Unravelling the current shortfalls, challenges, and opportunities in traumatic brain injury.
The brain is the control centre of the human body. Injury to the brain can have diverse and disabling effects. Yet there remain important unanswered questions for clinicians, those affected and their families. This special collection aims to advance understanding of how we can better diagnose, treat and support those affected by brain injury across the severity spectrum.


Neutrophil assays as modified for infants.
Infants and patients with neutropenia provide few neutrophils for study. Accordingly, assays measuring oxidative metabolism (chemiluminescence, glucose-1-C14 oxidation, nitroblue tetrazolium dye reduction and superoxide anion generation) were studied to determine the range of neutrophil concentrations over which results were directly related to the number of neutrophils per reaction, and to define the limits (particularly, the lower one) of cell numbers studied that would yield accurate and comparative data. The chemiluminescence assay was then performed employing low neutrophil concentrations to document that the modified technique could detect a metabolic defect in neutrophils from infants when compared to cells obtained from their mothers and controls.


Molecular and cellular mechanisms of pulmonary fibrosis.
Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease.


Overexpression of OsPAP10a, a root-associated acid phosphatase, increased extracellular organic phosphorus utilization in rice.
Phosphorus (P) deficiency is a major limitation for plant growth and development. Among the wide set of responses to cope with low soil P, plants increase their level of intracellular and secreted acid phosphatases (APases), which helps to catalyze inorganic phosphate (Pi) hydrolysis from organo-phosphates. In this study we characterized the rice (Oryza sativa) purple acid phosphatase 10a (OsPAP10a). OsPAP10a belongs to group Ia of purple acid phosphatases (PAPs), and clusters with the principal secreted PAPs in a variety of plant species including Arabidopsis. The transcript abundance of OsPAP10a is specifically induced by Pi deficiency and is controlled by OsPHR2, the central transcription factor controlling Pi homeostasis. In gel activity assays of root and shoot protein extracts, it was revealed that OsPAP10a is a major acid phosphatase isoform induced by Pi starvation. Constitutive overexpression of OsPAP10a results in a significant increase of phosphatase activity in both shoot and root protein extracts. In vivo root 5-bromo-4-chloro-3-indolyl-phosphate (BCIP) assays and activity measurements on external media showed that OsPAP10a is a root-associated APase. Furthermore, overexpression of OsPAP10a significantly improved ATP hydrolysis and utilization compared with wild type plants. These results indicate that OsPAP10a can potentially be used for crop breeding to improve the efficiency of P use.


Facilitators and barriers to eliciting physical function goals before and after surgery: A qualitative study with clinicians.
Describe clinicians' perspectives of facilitators and barriers to eliciting physical function goals from patients with multiple chronic conditions pre- and post-surgery. Semi-structured qualitative interviews were conducted with clinicians, recruited from an academic medical center, who treat adult patients with multiple chronic conditions. Purposive sampling ensured multiple provider types were represented. Interviews were conducted in person or via web conference and were audio recorded. Findings were summarized using descriptive qualitative content analysis. Of the 12 participating clinicians, 92% were female and 83% specialized in geriatrics. Clinicians had a mean of 10.7 (min-max: 1-30) years of experience. Key facilitators to goal-setting conversations were sufficient time, familial support, and patient cognitive ability. Barriers included lack of time, lack of training, patient challenges in choosing realistic and specific actionable goals, emotional barriers, and cognitive challenges. Some facilitators and barriers are modifiable, including time, inclusion of family members in the clinical encounter, and clinician training to enable actionable goal setting. These results highlight areas for intervention to facilitate goal elicitation for physical function in clinical care settings. Clinicians should be aware of the barriers impacting eliciting goals. Healthcare organizations could consider providing effective goal elicitation training and tools to facilitate goal setting conversation.


A higher order chromatin structure that is lost during differentiation of mouse neuroblastoma cells.
Application of differential scanning calorimetry to nuclei from rapidly growing mouse neuroblastoma cells showed a melting profile with four major thermal transitions: I (60 degrees C), II (76 degrees C), III (88 degrees C), and IV (105 degrees C). When neuroblastoma cells were induced to differentiate by serum withdrawal or treatment with sodium butyrate, transition IV disappeared, while transition III increased in magnitude. Comparison was made to nuclei from several types of nondividing cells as well as a number of samples from mature tissues. In rapidly dividing cells the predominant endotherm was IV (105 degrees C), while in nondividing cells, transition III (88 degrees C) predominated the calorimetric profile. Cellular differentiation thus appeared to be accompanied by a major change in chromatin structure, as evidenced by a shift in melting temperature from 105 to 90 degrees C, and this may serve to distinguish the Go phase of the cell cycle from G1.


Activation of the heat shock transcription factor by hypoxia in mammalian cells.
Members of the stress protein family such as HSP70 are induced in ischemic tissues and may contribute to the ability of cells to survive episodes of transient circulatory insufficiency. However, the biochemical events that lead to this induction, and their degree of similarity with pathways triggered by heat stress, have not been defined. In this study, we demonstrate that transient exposure of cultured C2C12 mouse myogenic cells to a hypoxic atmosphere stimulates DNA binding activity of the heat shock transcription factor through mechanisms that are independent of new protein synthesis. Activation of heat shock transcription factor in hypoxic cells is temporally associated with induction of endogenous HSP70 gene transcription and with induction of a heterologous reporter gene controlled by the human HSP70 promoter. Furthermore, induction of the human HSP70 promoter by hypoxia requires an intact heat shock element, indicating that other cis-acting transcriptional control elements contained within this complex promoter are not sufficient to transduce signals generated within hypoxic cells. These findings provide strong evidence that hypoxia and heat shock induce expression of the HSP70 gene by similar, if not identical, mechanisms.


Unique phenanthrenequinone imidazole-based fluorescent materials with aggregation-induced or two-photon emission.
Very recently, aggregation-induced emission (AIE) and two-photon (TP) emission materials have attracted great attention owing to their widespread applications. Herein, interestingly, we described a unique single fluorophore core with different substituents that can show either outstanding AIE or TP fluorescence properties. The introduction of an electron donating unit such as a tertiary amine group on the phenanthrenequinone imidazole core afforded a novel AIE-based fluorescent material PIN. The optical studies of PIN revealed that appropriate structural modifications on the phenanthrenequinone imidazole core could result in AIE character. On the other hand, modification of an electron-withdrawing moiety such as an indolium moiety on the same phenanthrenequinone imidazole-core provided a new material PID, which exhibited favorable TP emission, indicating that phenanthrenequinone imidazole derivatives could be exploited as TP materials. Furthermore, we have demonstrated that the novel AIE or TP materials constructed herein can be successfully applied for sensing targets of interest in aqueous and biological settings owing to their highly desirable emission profiles. The intriguing finding that careful modification of the phenanthrenequinone imidazole scaffold could afford excellent AIE or TP materials may open a new avenue to engineer robust materials with diverse properties based on a versatile core for various applications.


[Infant mouse test for the assay of thermostable (ST) enterotoxin from Escherichia coli. Histological studies and influence of mice age (author's transl)].
Mices with different ages ranging 1 to 60 days old were inoculated with thermostable (ST) enterotoxin of Escherichia coli, either by intragastric injection through the abdominal wall or by intubation. Doses were proportional to body weight and values obtained for intestines/carcass weight ratios (RI/C) of inoculated mice showed that mice remained susceptible to the enterotoxin up to 16 days old, with RI/C values equal or greater than 0.085. Older mice were completely resistant to ST activity as RI/C values demonstrated. Histological observations showed that whole gut's fixation of inoculated mice was absolutely necessary since any handling of intestinal loops evoked artifactual alterations. Even though, alterations were found, probably of mechanical nature, caused by intestinal distension consequent to the increased fluid volume into gut's lumen. These alterations did not differ from those observed for both cholera and LT-E. coli enterotoxins, characterized by lymphatic and blood vascular dilatation within mucosae lamina propria, eventually shrinkage of lamna propria just below the epithelium as well epithelial's vacuolizations.


