16 overlapping sources of inflammation and their downstream effects. A patient symptom survey and a retrospective chart review of 200 patients was therefore performed on those patients with chronic Lyme disease/PTLDS to identify those variables on the MSIDS model with the greatest potential effect on regaining health. Results indicate that dapsone combination therapy decreased the severity of eight major Lyme symptoms, and multiple sources of inflammation (other infections, immune dysfunction, autoimmunity, food allergies/sensitivities, leaky gut, mineral deficiencies, environmental toxins with detoxification problems, and sleep disorders) along with downstream effects of inflammation may all affect chronic symptomatology. In part two of our observational study and review paper, we postulate that the use of this model can represent an important and needed paradigm shift in the diagnosis and treatment of chronic disease.


Clinical characteristics and health resource use of men and women veterans with serious mental illness.
In this retrospective analysis of gender-specific differences among veterans with serious mental illness, the clinical characteristics and health service utilization of 57 women and 114 men were compared. Women had fewer comorbid psychiatric illnesses than men, and substance use disorders were the most frequent comorbid psychiatric illness for both genders. Unlike nonveteran samples with serious mental illness, the veterans in this study showed no gender differences in hospital length of stay. Atypical antipsychotics, used for only suboptimally responsive illness in the study group, were prescribed for 50 percent of women with primary psychosis, compared with 15.3 percent of men with primary psychosis. The results suggest that psychosis among women veterans is more severe or refractory than that among men veterans.


Postgraduate nurses' self-assessment of clinical competence and need for further training. A European cross-sectional survey.
Nursing practice requires application of knowledge, skills and values in various combinations and has undergone substantial changes the last decades. An increased focus on inter-professional collaboration and possible new and more independent roles for nurses are described. A variety of programs have been developed in order to educate registered nurses (RN) to meet the changes and demands in health and nursing care throughout the world. The aims were to 1) describe nurses' self-assessment of clinical competence and need for further training, and 2) explore possible differences between nurses in specialist vs master's programs. A cross-sectional survey design was applied. 97 nurses in postgraduate programs from five countries responded (response rate 45%). A revised version of the Professional Nurse Self-Assessment Scale of clinical core competencies (PROFFNurseSASII) was used for data collection. Independent student t-test and regression analyses were carried out. The respondents rated their competence highest in taking full responsibility, cooperation with other health professionals and in acting ethically. Items where they considered themselves needing further training most were competence on medications, interaction and side effects and differential diagnoses. For all items, nurses in master's programs rated their competence higher than nurses in the specialist programs. Nurses in specialist programs rated their need for more training for all items higher than nurses in master's degree programs, and for 47 out of the 50 items these differences were statistically significant. Even though the nurses rated their competence high for important competence aspects such as taking responsibility and cooperation with other health professionals, it is worrying that their need for further training was highest for effects and interaction of various types of medications. Further studies are needed to conclude if and how master's education improves patient outcome.


Suppression of thermal frequency noise in erbium-doped fiber random lasers.
Frequency and intensity noise are characterized for erbium-doped fiber (EDF) random lasers based on Rayleigh distributed feedback mechanism. We propose a theoretical model for the frequency noise of such random lasers using the property of random phase modulations from multiple scattering points in ultralong fibers. We find that the Rayleigh feedback suppresses the noise at higher frequencies by introducing a Lorentzian envelope over the thermal frequency noise of a long fiber cavity. The theoretical model and measured frequency noise agree quantitatively with two fitting parameters. The random laser exhibits a noise level of 6 Hz²/Hz at 2 kHz, which is lower than what is found in conventional narrow-linewidth EDF fiber lasers and nonplanar ring laser oscillators (NPROs) by a factor of 166 and 2, respectively. The frequency noise has a minimum value for an optimum length of the Rayleigh scattering fiber.