Cannabis use during pregnancy and hemodynamic responses to infant cues in pregnancy: an exploratory study.
Cannabis is one of the most commonly used substances during pregnancy and has the potential to negatively impact parent-infant relationships. The prefrontal cortex (PFC) response to infant cues during pregnancy has been associated with subsequent positive parenting behaviors. However, PFC activation is altered in individuals who use cannabis. As the potency of cannabis has changed over the years, little is known about the specific role of cannabis use on gestational parent brain responses to infant cues. Using functional Near-Infrared Spectroscopy (fNIRS) in the second trimester of pregnancy, we measured hemodynamic responses to an infant cry task and an infant faces task among individuals who were using cannabis (N = 14) and compared them with those who were not using cannabis (N = 45). For the infant cry task, pregnant individuals listened to cry sounds and matched white noise. For the infant faces task, they viewed happy, sad, and neutral faces. There was no significant difference between the two groups after adjusting for multiple comparisons. Without adjusting for multiple comparisons, we found preliminary evidence for the differences in the dorsomedial PFC associated with heightened response to infant cry among individuals who use cannabis. The groups were also different in the dorsolateral PFC associated with decreased response to infant sad faces among individuals who use cannabis. Our preliminary data suggests that cannabis use during pregnancy was associated with brain activation in the regions involved in the emotional regulation and information processes. However, the results did not survive after adjustment for multiple comparisons, thus future research with larger sample sizes is needed to confirm potential differences in brain function among cannabis-using pregnant individuals.


Inception of electronic damage of matter by photon-driven post-ionization mechanisms.
"Probe-before-destroy" methodology permitted diffraction and imaging measurements of intact specimens using ultrabright but highly destructive X-ray free-electron laser (XFEL) pulses. The methodology takes advantage of XFEL pulses ultrashort duration to outrun the destructive nature of the X-rays. Atomic movement, generally on the order of >50 fs, regulates the maximum pulse duration for intact specimen measurements. In this contribution, we report the electronic structure damage of a molecule with ultrashort X-ray pulses under preservation of the atoms' positions. A detailed investigation of the X-ray induced processes revealed that X-ray absorption events in the solvent produce a significant number of solvated electrons within attosecond and femtosecond timescales that are capable of coulombic interactions with the probed molecules. The presented findings show a strong influence on the experimental spectra coming from ionization of the probed atoms' surroundings leading to electronic structure modification much faster than direct absorption of photons. This work calls for consideration of this phenomenon in cases focused on samples embedded in, e.g., solutions or in matrices, which in fact concerns most of the experimental studies.


Diagnostic sensitivity of bone scintigraphy for equine stifle disorders.
Disorders of the stifle are a common cause of lameness in horses yet the accuracy of scintigraphy for diagnosis of stifle conditions is controversial. The aim of retrospective cross-sectional study was to determine the diagnostic sensitivity (Se) of bone scintigraphy in detecting stifle disease and to determine if two orthogonal scintigraphic images improve diagnostic Se. Horses that underwent scintigraphic examination during a two-year period were included. Horses were divided into two groups: group 1 (N = 23) had lameness that was localized to the stifle by intra-articular analgesia and group 2 (N = 182) had lameness that was localized to a different location. Scintigraphic studies (one image or two images) were independently and retrospectively analyzed by two radiologists (R1 and R2). Sensitivity, specificity (Sp) and predictive values (PV), and were calculated for each type of study (one image or two images) and for each radiologist (R1 or R2). The Se to detect stifle disorders varied between radiologists (29.2% and 20.8%). The Sp was 84.5% and 88.3%. When two images were evaluated a decrease in the positive PV for both readers occurred. The Cohen kappa coefficient (κ) between readers was poor when one image (0.084) or two images (0.117) were evaluated. Findings from this study indicated that bone-phase nuclear scintigraphy is reasonably specific but highly insensitive for detecting lameness originating from the stifle in a diverse population of both normal and affected horses. The addition of a caudal scintigraphic image acquisition did not improve diagnostic sensitivity.


Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury.
Radiation, a primary mode of cancer therapy, acutely damages cellular macromolecules and DNA and elicits stress responses that lead to cell death. The known cytoprotective activity of nitric oxide (NO) is blocked by thrombospondin-1, a potent antagonist of NO/cGMP signaling in ischemic soft tissues, suggesting that thrombospondin-1 signaling via its receptor CD47 could correspondingly increase radiosensitivity. We show here that soft tissues in thrombospondin-1-null mice are remarkably resistant to radiation injury. Twelve hours after 25-Gy hindlimb irradiation, thrombospondin-1-null mice showed significantly less cell death in both muscle and bone marrow. Two months after irradiation, skin and muscle units in null mice showed minimal histological evidence of radiation injury and near full retention of mitochondrial function. Additionally, both tissue perfusion and acute vascular responses to NO were preserved in irradiated thrombospondin-1-null hindlimbs. The role of thrombospondin-1 in radiosensitization is specific because thrombospondin-2-null mice were not protected. However, mice lacking CD47 showed radioresistance similar to thrombospondin-1-null mice. Both thrombospondin-1- and CD47-dependent radiosensitization is cell autonomous because vascular cells isolated from the respective null mice showed dramatically increased survival and improved proliferative capacity after irradiation in vitro. Therefore, thrombospondin-1/CD47 antagonists may have selective radioprotective activity for normal tissues.


A Skeptic's Guide to Bacterial Mechanosensing.
Surface sensing in bacteria is a precursor to the colonization of biotic and abiotic surfaces, and an important cause of drug resistance and virulence. As a motile bacterium approaches and adheres to a surface from the bulk fluid, the mechanical forces that act on it change. Bacteria are able to sense these changes in the mechanical load through a process termed mechanosensing. Bacterial mechanosensing has featured prominently in recent literature as playing a key role in surface sensing. However, the changes in mechanical loads on different parts of the cell at a surface vary in magnitudes as well as in signs. This confounds the determination of a causal relationship between the activation of specific mechanosensors and surface sensing. Here, we explain how contrasting mechanical stimuli arise on a surface-adherent cell and how known mechanosensors respond to these stimuli. The evidence for mechanosensing in select bacterial species is reinterpreted, with a focus on mechanosensitive molecular motors. We conclude with proposed criteria that bacterial mechanosensors must satisfy to successfully mediate surface sensing.


Disease Damage Influences Cardiovascular Risk Reclassification Based on Carotid Ultrasound in Patients with Systemic Lupus Erythematosus.
Composite scores of cardiovascular (CV) risk factors underestimate the CV risk in patients with systemic lupus erythematosus (SLE). Carotid artery ultrasound (US) was found useful in identifying high CV-risk patients with inflammatory arthritis. We assessed the effect of carotid US assessments on the CV risk stratification of patients with SLE. This cross-sectional study included 276 patients with SLE. These indices were measured: lipid profile, Systematic COronary Risk Evaluation (SCORE) risk calculation, and disease activity (SLE Disease Activity Index), severity (Katz), and damage [Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology Damage Index]. Carotid plaques were assessed by US. A multivariable regression analysis, adjusted for classic CV-related factors, was performed to evaluate how risk reclassification was influenced by disease characteristics in patients with SLE. Thirty-six percent of patients had carotid plaques. However, only 6% of them fulfilled the definitions for high or very high risk according to the SCORE risk charts. Following carotid US assessment, 32% of the patients were reclassified as very high risk. Disease duration (OR 1.04, 95% CI 1.00-1.07, p = 0.025) and a SLICC > 0 (OR 2.48 95% CI 1.15-5.34, p = 0.020) were independently associated with a higher risk of reclassification. A predictive model for reclassification included age (cutoff 52 yrs, sensitivity 60%, specificity 86%), disease duration (cutoff 24 yrs, sensitivity 40%, specificity 82%), presence of hypertension, SLICC > 0, waist circumference (cutoff 102 cm, sensitivity 48%, specificity 84%), and C3 (cutoff 127 mg/dl, sensitivity 52%, specificity 92%) and triglyceride (cutoff 140 mg/dl, sensitivity 68%, specificity 79%) serum levels. Reclassification into a very high-risk category is frequent after carotid US assessments in patients with SLE. This is independently influenced by disease damage.


[Social representation of fathers regarding their premature child in the Neonatal Intensive Care Unit].
Qualitative study that aimed at understanding the social representation of a parent with a premature child. The data were collected between May and June 2008, in a semi-structured interview with 17 parents whose premature children were hospitalized in the NICU of two public institutions in Natal, Brazil. The reports were analyzed based on the Social Representations Theory (SRT). The results reveal that the hospitalization of their children causes parents to experience emotions of fear, anguish, anxiety, loneliness interspersed with those of faith, joy and hope. For a parent the NICU is a frightening environment, albeit necessary for the specialized care that the conditions of the premature newborn require.