Corticosteroid use in rheumatoid arthritis: prevalence, predictors, correlates, and outcomes.
To determine the rate of current and lifetime use of corticosteroids, the degree of association between corticosteroids and rheumatoid arthritis (RA) activity and outcome, corticosteroid initiation and discontinuation rates, and the predictors associated with initiation and discontinuation. A total of 12,749 patients with RA were evaluated semiannually as to corticosteroid use, RA activity measures, RA outcomes, and predictors of initiation and discontinuation of corticosteroids. Current corticosteroid use was 35.5% and lifetime use was 65.5%. Rheumatologists varied substantially in their use of corticosteroids. The primary patient-derived determinant of corticosteroid initiation, current use, and discontinuation was symptom severity, although 21-25% of patients in remission or with minimal disease activity continued taking corticosteroids. Within the pool of current users, 24.3% [95% confidence interval (CI) 23.2-25.3%] discontinued corticosteroids yearly, and among patients newly starting corticosteroids this rate was 56.9% (95% CI 53.4-60.7%). Corticosteroid initiation occurred at a rate of 8.9% (95% CI 8.4-9.3%) per year. Among corticosteroid users, persistent use (> 5 years) occurs in about one-third of patients. Corticosteroid use and duration of use is associated with severe outcomes for current and past users. For current users versus non-current users, covariate adjusted outcomes were: mortality 5.7% versus 2.6%, work disability 28.4% versus 17.2%, and total joint replacement 18.5% versus 13.0%. Corticosteroid use is dynamic and is associated with RA severity. Corticosteroid use is also associated with adverse longterm outcomes, but the ability to discern causal associations is severely limited by confounding by indication. The idea of "once on corticosteroids, always on corticosteroids" is incorrect and applies to only a minority of patients.


Differential regulation and ATP requirement for caspase-8 and caspase-3 activation during CD95- and anticancer drug-induced apoptosis.
Apoptosis is induced by different stimuli, among them triggering of the death receptor CD95, staurosporine, and chemotherapeutic drugs. In all cases, apoptosis is mediated by caspases, although it is unclear how these diverse apoptotic stimuli cause protease activation. Two regulatory pathways have been recently identified, but it remains unknown whether they are functionally independent or linked to each other. One is mediated by recruitment of the proximal regulator caspase-8 to the death receptor complex. The other pathway is controlled by the release of cytochrome c from mitochondria and the subsequent ATP-dependent activation of the death regulator apoptotic protease-activating factor 1 (Apaf-1). Here, we report that both pathways can be dissected by depletion of intracellular ATP. Prevention of ATP production completely inhibited caspase activation and apoptosis in response to chemotherapeutic drugs and staurosporine. Interestingly, caspase-8, whose function appeared to be restricted to death receptors, was also activated by these drugs under normal conditions, but not after ATP depletion. In contrast, inhibition of ATP production did not affect caspase activation after triggering of CD95. These results suggest that chemotherapeutic drug-induced caspase activation is entirely controlled by a receptor-independent mitochondrial pathway, whereas CD95-induced apoptosis can be regulated by a separate pathway not requiring Apaf-1 function.


Convex and semi-nonnegative matrix factorizations.
We present several new variations on the theme of nonnegative matrix factorization (NMF). Considering factorizations of the form X=FG(T), we focus on algorithms in which G is restricted to containing nonnegative entries, but allowing the data matrix X to have mixed signs, thus extending the applicable range of NMF methods. We also consider algorithms in which the basis vectors of F are constrained to be convex combinations of the data points. This is used for a kernel extension of NMF. We provide algorithms for computing these new factorizations and we provide supporting theoretical analysis. We also analyze the relationships between our algorithms and clustering algorithms, and consider the implications for sparseness of solutions. Finally, we present experimental results that explore the properties of these new methods.


Two-dimensional image transmission through a single optical fiber by wavelength-time multiplexing.
Serial transmission of image data through an optical fiber is inefficient in the utilization of the channel capacity of the fiber. Parallel image transmission techniques, on the other hand, generally limit the transmission length to a few meters. A novel approach is introduced with which 2-D image data can be transmitted efficiently at high speed over a single optical fiber using wavelength-time multiplexing. Several system configurations designed for different types of input are presented.