NADPH oxidase 4 is required for the generation of macrophage migration inhibitory factor and host defense against Toxoplasma gondii infection.
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) are an important family of catalytic enzymes that generate reactive oxygen species (ROS), which mediate the regulation of diverse cellular functions. Although phagocyte Nox2/gp91phox is closely associated with the activation of host innate immune responses, the roles of Nox family protein during Toxoplasma gondii (T. gondii) infection have not been fully investigated. Here, we found that T. gondii-mediated ROS production was required for the upregulation of macrophage migration inhibitory factor (MIF) mRNA and protein levels via activation of mitogen-activated protein kinase and nuclear factor-κB signaling in macrophages. Interestingly, MIF knockdown led to a significant increase in the survival of intracellular T. gondii in bone marrow-derived macrophages (BMDMs). Moreover, Nox4 deficiency, but not Nox2/gp91phox and the cytosolic subunit p47phox, resulted in enhanced survival of the intracellular T. gondii RH strain and impaired expression of T. gondii-mediated MIF in BMDMs. Additionally, Nox4-deficient mice showed increased susceptibility to virulent RH strain infection and increased cyst burden in brain tissues and low levels of MIF expression following infection with the avirulent ME49 strain. Collectively, our findings indicate that Nox4-mediated ROS generation plays a central role in MIF production and resistance to T. gondii infection.


The somatic antigen of a phage-resistant variant of Phase II Shigella sonnei.
1. A phage-resistant variant of Phase II Shigella sonnei has been isolated and the type-specific antigen from it has been obtained. 2. The antigen of the variant microorganism, II/3, 4, 7, differs from that of the parent Phase II bacillus in serological specificity and in chemical make-up. 3. Although the antigen of Phase II Sh. sonnei inhibits all T phages to which the bacillus is susceptible, that of the variant fails to inhibit T(3), T(4), and T(7).


Biodegradation of resin-dentin interfaces increases bacterial microleakage.
Bis-GMA-containing resin composites and adhesives undergo biodegradation by human-saliva-derived esterases, yielding Bis-hydroxy-propoxy-phenyl-propane (Bis-HPPP). The hypothesis of this study is that the exposure of dental restorations to saliva-like esterase activities accelerates marginal bacterial microleakage. Resin composites (Scotchbond, Z250, 3M) bonded to human dentin were incubated in either buffer or dual-esterase media (pseudocholinesterase/cholesterol-esterase; PCE+CE), with activity levels simulating those of human saliva, for up to 90 days. Incubation solutions were analyzed for Bis-HPPP by high-performance liquid chromatography. Post-incubation, specimens were suspended in a chemostat-based biofilm fermentor cultivating Streptococcus mutans NG8, a primary species associated with dental caries, for 7 days. Bacterial microleakage was assessed by confocal laser scanning microscopy. Bis-HPPP production and depth and spatial volume of bacterial cell penetration within the interface increased with incubation time and were higher for 30- and 90-day PCE+CE vs. buffer-incubated groups, suggesting that biodegradation can contribute to the formation of recurrent decay.


Insulin resistance in Hispanic large-for-gestational-age neonates at birth.
Intrauterine exposure to maternal diabetes and large size at birth are known risk factors for the subsequent development of insulin resistance and metabolic syndrome. Although Hispanic youth have been shown to have a high prevalence of metabolic syndrome, it is unknown whether metabolic abnormalities and a predisposition for glucose intolerance are present at birth. The objective of the study was to determine whether abnormalities in insulin sensitivity exist at or soon after birth in large-for-gestational-age neonates born to Hispanic women with and without gestational diabetes. DESIGN/PATIENTS/SETTING: Forty-two term Hispanic neonates were enrolled for cross-sectional studies at 24-48 h after birth and included nine large-for-gestational-age neonates delivered of women with gestational diabetes (large-for-gestational-age-IDM), 12 large-for-gestational-age but not IDM neonates, 11 poorly grown (at the fifth to 10th percentile), and 10 appropriate-for-gestational-age neonates. Insulin sensitivity and secretion were measured by shortened fasting iv glucose tolerance test. Insulin sensitivity index was measured within 48 h of birth. Neonates were studied at 36 +/- 11 h postnatally, and all groups were euglycemic at the time of study. However, insulin sensitivity was significantly lower (P < 0.05, ANOVA) in large-for-gestational-age-IDM [3.0 +/- 0.7 (sem) mU/liter.min] and large-for-gestational-age-non-IDM (2.2 +/- 0.4 mU/liter.min) cohorts in comparison with poorly grown (5.0 +/- 0.7 mU/liter.min) and appropriate-for-gestational-age controls (5.4 +/- 0.8 mU/liter.min). Insulin secretion did not differ between groups. Reduced insulin sensitivity is present soon after birth in Hispanic large-for-gestational-age neonates born to mothers with and without gestational diabetes, demonstrating the onset of insulin resistance before birth and evidence of altered fetal programming.


Extracellular vesicles as central regulators of blood vessel function in cancer.
Blood vessels deliver oxygen and nutrients that sustain tumor growth and enable the dissemination of cancer cells to distant sites and the recruitment of intratumoral immune cells. In addition, the structural and functional abnormalities of the tumor vasculature foster the development of an aggressive tumor microenvironment and impair the efficacy of existing cancer therapies. Extracellular vesicles (EVs) have emerged as major players of tumor progression, and a growing body of evidence has demonstrated that EVs derived from cancer cells trigger multiple responses in endothelial cells that alter blood vessel function in tumors. EV-mediated signaling in endothelial cells can occur through the transfer of functional cargos such as miRNAs, lncRNAs, cirRNAs, and proteins. Moreover, membrane-bound proteins in EVs can elicit receptor-mediated signaling in endothelial cells. Together, these mechanisms reprogram endothelial cells and contribute to the sustained exacerbated angiogenic signaling typical of tumors, which, in turn, influences cancer progression. Targeting these angiogenesis-promoting EV-dependent mechanisms may offer additional strategies to normalize tumor vasculature. Here, we discuss the current knowledge pertaining to the contribution of cancer cell-derived EVs in mechanisms regulating blood vessel functions in tumors. Moreover, we discuss the translational opportunities in targeting the dysfunctional tumor vasculature using EVs and highlight the open questions in the field of EV biology that can be addressed using mass spectrometry-based proteomics analysis.


Structure of ubiquitin refined at 1.8 A resolution.
The crystal structure of human erythrocytic ubiquitin has been refined at 1.8 A resolution using a restrained least-squares procedure. The crystallographic R-factor for the final model is 0.176. Bond lengths and bond angles in the molecule have root-mean-square deviations from ideal values of 0.016 A and 1.5 degrees, respectively. A total of 58 water molecules per molecule of ubiquitin are included in the final model. The last four residues in the molecule appear to have partial occupancy or large thermal motion. The overall structure of ubiquitin is extremely compact and tightly hydrogen-bonded; approximately 87% of the polypeptide chain is involved in hydrogen-bonded secondary structure. Prominent secondary structural features include three and one-half turns of alpha-helix, a short piece of 3(10)-helix, a mixed beta-sheet that contains five strands, and seven reverse turns. There is a marked hydrophobic core formed between the beta-sheet and alpha-helix. The molecule features a number of unusual secondary structural features, including a parallel G1 beta-bulge, two reverse Asx turns, and a symmetrical hydrogen-bonding region that involves the two helices and two of the reverse turns.


Altered brain activation in cognitively intact individuals at high risk for Alzheimer's disease.
To determine whether brain function is altered in cognitively normal individuals at high risk for AD several years before the typical age at onset for this illness. Neuropathologic alterations in AD precede cognitive impairment by several years. It is unknown whether functional alterations in neural circuitry accompany these neuropathologic changes, and if so, whether they may be detectable before onset of symptoms. We used functional MRI to compare cortical activation between two groups of cognitively normal women differing only in their risk for developing AD. Visual naming and letter fluency tasks were used to activate brain areas subserving object and face recognition, previously described sites of hypometabolism and neuropathologic alteration in AD. The risk groups differed in family history of AD and apolipoprotein E allele status, but were matched in age, education, and measures of cognitive performance. Average age of the study participants was 52 years. The regional patterns of brain activation were similar between groups. However, the high risk group showed areas of significantly reduced activation in the mid- and posterior inferotemporal regions bilaterally during both tasks despite identical naming and letter fluency performance. Cognitively normal individuals at high risk for AD demonstrate decreased brain activation in key areas engaged during naming and fluency tasks. Decreased activation in the high risk group may be a consequence of the presence of subclinical neuropathology in the inferotemporal region or in the inputs to that region. If so, these findings provide evidence of a window of opportunity for disease-modifying treatment before the onset of symptomatic AD.


Long-term seizure outcome after mesial temporal lobe epilepsy surgery: corticalamygdalohippocampectomy versus selective amygdalohippocampectomy.
Resection strategies for the treatment of temporal lobe epilepsy (TLE) are a matter of discussion, and little information is available. The aim of this study was to compare seizure outcomes at the 5-year follow-up in patients with medically refractory unilateral mesial TLE (MTLE) due to hippocampal sclerosis (HS) who were treated using a cortical amygdalohippocampectomy (CorAH) or a selective AH (SelAH). The authors obtained data from 100 adult patients who underwent surgery for MTLE. Fifty patients underwent a CorAH and 50 underwent an SelAH. Seizure control achieved with each technique was compared using the Engel classification scheme. Overall, at the 5-year follow-up, favorable (Engel Classes I and II) seizure outcomes were noted in 82 and 90% of patients who had undergone CorAH and SelAH, respectively. Furthermore, 40% of the patients who had undergone a CorAH and 58% of those who had undergone an SelAH were seizure free (Engel Class Ia). There was no statistically significant difference between the 2 surgical approaches in terms of seizure outcome at the 5-year follow-up (p = 0.38). Both CorAH and SelAH can lead to similar favorable seizure control in patients with MTLE/HS. However, the authors suggest that the transcortical selective approach has the great advantage of minimizing or completely abolishing the impact of dividing several venous and arterial adhesions which are tedious, time consuming, and, at times, associated with some degree of cerebral swelling.


Cytochrome P450 3A5 polymorphism affects the metabolism of sorafenib and its toxicity for hepatocellular carcinoma cells in vitro.
Cytochrome P450 3A5 (CYP3A5) is a highly polymorphic gene and the encoded protein variants differ in catalytic activity, leading to inter-individual variation in metabolic ability. The aim of the current study was to investigate the effects of seven allelic variants on the ability of CYP3A5 to metabolize sorafenib in vitro and further explore the impacts of CYP3A5 polymorphism on the proliferation and apoptosis of hepatocellular carcinoma cell line (HepG2) induced by sorafenib. Wild-type and variant CYP3A5 enzymes were expressed in Spodoptera frugiperda insect cells using a baculovirus dual-expression system, and protein expression was checked by western blot. The enzymes were incubated with sorafenib at 37°C for 30 min, and formation of the major metabolite sorafenib N-oxide was assayed using ultra-performance liquid chromatography and tandem mass spectrometry. Intrinsic clearance values (Vmax/Km) were calculated for each enzyme. Additionally, recombinant HepG2 cells transfecting with CYP3A5 variants were used to investigate the effects of sorafenib on the proliferation of HepG2 cells. Intrinsic clearance of the six variants CYP3A5*2, CYP3A5*3A, CYP3A5*3C, CYP3A5*4, CYP3A5*5, and CYP3A5*7 was 26.41-71.04% of the wild-type (CYP3A5*1) value. In contrast, the clearance value of the variant CYP3A5*6 was significantly higher (174.74%). Additionally, the decreased ATP levels and cell viability and the increased cell apoptosis in HepG2 cells transfected with CYP3A5*2, CYP3A5*3A, CYP3A5*3C, CYP3A5*4, CYP3A5*5, and CYP3A5*7 were observed, whereas, the increased ATP levels and cell viability and the reduced cell apoptosis in HepG2 cells transfected with CYP3A5*6 were also investigated when compared to CYP3A5*1. Our results suggest that CYP3A5 polymorphism influences sorafenib metabolism and pharmacotherapeutic effect in hepatic carcinomas. These data may help explain differential response to drug therapy for hepatocellular carcinoma, and they support the need for individualized treatment.


[Analysis of occupational exposure to asbestos in cases of mesothelioma registered in Romagna (1986-1998)].
The aim of this study was to evaluate the prevalence and major correlates of occupational exposure to asbestos among the 125 cases of mesothelioma of the pleura, peritoneum, and pericardium registered in the Romagna Region of Italy between 1986 and 1998. Adequate occupational information was obtained for 122 (98%) cases. Among these, the male:female ratio was 81:41 (2.0), the median age was 68 years (range, 25-92), and the pleural location accounted for 96 (79%) cases. According to job history, 61 (50%) cases had had definite (23), probable (12), and possible (26) occupational exposure to asbestos. The probability (multiple logistic regression estimate) was greater for males (odds ratio, 10.8) but decreased for cases with mesothelioma of the peritoneum and pericardium (0.21) as well as those above the median age (0.38). Time period, residence, mode of diagnosis (histology, cytology, other), source of information (patient, wife/husband, others), and smoking habits exerted no independent effect. For 35 (57%) cases, occupational exposure was related to asbestos pollution of the workplace and not to the specific work task. Cases with definite, probable, and possible occupational exposure showed no significant difference in the distribution (Kruskal-Wallis test) by year of initial employment at risk, duration of exposure, and latency (median, 36 years). Occupational exposure occurred in a total of 22 workplaces. Three of these accounted for 21 (34%) cases. Multiple (> or = 2) cases (total 27 or 44%) were observed in six workplaces.


UV damage induces G3BP1-dependent stress granule formation that is not driven by mTOR inhibition-mediated translation arrest.
Translation arrest is a part of the cellular stress response that decreases energy consumption and enables rapid reprioritisation of gene expression. Often translation arrest leads to condensation of untranslated messenger ribonucleoproteins (mRNPs) into stress granules (SGs). Studies into mechanisms of SG formation and functions are complicated because various types of stress cause formation of SGs with different properties and composition. In this work, we focused on the mechanism of SG formation triggered by UV damage. We demonstrate that UV-induced inhibition of translation does not involve inhibition of the mechanistic target of rapamycin (mTOR) signaling or dissociation of the 48S preinitiation complexes. The general control non-derepressible 2 (GCN2; also known as EIF2AK4) kinase contributes to UV-induced SG formation, which is independent of the phosphorylation of the eukaryotic translation initiation factor 2α. Like many other types of SGs, condensation of UV-induced granules requires the Ras-GTPase-activating protein SH3-domain-binding protein 1 (G3BP1). Our work reveals that, in UV-treated cells, the mechanisms of translation arrest and SG formation may be unlinked, resulting in SGs that do not contain the major type of polysome-free preinitiation complexes that accumulate in the cytoplasm.This article has an associated First Person interview with the first author of the paper.


Outcome of central nervous system relapses in childhood acute lymphoblastic leukaemia--prospective open cohort analyses of the ALLR3 trial.
The outcomes of Central Nervous System (CNS) relapses in children with acute lymphoblastic leukaemia (ALL) treated in the ALL R3 trial, between January 2003 and March 2011 were analysed. Patients were risk stratified, to receive a matched donor allogeneic transplant or fractionated cranial irradiation with continued treatment for two years. A randomisation of Idarubicin with Mitoxantrone closed in December 2007 in favour of Mitoxantrone. The estimated 3-year progression free survival for combined and isolated CNS disease were 40.6% (25·1, 55·6) and 38.0% (26.2, 49.7) respectively. Univariate analysis showed a significantly better survival for age <10 years, progenitor-B cell disease, good-risk cytogenetics and those receiving Mitoxantrone. Adjusting for these variables (age, time to relapse, cytogenetics, treatment drug and gender) a multivariate analysis, showed a poorer outcome for those with combined CNS relapse (HR 2·64, 95% CI 1·32, 5·31, p = 0·006 for OS). ALL R3 showed an improvement in outcome for CNS relapses treated with Mitoxantrone compared to Idarubicin; a potential benefit for matched donor transplant for those with very early and early isolated-CNS relapses. Controlled-Trials.com ISRCTN45724312.


Animals Experimentally Infected with SARS-CoV-2 Generate Functional Autoantibodies against G-Protein-Coupled Receptors.
(1) Background: SARS-CoV-2 infection has been linked to diverse clinical manifestations in humans, including cardiovascular complications. Functional autoantibodies targeting G-protein-coupled receptors have emerged as potential contributors to these effects. This study sought to investigate the production and activity of functional autoantibodies targeting G-protein-coupled receptors after SARS-CoV-2 infection of selected animal species. (2) Methods: The presence of functional autoantibodies such as 2-adrenoceptor, angiotensin II AT1 receptor, muscarinic M2 receptor, and angiotensin 1-7 MAS receptor was assessed in cattle and ferrets experimentally infected with SARS-CoV-2. Bioassays were conducted to evaluate the positive or negative chronotropic responses induced by these autoantibodies. Further experiments identified the extracellular domains to which the functional autoantibodies bind, and receptor antagonists were employed to block the induced responses. (3) Results: Only two out of six cattle that were inoculated with SARS-CoV-2 displayed viral replication and tested positive for functional autoantibodies against G-protein-coupled receptors. These functional autoantibodies specifically recognized β2-adrenoceptor, angiotensin II AT1 receptor, muscarinic M2 receptor, and angiotensin 1-7 MAS receptor and induced distinct positive and negative chronotropic effects in the bioassay. Infected ferrets generated functional autoantibodies against β2-adrenoceptor and muscarinic M2 receptor and presented bioactivity similar to that in cattle. (4) Conclusions: This study uncovers functional autoantibodies targeting G-protein-coupled receptors in cattle and ferrets post-SARS-CoV-2 infection, with implications for cardiovascular function.