Transformation of MCF-10A cells by random mutagenesis with frameshift mutagen ICR191: a model for identifying candidate breast-tumor suppressors.
Widely accepted somatic mutation theory of carcinogenesis states that mutations in oncogenes and tumor suppressor genes in genomes of somatic cells is the cause of neoplastic transformation. Identifying frequent mutations in cancer cells suggests the involvement of mutant genes in carcinogenesis. To develop an in vitro model for the analysis of genetic alterations associated with breast carcinogenesis, we used random mutagenesis and selection of human non-tumorigenic immortalized breast epithelial cells MCF-10A in tissue-culture conditions that mimic tumor environment. Random mutations were generated in MCF-10A cells by cultivating them in a tissue-culture medium containing the frameshift-inducing agent ICR191. The first selective condition we used to transform MCF1-10A cells was cultivation in a medium containing mutagen at a concentration that allowed cell replication despite p53 protein accumulation induced by mutagen treatment. The second step of selection was either cell cultivation in a medium with reduced growth-factor supply or in a medium that mimics a hypoxia condition or growing in soft agar. Using mutagenesis and selection, we have generated several independently derived cultures with various degrees of transformation. Gene Identification by Nonsense-mediated mRNA decay Inhibition (GINI) analysis has identified the ICR191-induced frameshift mutations in the TP53, smoothelin, Ras association (RalGDS/AF-6) domain family 6 (RASSF6) and other genes in the transformed MCF-10A cells. The TP53 gene mutations resulting in the loss of protein expression had been found in all independently transformed MCF-10A cultures, which form large progressively growing tumors with sustained angiogenesis in nude mice. Identifying genes containing bi-allelic ICR191-induced frameshift mutations in the transformed MCF-10A cells generated by random mutagenesis and selection indicates putative breast-tumor suppressors. This can provide a model for studying the role of mutant genes in breast carcinogenesis.


In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation.
A novel nonmyeloablative conditioning regimen was investigated in 44 patients with hematologic malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. Recipient conditioning consisted of CAMPATH-1H, 20 mg/day on days -8 to -4; fludarabine, 30 mg/m(2) on days -7 to -3; and melphalan, 140 mg/m(2) on day -2. Thirty-six recipients received unmanipulated granculocyte colony-stimulating factor-mobilized peripheral blood stem cells from HLA-identical siblings, and 8 received unmanipulated marrow from matched unrelated donors. GVHD prophylaxis was with cyclosporine A alone for 38 patients and cyclosporine A plus methotrexate for 6 sibling recipients. Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite polymerase chain reaction indicate that 18 of 31 patients studied were full-donor chimeras while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range 3 to 29 months), 33 patients remain alive in complete remission or with no evidence of disease progression. Seven patients relapsed or progressed post-transplantation, and 4 of them subsequently died. Four patients died of regimen-related complications. There were no cases of grades III-IV acute GVHD. Only 2 patients developed grade II acute GVHD, and only 1 had chronic GVHD. The estimated probability of nonrelapse mortality was 11%. Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity, and low incidence of GVHD.


Doxorubicin-loaded protease-activated near-infrared fluorescent polymeric nanoparticles for imaging and therapy of cancer.
Despite significant progress in the field of oncology, cancer remains one of the leading causes of death. Chemotherapy is one of the most common treatment options for cancer patients but is well known to result in off-target toxicity. Theranostic nanomedicines that integrate diagnostic and therapeutic functions within an all-in-one platform can increase tumor selectivity for more effective chemotherapy and aid in diagnosis and monitoring of therapeutic responses. In this work, theranostic nanoparticles were synthesized with commonly used biocompatible and biodegradable polymers and used as cancer contrast and therapeutic agents for optical imaging and treatment of breast cancer. These core-shell nanoparticles were prepared by nanoprecipitation of blends of the biodegradable and biocompatible amphiphilic copolymers poly(lactic-co-glycolic acid)-b-poly-l-lysine and poly(lactic acid)-b-poly(ethylene glycol). Poly-l-lysine in the first copolymer was covalently decorated with near-infrared fluorescent Alexa Fluor 750 molecules. The spherical nanoparticles had an average size of 60-80 nm. The chemotherapeutic drug doxorubicin was encapsulated in the core of nanoparticles at a loading of 3% (w:w) and controllably released over a period of 30 days. A 33-fold increase in near-infrared fluorescence, mediated by protease-mediated cleavage of the Alexa Fluor 750-labeled poly-l-lysine on the surface of the nanoparticles, was observed upon interaction with the model protease trypsin. The cytocompatibility of drug-free nanoparticles and growth inhibition of drug-loaded nanoparticles on MDA-MB-231 breast cancer cells were investigated with a luminescence cell-viability assay. Drug-free nanoparticles were found to cause minimal toxicity, even at high concentrations (0.2-2,000 µg/mL), while doxorubicin-loaded nanoparticles significantly reduced cell viability at drug concentrations >10 µM. Finally, the interaction of the nanoparticles with breast cancer cells was studied utilizing fluorescence microscopy, demonstrating the potential of the nanoparticles to act as near-infrared fluorescence optical imaging agents and drug-delivery carriers. Doxorubicin-loaded, enzymatically activatable nanoparticles of less than 100 nm were prepared successfully by nanoprecipitation of copolymer blends. These nanoparticles were found to be suitable as controlled drug delivery systems and contrast agents for imaging of cancer cells.