Outbreak of Salmonella Newport Infections with Decreased Susceptibility to Azithromycin Linked to Beef Obtained in the United States and Soft Cheese Obtained in Mexico - United States, 2018-2019.
In September 2018, CDC identified Salmonella enterica serotype Newport (Newport) infections that were multidrug resistant (MDR), with decreased susceptibility to azithromycin, a recommended oral treatment agent. Until 2017, decreased susceptibility to azithromycin had occurred in fewer than 0.5% of Salmonella isolates from U.S. residents. This report summarizes the investigation of a multistate MDR Salmonella outbreak conducted by CDC, state and local health departments, and the U.S. Department of Agriculture's Food Safety and Inspection Service. During June 2018-March 2019, 255 cases of infection with the outbreak strain were identified in 32 states; 43% of patients (89 of 206 with information on travel) reported recent travel to Mexico. Infections were linked to consumption of soft cheese obtained in Mexico and beef obtained in the United States. Consumers should avoid eating soft cheese that could be made from unpasteurized milk, regardless of the source of the cheese. When preparing beef, a food thermometer should be used to ensure that appropriate cooking temperatures are reached. When antibiotic treatment is needed for a patient, clinicians should choose antibiotics based on susceptibility testing wherever possible.


The use of visible speech cues for improving auditory detection of spoken sentences.
Classic accounts of the benefits of speechreading to speech recognition treat auditory and visual channels as independent sources of information that are integrated fairly early in the speech perception process. The primary question addressed in this study was whether visible movements of the speech articulators could be used to improve the detection of speech in noise, thus demonstrating an influence of speechreading on the ability to detect, rather than recognize, speech. In the first experiment, ten normal-hearing subjects detected the presence of three known spoken sentences in noise under three conditions: auditory-only (A), auditory plus speechreading with a visually matched sentence (AV(M)) and auditory plus speechreading with a visually unmatched sentence (AV(UM). When the speechread sentence matched the target sentence, average detection thresholds improved by about 1.6 dB relative to the auditory condition. However, the amount of threshold reduction varied significantly for the three target sentences (from 0.8 to 2.2 dB). There was no difference in detection thresholds between the AV(UM) condition and the A condition. In a second experiment, the effects of visually matched orthographic stimuli on detection thresholds was examined for the same three target sentences in six subjects who participated in the earlier experiment. When the orthographic stimuli were presented just prior to each trial, average detection thresholds improved by about 0.5 dB relative to the A condition. However, unlike the AV(M) condition, the detection improvement due to orthography was not dependent on the target sentence. Analyses of correlations between area of mouth opening and acoustic envelopes derived from selected spectral regions of each sentence (corresponding to the wide-band speech, and first, second, and third formant regions) suggested that AV(M) threshold reduction may be determined by the degree of auditory-visual temporal coherence, especially between the area of lip opening and the envelope derived from mid- to high-frequency acoustic energy. Taken together, the data (for these sentences at least) suggest that visual cues derived from the dynamic movements of the fact during speech production interact with time-aligned auditory cues to enhance sensitivity in auditory detection. The amount of visual influence depends in part on the degree of correlation between acoustic envelopes and visible movement of the articulators.


Evaluation of different diameter arterial tubing and arterial cannulae in simulated neonatal/pediatric cardiopulmonary bypass circuits.
The objective of this study is to evaluate three different diameters of arterial tubing and three diameters of arterial cannulae in terms of pressure drop, and hemodynamic energy delivery in simulated neonatal/pediatric cardiopulmonary bypass (CPB) circuits. The CPB circuit consisted of a Terumo Capiox Baby FX05 oxygenator (Terumo Corporation, Tokyo, Japan), arterial tubing (1/4 in, 3/16 in, or 1/8 in × 150 cm), and a Medtronic Bio-Medicus arterial cannula (8, 10, or 12 Fr; Medtronic, Inc., Minneapolis, MN, USA). The pseudo patient's pressure was maintained at 50 mm Hg. The circuit was primed using lactated Ringer's solution and heparinized packed human red blood cells (hematocrit 30%). Trials were conducted at different flow rates and temperatures (35 and 28°C). Flow and pressure data were collected using a custom-based data acquisition system. Using 8 Fr arterial cannula at 500 mL/min, small diameter arterial tubing generated higher circuit pressure (294.6 ± 0.1 mm Hg [1/8 in], 213.5 ± 0.5 mm Hg [3/16 in], 208.4 ± 0.4 mm Hg [1/4 in] at 35°C) and arterial line pressure drop (158.3 ± 0.1 mm Hg [1/8 in], 79.6 ± 0.1 mm Hg [3/16 in], 62.1 ± 0.1 mm Hg [1/4 in] at 35°C). Using 10 Fr arterial cannula at 1000 mL/min, pre-oxygenator pressures were 266.8 ± 0.2 mm Hg (3/16 in) and 248.0 ± 0.3 mm Hg (1/4 in); arterial line pressure drops were 111.6 ± 0.0 mm Hg (3/16 in) and 74.0 ± 0.1 mm Hg (1/4 in) at 35°C. When using 12 Fr arterial cannula at 1500 mL/min, preoxygenator pressures reached 324.4 ± 0.3 mm Hg (3/16 in) and 302.5 ± 0.4 mm Hg (1/4 in); arterial line pressure drops were 154.0 ± 0.1 mm Hg (3/16 in) and 92.0 ± 0.2 mm Hg (1/4 in) at 35°C. Pressure drops across arterial line tubing were main CPB circuit pressure drops. High flow rate, hypothermia, small diameter arterial tubing. and arterial cannula created more hemodynamic energy at the preoxygenator site, but energy loss across CPB circuit also increased. Although small diameter (<1/4 in ID) arterial tubing may decrease total CPB priming volume, it also led to significantly higher circuit pressure, higher pressure drop, and more hemodynamic energy loss across CPB circuit. Larger diameter arterial cannula had less pressure drop and allowed more hemodynamic energy delivery to the patient.


Phenotypic and genotypic characterization of colistin-resistant Escherichia Coli with mcr-4, mcr-5, mcr-6, and mcr-9 genes from broiler chicken and farm environment.
Colistin is an antibiotic used as a last-resort to treat multidrug-resistant Gram-negative bacterial infections. Colistin had been used for a long time in veterinary medicine for disease control and as a growth promoter in food-producing animals. This excessive use of colistin in food animals causes an increase in colistin resistance. This study aimed to determine molecular characteristics of colistin-resistant Escherichia coli in broiler chicken and chicken farm environments. Four hundred fifty-three cloacal and farm environment samples were collected from six different commercial chicken farms in Kelantan, Malaysia. E. coli was isolated using standard bacteriological methods, and the isolates were tested for antimicrobial susceptibility using disc diffusion and colistin minimum inhibitory concentration (MIC) by broth microdilution. Multiplex PCR was used to detect mcr genes, and DNA sequencing was used to confirm the resistance genes. Virulence gene detection, phylogroup, and multilocus sequence typing (MLST) were done to further characterize the E. coli isolates. Out of the 425 (94%; 425/453) E. coli isolated from the chicken and farm environment samples, 10.8% (48/425) isolates were carrying one or more colistin-resistance encoding genes. Of the 48 colistin-resistant isolates, 54.2% (26/48) of the mcr positive isolates were genotypically and phenotypically resistant to colistin with MIC of colistin ≥ 4 μg/ml. The most prominent mcr gene detected was mcr-1 (47.9%; 23/48), followed by mcr-8 (18.8%; 9/48), mcr-7 (14.5%; 7/48), mcr-6 (12.5%; 6/48), mcr-4 (2.1%; 1/48), mcr-5 (2.1%; 1/48), and mcr-9 (2.1%; 1/48) genes. One E. coli isolate originating from the fecal sample was found to harbor both mcr-4 and mcr-6 genes and another isolate from the drinking water sample was carrying mcr-1 and mcr-8 genes. The majority of the mcr positive isolates were categorized under phylogroup A followed by phylogroup B1. The most prevalent sequence typing (ST) was ST1771 (n = 4) followed by ST206 (n = 3). 100% of the mcr positive E. coli isolates were multidrug resistant. The most frequently detected virulence genes among mcr positive E. coli isolates were ast (38%; 18/48) followed by iss (23%; 11/48). This is the first research to report the prevalence of mcr-4, mcr-5, mcr-6, mcr-7, and mcr-8 genes in E. coli from broiler chickens and farm environments in Malaysia. Our findings suggest that broiler chickens and broiler farm environments could be reservoirs of colistin-resistant E. coli, posing a risk to public health and food safety.