Medicaid and SCHIP coverage: findings from California and North Carolina.
This article examines experiences under Medicaid and the State Children's Health Insurance Program (SCHIP), drawing on surveys of over 3,000 enrollees in California and North Carolina in 2002. In both States, Medicaid enrollees were less likely than SCHIP enrollees to have parents who were covered by employer-sponsored insurance (ESI). With the exception of dental care and provider perceptions, access experiences were fairly comparable across the two programs, despite differences in the characteristics of the children served by the two programs. Relative to being uninsured, Medicaid enrollment was found to improve access to care along a number of different dimensions, controlling for other factors. Furthermore, this study emphasizes the need for continued evaluation of access to care for both programs.


Oulu Patient Classification instrument within primary health care.
As patients have become older their care needs have increased, and this has consequences for the working conditions within primary health care. The aim of this study was to evaluate, whether the OPC instrument, which has been developed for hospital care, is valid and useful within primary healthcare for older people. Reliability and validity testing of the OPC instrument was carried out at a health care centre in Eastern Finland spring 2004. A total number of 92 questionnaires were handed out, and the response rate was 67% (n=61) in order to test the validity. The inter-rater reliability was tested through parallel classification. A total number of 860 patient's were classified; in total 1722 classifications ware done. Cohens Kappa was chosen as the measurement for the consensus between the nurses' classification. The consensus of the NI scores in total (OPC points) was 71%. The consensus measured with Kappa (k) showed a strong (0.65) consensus degree. It can be said that the OPC instrument achieved a high enough reliability and validity in order to be seen as a reliable and useful instrument to measure the NCI within primary healthcare for the elderly. The OPC instrument can be seen as providing a fairly comprehensive view of the patient's caring needs, without claiming to be covering everything.


Marangoni puffs: dramatically enhanced dissolution of droplets with an entrapped bubble.
We present a curious effect observed during the dissolution process of water-immersed long-chain alcohol drops with an entrapped air bubble. These droplets dissolve while entrapping an air bubble pinned at the substrate. We qualitatively describe and explain four different phases that are found during the dissolution of this kind of system. The dissolution rate in the four phases differ dramatically. When the drop-water interface and the air bubble contact each other, rapid cyclic changes of the morphology are found: The breakage of the thin alcohol layer in between the bubble and the water leads to the formation of a three phase contact line. If the surface tension of the water-air interface supersedes those of the alcohol-water and alcohol-air interfaces, alcohol from the droplet is pulled upwards, leading to a closure of the air-water interface and the formation of a new thin alcohol film, which then dissolves again, leading to a repetition of the series of events. We call this sequence of events Marangoni puffing. This only happen for alcohols of appropriate surface tension. The Marangoni puffing is an intermediate state. In the final dissolution phases the Marangoni forces dramatically accelerate the dissolution rate, which then becomes one order of magnitude faster than the purely buoyancy-convective driven dissolution. Our results have bearing on various dissolution processes in multicomponent droplet systems.


Increased expression of extracellular matrix proteins in rapid atrial pacing-induced atrial fibrillation.
Atrial fibrillation (AF) is characterized by structural remodeling of the extracellular matrix (ECM) in cardiac atrium. The purpose of this study was to gain further insight into atrial ECM remodeling at the molecular level and to test whether altered expression of ECM proteins was associated with the disease. Sustained AF was induced in nine adult pigs after 3-4 weeks of continuous rapid atrial pacing at a rate of 600 bpm. Histologic studies and immunohistochemical stain were performed to identify the potential pathologic substrate underlying abnormalities in atrial tissues with sustained AF. In the pathologic findings, the fraction of myocardial ECM (ECM%) was measured, with a significantly greater ECM% found in the AF group compared with the sham operated group (n = 6; i.e., pigs with normal sinus rhythm [SR]). A set of 9,182 genes was screened with cDNA microarray analysis. In AF animals, expression of 121 genes increased and 24 genes decreased by > or =1.75-fold compared with SR animals. Significant up-regulation of fibronectin-1 (4.9-fold), fibrillin-1 (3.1-fold), and fibromodulin (1.9-fold) in the fibrillating atria was confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction. Western blot analysis revealed significantly increased atrial fibronectin-1, fibrillin-1, and fibromodulin in the AF group compared with the SR group (1.5-, 2.7-, and 2.1-fold, respectively). Immunohistochemical staining of AF tissue displayed increased accumulation of fibronectin-1 and fibrillin-1 in the atrial interstitial space. Increased expression of ECM proteins in fibrillating atria supports the hypothesis that ECM metabolism contributes to the development of AF.


Effects of Hand Configuration on the Grasping, Holding, and Placement of an Instrumented Object in Patients With Hemiparesis.
Objective: Limitations with manual dexterity are an important problem for patients suffering from hemiparesis post stroke. Sensorimotor deficits, compensatory strategies and the use of alternative grasping configurations may influence the efficiency of prehensile motor behavior. The aim of the present study is to examine how different grasp configurations affect patient ability to regulate both grip forces and object orientation when lifting, holding and placing an object. Methods: Twelve stroke patients with mild to moderate hemiparesis were recruited. Each was required to lift, hold and replace an instrumented object. Four different grasp configurations were tested on both the hemiparetic and less affected arms. Load cells from each of the 6 faces of the instrumented object and an integrated inertial measurement unit were used to extract data regarding the timing of unloading/loading phases, regulation of grip forces, and object orientation throughout the task. Results: Grip forces were greatest when using a palmar-digital grasp and lowest when using a top grasp. The time delay between peak acceleration and maximum grip force was also greatest for palmar-digital grasp and lowest for the top grasp. Use of the hemiparetic arm was associated with increased duration of the unloading phase and greater difficulty with maintaining the vertical orientation of the object at the transitions to object lifting and object placement. The occurrence of touch and push errors at the onset of grasp varied according to both grasp configuration and use of the hemiparetic arm. Conclusion: Stroke patients exhibit impairments in the scale and temporal precision of grip force adjustments and reduced ability to maintain object orientation with various grasp configurations using the hemiparetic arm. Nonetheless, the timing and magnitude of grip force adjustments may be facilitated using a top grasp configuration. Conversely, whole hand prehension strategies compound difficulties with grip force scaling and inhibit the synchrony of grasp onset and object release.


Compartment syndrome associated with expansile antebrachial tumors in two dogs.
A 10-year-old spayed female Jack Russell Terrier and a 7-year-old neutered male mixed-breed dog were evaluated because of acute, progressive, unilateral forelimb lameness associated with signs of pain and turgid antebrachial swelling. For either dog, there were no salient pathological or diagnostic imaging abnormalities. A diagnosis of compartment syndrome was confirmed on the basis of high caudal antebrachial compartmental pressure in the affected forelimb. Both dogs underwent surgical exploration of the affected forelimb. In each case, an intramuscular tumor (mast cell tumor in the Jack Russell Terrier and suspected sarcoma in the mixed-breed dog) was detected and presumed to be the cause of the high compartmental pressure. At 6 months following tumor excision, the dog with the mast cell tumor did not have any clinical signs of disease. The dog with a suspected sarcoma underwent tumor excision and forelimb amputation at the proximal portion of the humerus followed by chemotherapy; the dog was euthanized approximately 1 year following treatment because of pulmonary metastasis. Compartment syndrome is a serious but rarely reported condition in dogs and is typically ascribed to intracompartmental hemorrhage. These 2 cases illustrate the potential for expansile intramuscular antebrachial tumors to cause compartment syndrome in dogs.


Electron Decoupling with Dynamic Nuclear Polarization in Rotating Solids.
Dynamic nuclear polarization (DNP) can enhance NMR sensitivity by orders of magnitude by transferring spin polarization from electron paramagnetic resonance (EPR) to NMR. However, paramagnetic DNP polarizing agents can have deleterious effects on NMR signals. Electron spin decoupling can mitigate these paramagnetic relaxation effects. We demonstrate electron decoupling experiments in conjunction with DNP and magic-angle-spinning NMR spectroscopy. Following a DNP and spin diffusion period, the microwave irradiation frequency is quickly tuned on-resonance with electrons on the DNP polarizing agent. The electron decoupling performance shows a strong dependence on the microwave frequency and DNP polarization time. Microwave frequency sweeps through the EPR line shape are shown as a time domain strategy to significantly improve electron decoupling. For 13C spins on biomolecules frozen in a glassy matrix, electron decoupling reduces the line widths by 11% (47 Hz) and increases the intensity by 14%.