The structure and function of murine factor V and its inactivation by protein C.
Factor V (FV) is a central regulator of hemostasis, serving both as a critical cofactor for the prothrombinase activity of factor Xa and the target for proteolytic inactivation by the anticoagulant, activated protein C (APC). To examine the evolutionary conservation of FV procoagulant activity and functional inactivation by APC, we cloned and sequenced the coding region of murine FV cDNA and generated recombinant wild-type and mutant murine FV proteins. The murine FV cDNA encodes a 2,183-amino acid protein. Sequence comparison shows that the A1-A3 and C1-C2 domains of FV are highly conserved, demonstrating greater than 84% sequence identity between murine and human, and 60% overall amino acid identity among human, bovine, and murine FV sequences. In contrast, only 35% identity among all three species is observed for the poorly conserved B domain. The arginines at all thrombin cleavage sites and the R305 and R504 APC cleavage sites (corresponding to amino acid residues R306 and R506 in human FV) are invariant in all three species. Point mutants were generated to substitute glutamine at R305, R504, or both (R305/R504). Wild-type and all three mutant FV recombinant proteins show equivalent FV procoagulant activity. Single mutations at R305 or R504 result in partial resistance of FV to APC inactivation, whereas recombinant murine FV carrying both mutations (R305Q/R504Q) is nearly completely APC resistant. Thus, the structure and function of FV and its interaction with APC are highly conserved across mammalian species.


Ultrastructural aspects of sporogenesis in the apogamous fern Dryopteris borreri.
The events that accompany sporogenesis in the apogamous fern Dryopteris borreri parallel those seen in sexually reproducing ferns. Organelles dedifferentiate and redifferentiate, and form a discrete band across the equator of dyads; nuclear vacuoles and lipid spherosomes appear during prophase, and the major part of the ribosome population is removed and subsequently replaced during meiosis. Similar events have been found to occur during sporogenesis in mosses, gymnosperms and angiosperms, and therefore characteristic of the meiotic transition from sporophyte to gametophyte, even in the absence of a transition from diplophase to haplophase. The novel aspects of meiosis in D. borreri are largely those connected with the restitution event that precedes meiosis I and serves to maintain the sporophytic chromosome number throughout the life cycle of this fern. Pre-meiotic cells are regularly found to be cleaved by annular wall ingrowths, which traverse the cytoplasm but not the nuclei. The significance of these ingrowths in relation to theories concerning apogamy and plant cell division are discussed.


Cytolethal distending toxin-producing Escherichia coli strains causing severe diarrhoea in young Mexican children.
Introduction. Cytolethal distending toxins (CDTs), encoded by cdt genes, have DNase activity leading to cellular and nuclear distension, resulting in irreversible cell cycle arrest and apoptosis of target cells. cdt-positive Escherichia coli strains have been isolated from children with diarrhoea. There is, however, scant information on the prevalence and clinical presentation of diarrhoeal disease caused by these strains. Furthermore, toxin production of cdt-positive strains is rarely confirmed. We report five young children with diarrhoea caused by CDT-producing E. coli in whom stools were negative for other bacterial or enteric pathogens. Case presentation. On admission to hospital, all children presented watery diarrhoea with high stool output (range 7-20 stools/24 h); five had fever of 38 °C or more and four presented vomiting. Dehydration was present in four patients, one of whom had hypovolaemic shock; one child also presented hyponatraemia and hypokalaemia. In two children, cdt-positive strains were classified as typical and atypical enteropathogenic E. coli, and the remaining three harboured cdt-positive strains that did not belong to any diarrhoeagenic pathogroup. One cdt-positive strain from each case was characterized by a CDT cytotoxic assay and a cdt type-specific PCR. All strains produced the characteristic cellular intoxication due to CDT. Two strains carried the cdt-I, one cdt-III, one cdt-IV, and one concurrently had cdt-I, cdt-II and cdt-III genes. Conclusion. Our results suggest that CDT-producing E. coli strains are an infrequent, albeit significant, cause of severe diarrhoeal illness in children. Future research should measure the true burden of cdt-positive E. coli diarrhoea among children.


Response surface optimization of the critical medium components for the production of alpha-galactosidase from Aspergillus parasiticus MTCC-2796.
Response surface methodology was used to evaluate the effect of main variables such as concentration of galactose, yeast extract and wheat bran on alpha-galactosidase production from Aspergillus parasiticus MTCC-2796 under submerged fermentation conditions. A full factorial Central Composite Design was applied to study these main factors that affected alpha-galactosidase production. The experimental results showed that the optimum concentration of galactose, yeast extract and wheat bran were 1.5 %, 0.06 % and 1.5 %, respectively. This method was efficient as only 20 experiments were necessary to asses these conditions, and model adequacy was very satisfactory as the coefficient of determination was 0.9921.


[Effect of immobilized adrenaline on the state of the adenylate cyclase system in the cardiac and skeletal muscles of rats in the recuperative period after physical exertion].
It is shown that in the rehabilitation period after a single long physical load the adenylate cyclase activity and cAMP content in the skeletal muscle are low and normalize by the 48th and 36th h, respectively. These indices in the myocardium in the nearest rehabilitation period increase considerably, gradually normalizing by 24th and 48th h, respectively. Immobilized epinephrine accelerates normalization of the adenylate cyclase activity and cAMP content in the skeletal muscle and in myocardium in the rehabilitation period after physical load, the phosphodiesterase activity being unchanged.


Mucuna pruriens Administration Minimizes Neuroinflammation and Shows Anxiolytic, Antidepressant and Slimming Effects in Obese Rats.
This study evaluated the effect of Mucuna pruriens (MP) administration on neuroinflammation and behavioral and murinometric parameters in obese rats. Proximate composition, oligosaccharide and phenolic compound profile of MP were determined. Wistar adult male rats were randomized into healthy (HG) and obese group (OG). The HG consumed a control chow diet while OG consumed a cafeteria diet for eight weeks. Then, they were subdivided into: Healthy (HG); Healthy with MP administration (HGMP); Obese (OG); Obese with MP administration (OGMP), with the consumption of the respective diets remaining for another eight weeks, in addition to gavage with MP extract to supplemented groups (750 mg/kg weight). MP presented a composition rich in proteins and phenolic compounds, especially catechin, in addition to 1-kestose and levodopa. Supplementation reduced food intake, body weight, and thoracic and abdominal circumferences in obese rats. MP showed anxiolytic and antidepressant effects and reduced morphological damage and expression of interleukin 6 in the hippocampus of obese rats. MP treatment showed satietogenic, slimming, anxiolytic and antidepressant effects, besides to minimizing hippocampal neuroinflammation in obese rats. Our results demonstrated the potential anti-obesity of MP which are probably related to the high content of bioactive compounds present in this plant extract.


QDD version 3.1: a user-friendly computer program for microsatellite selection and primer design revisited: experimental validation of variables determining genotyping success rate.
Microsatellite marker development has been greatly simplified by the use of high-throughput sequencing followed by in silico microsatellite detection and primer design. However, the selection of markers designed by the existing pipelines depends either on arbitrary criteria, or older studies on PCR success. Based on wet laboratory experiments, we have identified the following factors that are most likely to influence genotyping success rate: alignment score between the primers and the amplicon; the distance between primers and microsatellites; the length of the PCR product; target region complexity and the number of reads underlying the sequence. The QDD pipeline has been modified to include these most pertinent factors in the output to help the selection of markers. Furthermore, new features are also included in the present version: (i) not only raw sequencing reads are accepted as input, but also contigs, allowing the analysis of assembled high-coverage data; (ii) input data can be both in fasta and fastq format to facilitate the use of Illumina and IonTorrent reads; (iii) A comparison to known transposable elements allows their detection; (iv) A contamination check can be carried out by BLASTing potential markers against the nucleotide (nt) database of NCBI; (v) QDD3 is now also available imbedded into a virtual machine making installation easier and operating system independent. It can be used both on command-line version as well as integrated into a Galaxy server, providing a user-friendly interface, as well as the possibility to utilize a large variety of NGS tools.


Is any job better than no job? Labor market experiences and depressive symptoms in people living with HIV.
The purpose of this study is to determine the relationship between the psychosocial work environment and labor market experiences (including unemployment) on mental health among adults living with HIV. We used data provided by 538 participants at clinical and community sites across Ontario, Canada. Generalized estimating equation models showed that employment was associated with lower depressive symptoms. For employed participants, adverse psychosocial work conditions, specifically job insecurity, psychological demands, and decision authority were associated with depressive symptoms. For the entire sample, the number of adverse psychosocial work conditions was associated with higher depressive symptoms while participants working in poor quality jobs reported similar levels of depressive symptoms than those who were unemployed or not in the labor force. This study showed that poor quality employment (as assessed by having a high number of adverse psychosocial work exposures) was associated with a similar level of depressive symptoms as unemployment, suggesting that "bad jobs" may not offer the same mental health benefits as "good jobs." Policies to improve employment outcomes should take the quality of employment into account to maximize mental health benefits as better employment may lead to better mental health.


Optical tracking of superficial dynamics from an acoustic radiation force-induced excitation.
Acoustic radiation force (ARF) has become a common excitation mechanism in elasticity imaging. The high acoustic intensities and subsequent generation of harmonics, however, hamper the effectiveness of using conventional radiofrequency (rf) tracking to investigate the dynamics of tissues and catheter-based transducers, especially during the excitation. Optical tracking, on the other hand, does not utilize acoustic echo and thus is not affected by ARF-generated interference. Additionally, it is able to track equally well in two dimensions, something that rf tracking is unable to do. Despite the inherent near-field scattering that will likely preclude optical (i.e., visible spectrum) tracking from supplanting current ultrasound-based methods in a clinical setting, it could offer valuable new tools in the pursuit of a better understanding of ARF-induced dynamic responses. We utilized an optically-based method to track the dynamic response resulting from an ARF-induced excitation on the surface of a tissue-mimicking phantom and on an unbounded catheter. These tracking data were then compared to tracking data obtained from the conventional rf tracking method. Both impulsive and harmonic (i.e., amplitude-modulated) excitations were investigated. In general, there was good agreement between the conventional (i.e., ultrasound-based) and optically-based tracking methods. Disparities between displacement estimates from the two tracking methods is thought to be a result of the finite length of the tracking marker, which was assumed to move as an infinitesimal point, and aberration of reflected light due to surface waves. Given the reasonable agreement seen for the harmonic and impulsive excitation cases, an optical tracking method could be insightful in future investigations of tissue/transducer response to ARF-induced excitations in controlled experimental settings.


NIAAA's College Alcohol Intervention Matrix.
The College Alcohol Intervention Matrix (CollegeAIM) is a user-friendly, interactive decision tool based on a synthesis of the substantial and growing literature on campus alcohol use prevention. It includes strategies targeted at both the individual and environmental levels. Commissioned by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), CollegeAIM reflects the collective knowledge of 16 separate experts in the field, which makes it unique relative to other summaries of the science. CollegeAIM is designed to help college stakeholders compare and contrast different evidence-based prevention strategies to select a mix of individual and environmental strategies that will work best on and around their campuses. CollegeAIM is a living document, which will be updated to keep pace with the science. Colleges are therefore encouraged to ensure that evaluations of individual- or environmental-focused strategies on their campuses or in their communities make it into the published literature.


Climate change, wildfire, and vegetation shifts in a high-inertia forest landscape: Western Washington, U.S.A.
Future vegetation shifts under changing climate are uncertain for forests with infrequent stand-replacing disturbance regimes. These high-inertia forests may have long persistence even with climate change because disturbance-free periods can span centuries, broad-scale regeneration opportunities are fewer relative to frequent-fire systems, and mature tree species are long-lived with relatively high tolerance for sub-optimal growing conditions. Here, we used a combination of empirical and process-based modeling approaches to examine vegetation projections across high-inertia forests of Washington State, USA, under different climate and wildfire futures. We ran our models without forest management (to assess inherent system behavior/potential) and also with wildfire suppression. Projections suggested relatively stable mid-elevation forests through the end of the century despite anticipated increases in wildfire. The largest changes were projected at the lowest and uppermost forest boundaries, with upward expansion of the driest low-elevation forests and contraction of cold, high-elevation subalpine parklands. While forests were overall relatively stable in simulations, increases in early-seral conditions and decreases in late-seral conditions occurred as wildfire became more frequent. With partial fire suppression, projected changes were dampened or delayed, suggesting a potential tool to forestall change in some (but not all) high-inertia forests, especially since extending fire-free periods does little to alter overall fire regimes in these systems. Model projections also illustrated the importance of fire regime context and projection limitations; the time horizon over which disturbances will eventually allow the system to shift are so long that the prevailing climatic conditions under which many of those shifts will occur are beyond what most climate models can predict with any certainty. This will present a fundamental challenge to setting expectations and managing for long-term change in these systems.


[Angiocardiographic and echocardiographic diagnosis of complete transposition of great vessels in association with pathology of the aorta].
The article analyses experience in the diagnosis of a pathological condition of the aorta in complete transposition of the great vessels (CTGV) in infants. Pathology of the aorta was revealed in 9 (2.6%) of the 350 patients who were examined. Six patients with CTGV had coarctation of the aorta (CA), 2 had subaortic stenosis, and one patient had complete interruption of the arch of the aorta. Our experience provides evidence that two-dimensional echocardiography allows the region of the thoracic aorta to be located from a suprasternal or a high right parasternal approach. Subaortic stenosis was diagnosed in 2 patients during autopsy. Retrospective analysis of the echocardiograms and angiocardiograms revealed characteristic signs of subaortic obstruction. Absence of the continuity of the arch and descending aorta is an echocardiographic sign of interruption of the arch of the aorta which was recognized retrospectively only after angiocardiography. Right and left ventriculography must be performed for precise anatomical diagnosis of CTGV with an intact interventricular septum combined with coarctation of the aorta. In patients with concomitant interventricular septal defect this examination is supplemented by antegrade and retrograde aortography from the ascending aorta to exclude patent ductus arteriosus and for better visualization of CA. Catheterization of all heart cavities, right and left ventriculography, aortography, and pulmonary arteriography must be carried out in all patients with total interruption of the continuity of the arch of the aorta.


Polylysine crosslinked AIE dye based fluorescent organic nanoparticles for biological imaging applications.
Fluorescent organic nanoparticles based on aggregation induced emission dyes are fabricated through a ring-opening reaction using polylysine as the linker. The fluorescent organic nanoparticles obtained are characterized by a series of techniques including UV-vis absorption spectroscopy, fluorescence spectroscopy, Fourier Transform infrared spectroscopy, and transmission electron microscopy. A biocompatibility evaluation and the cell uptake behavior of the fluorescent organic nanoparticles are further investigated to evaluate their potential biomedical applications. It is demonstrated that these fluorescent organic nanoparticles can be obtained at room temperature in an air atmosphere without the need for catalyst or initiator. Furthermore, these crosslinked aggregation induced emission dye based fluorescent organic nanoparticles show uniform morphology, strong red fluorescence, high water dispersability, and excellent biocompatibility, making them promising candidates for various biomedical applications.


Ferroptosis-Related Flavoproteins: Their Function and Stability.
Ferroptosis has been described recently as an iron-dependent cell death driven by peroxidation of membrane lipids. It is involved in the pathogenesis of a number of diverse diseases. From the other side, the induction of ferroptosis can be used to kill tumor cells as a novel therapeutic approach. Because of the broad clinical relevance, a comprehensive understanding of the ferroptosis-controlling protein network is necessary. Noteworthy, several proteins from this network are flavoenzymes. This review is an attempt to present the ferroptosis-related flavoproteins in light of their involvement in anti-ferroptotic and pro-ferroptotic roles. When available, the data on the structural stability of mutants and cofactor-free apoenzymes are discussed. The stability of the flavoproteins could be an important component of the cellular death processes.