Endothelin-1 is a transcriptional target of p53 in epidermal keratinocytes and regulates ultraviolet-induced melanocyte homeostasis.
Keratinocytes contribute to melanocyte activity by influencing their microenvironment, in part, through secretion of paracrine factors. Here, we discovered that p53 directly regulates Edn1 expression in epidermal keratinocytes and controls UV-induced melanocyte homeostasis. Selective ablation of endothelin-1 (EDN1) in murine epidermis (EDN1(ep-/-) ) does not alter melanocyte homeostasis in newborn skin but decreases dermal melanocytes in adult skin. Results showed that keratinocytic EDN1 in a non-cell autonomous manner controls melanocyte proliferation, migration, DNA damage, and apoptosis after ultraviolet B (UVB) irradiation. Expression of other keratinocyte-derived paracrine factors did not compensate for the loss of EDN1. Topical treatment with EDN1 receptor (EDNRB) antagonist BQ788 abrogated UV-induced melanocyte activation and recapitulated the phenotype seen in EDN1(ep-/-) mice. Altogether, the present studies establish an essential role of EDN1 in epidermal keratinocytes to mediate UV-induced melanocyte homeostasis in vivo.


Exploring the validity of HPQ-based presenteeism measures to estimate productivity losses in the health and education sectors.
Illness-related presenteeism (suboptimal work performance) may be a significant factor in worker productivity. Until now, there has been no generally accepted best method of measuring presenteeism across different industries and occupations. This study sought to validate the Health and Work Performance Questionnaire (HPQ)-based measure of presenteeism across occupations and industries and assess the most appropriate method for data analysis. . Work performance was measured using the modified version of the HPQ conducted in workforce samples from the education and health workforce in Queensland, Australia (N = 30,870) during 2005 and 2006. Three approaches to data analysis of presenteeism measures were assessed using absolute performance, the ratio of own performance to others' performance, and the difference between others' and own performance. The best measure is judged by its sensitivity to changes in health indicators. . The measure that best correlated to health indicators was absolute presenteeism. For example, in the health sector, correlations between physical health status and absolute presenteeism were 4 to 5 times greater than the ratio or difference approaches, and in the education sector, these correlations were twice as large. Using this approach, the estimated cost of presenteeism in 2006 was $Aus8338 and $Aus8092 per worker per annum for the health and education sectors, respectively. . The HPQ is a valid measure of presenteeism. Transforming responses by perceived performance of peers is unnecessary as absolute presenteeism correlated best with health indicators. Absolute presenteeism was more insightful for ascertaining the cost of presenteeism.


Prevention of experimental cerebral malaria by anticytokine antibodies. Interleukin 3 and granulocyte macrophage colony-stimulating factor are intermediates in increased tumor necrosis factor production and macrophage accumulation.
IL-3 and granulocyte/macrophage colony stimulating factor (GM-CSF) are two cytokines released by activated T lymphocytes that stimulate the growth and differentiation of various hematopoietic cell lines, among which are macrophages. It has been shown that TNF/cachectin, another cytokine that is released mostly by activated macrophages, plays a central role in experimental cerebral malaria (CM), an acute and lethal neurological syndrome induced by Plasmodium berghei ANKA infection in CBA mice. Since CM requires functional CD4+ T lymphocytes to occur, we explored, by injecting rabbit antibodies to murine rIL-3 and/or GM-CSF, whether these cytokines are intermediates in the marked TNF release leading to CM. Treatment of infected mice with each antibody separately had no protective effect. In contrast, when both anti-rGM-CSF and anti-rIL-3 antibodies were injected together; (a) the occurrence of neurological syndrome was prevented in 90% of the cases; (b) the rise in serum TNF was prevented; and (c) macrophage accumulation in the spleen was significantly reduced. Murine CM appears to involve a cytokine cascade in which IL-3 and GM-CSF lead to the accumulation of TNF-releasing macrophages in vivo.