Co-morbidity and age-related prevalence of psoriasis: Analysis of health insurance data in Germany.
Epidemiological studies indicate an increased risk of co-morbidities and an association with other inflammatory diseases in psoriasis. However, most analyses have been performed on small samples of patients. The aim of this study was to evaluate the prevalence of co-morbidities in psoriasis based on a large set of health insurance data. The database of 1.3 million patients in a German nationwide statutory health insurance scheme was analysed. Data-sets of patients with confirmed psoriasis were extracted and analysed for co-morbidities. Of 1,344,071 subjects, 33,981 had a diagnosis of psoriasis (prevalence 2.5%). Metabolic syndrome was 2.9-fold more frequent among these patients. The most common diagnoses were arterial hypertension (35.6% in psoriasis vs. 20.6% in controls) and hyperlipidaemia (29.9% vs. 17.1%). The frequencies of rheumatoid arthritis (prevalence ratio (PR) 3.8), Crohn's disease (PR 2.1) and ulcerative colitis (PR 2.0) were also increased among patients with psoriasis. In conclusion, psoriasis is associated with significant co-morbidities that imply an elevated risk of severe complications.


Modulating the antitumor immunity of MBT-2 murine bladder tumor bearing mice by postoperative administration of interferon-alpha.
This study was conducted mainly to investigate the effect of interferon-alpha (IFN-alpha) on the antitumor immunity of a tumor bearing host (TBH) when postoperatively administrated with or without lethally irradiated autologous tumor cells. Using the C3H/He-MBT-2 murine bladder tumor model, a status of postoperative residual tumor was mimicked by rechallenging tumor cells 24 hours after resecting the day-17 tumor. Using immunohistochemical analysis we demonstrated that after treating with lethally irradiated MBT-2 tumor cells (IRMBT-2) + IL-2 cells of CD4+, CD8+, CD44+ and CD11b+ phenotypes prominently infiltrate the subcutaneous local injection sites. In contrast, only scanty immune responding cells could be seen locally if treated with IRMBT-2 + IFN-alpha 2b, albeit in the presence of interleukin-2 (IL-2). However, the spleens of D17TBM treated with IRMBT-2 + IFN-alpha 2b contained the highest percentage of CD44+ memory T cells and cells of the CD11b+ phenotype; moreover, their natural killer (NK), lymphokine activated killer (LAK) and cytotoxic T lymphocytes (CTL) activities were significantly augmented. The results of in vivo tumor rechallenge revealed that administration of IFN-alpha, either alone or combined with IRMBT-2, could both effectively suppress the outgrowth of perioperative rechallenged tumor cells as well as prolong the survival of TBH. We conclude that despite the presence of autologous tumor vaccine, postoperative administration of IFN-alpha can further enhance the antitumor immunity of TBH and therefore can be an effective adjuvant therapy to improve the therapeutic results of surgery on a tumor bearing host.


UMONS-TAICHI: A multimodal motion capture dataset of expertise in Taijiquan gestures.
In this article, we present a large 3D motion capture dataset of Taijiquan martial art gestures (n = 2200 samples) that includes 13 classes (relative to Taijiquan techniques) executed by 12 participants of various skill levels. Participants levels were ranked by three experts on a scale of [0-10]. The dataset was captured using two motion capture systems simultaneously: 1) Qualisys, a sophisticated optical motion capture system of 11 cameras that tracks 68 retroreflective markers at 179 Hz, and 2) Microsoft Kinect V2, a low-cost markerless time-of-flight depth sensor that tracks 25 locations of a person׳s skeleton at 30 Hz. Data from both systems were synchronized manually. Qualisys data were manually corrected, and then processed to complete any missing data. Data were also manually annotated for segmentation. Both segmented and unsegmented data are provided in this dataset. This article details the recording protocol as well as the processing and annotation procedures. The data were initially recorded for gesture recognition and skill evaluation, but they are also suited for research on synthesis, segmentation, multi-sensor data comparison and fusion, sports science or more general research on human science or motion capture. A preliminary analysis has been conducted by Tits et al. (2017) [1] on a part of the dataset to extract morphology-independent motion features for skill evaluation. Results of this analysis are presented in their communication: "Morphology Independent Feature Engineering in Motion Capture Database for Gesture Evaluation" (10.1145/3077981.3078037) [1]. Data are available for research purpose (license CC BY-NC-SA 4.0), at https://github.com/numediart/UMONS-TAICHI.


Mean annual attachment, bone level, and tooth loss: A systematic review.
Rate of progression of periodontitis has been used to inform the design of classifications of periodontal diseases. However, the evidence underpinning this topic is unclear and no systematic review has yet been conducted. The focused question for this systematic review was: in adults, what is the progression of periodontitis in terms of clinical attachment loss, radiographic bone loss, and tooth loss? Highly sensitive electronic search was conducted for published data in MEDLINE, EMBASE, LILACS, and unpublished grey literature in OpenGrey up to February 2016. Reference lists of retrieved studies for full-text screening and reviews were hand-searched for potentially eligible studies. Prospective, longitudinal observational studies with follow-up of at least 12 months and presenting data on the primary outcome, change in clinical attachment level, in adults (age ≥18 years). Secondary outcomes, tooth loss and bone level change, were only assessed in studies reporting the primary outcome. Studies investigating specific disease populations or only on treated periodontitis patients were excluded. Risk of bias and methodology were assessed using the Newcastle-Ottawa Scale with two additional questions on security of outcome assessment. Studies were pooled by abstracting or estimating mean annual attachment or bone level change and annual tooth loss. Random effects meta-analysis was conducted with investigation of effect of potential modifiers where possible. A total 11,482 records were screened for eligibility; 33 publications of 16 original studies reporting on more than 8,600 participants were finally included as eligible for the review. The studies represented populations from both developing and developed economies. Mean annual attachment loss was 0.1 mm per year (95% CI 0.068, 0.132; I2 = 99%) and mean annual tooth loss was 0.2 teeth per year (95% CI 0.10, 0.33; I2 = 94%). Observational analysis of highest and lowest mean attachment change quintiles suggested substantial differences between groups with minimal annual change in the lowest quintile and an average deterioration of 0.45 mm mean attachment loss per year in the highest group. This value increased to 0.6 mm per year with periodontitis alone. There was surprisingly little effect of age or gender on attachment level change. Geographic location, however, was associated with more than three times higher mean annual attachment loss in Sri Lanka and China (0.20 mm, 95% CI 0.15, 0.27; I2 = 83%) vs North America and Europe (0.056 mm, 95% CI 0.025, 0.087; I2 = 99%) P < 0.001. There were a limited number of studies (N = 16), high variability of design in key study components (sampling frames, included ages, data analyses), and high statistical heterogeneity that could not be explained. Within the limitations of the research, the data show that mean annual attachment level change varies considerably both within and between populations. Overall, the evidence does not support or refute the differentiation between forms of periodontal diseases based upon progression of attachment level change.


Surgery for impotence.
The role of surgery in the treatment of impotence has greatly increased during the last 5 years. The recognition and surgical correction of those mechanical derangements of the penis that prevent coitus have enabled many men to resume or commence intercourse. Men with irreversible impotence usually find it possible to resume coitus following the insertion of a Silastic penile prosthesis. The need to diagnose organic impotence has in turn stimulated the development of new diagnostic techniques and these have increased our knowledge of the pathophysiology of erectile function.


Associations of Birth Order with Early Adolescent Growth, Pubertal Onset, Blood Pressure and Size: Evidence from Hong Kong's "Children of 1997" Birth Cohort.
Birth order has been proposed as a cardiovascular risk factor, because the lower birth weight and greater infant weight gain typical of firstborns could programme metabolism detrimentally. We examined the associations of birth order (firstborn or laterborn) with birth weight-for-gestational age, length/height and body mass index (BMI) z-scores during infancy, childhood, and puberty using generalized estimating equations, with age at pubertal onset using interval-censored regression and with age-, sex- and height-standardized blood pressure, height and BMI z-scores at 13 years using linear regression in a population-representative Chinese birth cohort: "Children of 1997" (n = 8,327). Compared with laterborns, firstborns had lower birth weight-for-gestational age (mean difference = -0.18 z-score, 95% confidence interval (CI) -0.23, -0.14), lower infant BMI (-0.09 z-score, 95% CI -0.14, -0.04), greater childhood height (0.10 z-score, 95% CI 0.05, 0.14) and BMI (0.08 z-score, 95% CI 0.03, 0.14), but not greater pubertal BMI (0.05 z-score, 95% CI -0.02, 0.11), adjusted for sex, parental age, birthplace, education and income. Firstborns had earlier onset of pubic hair (time ratio = 0.988, 95% CI 0.980, 0.996), but not breast or genitalia, development. Firstborns had greater BMI (0.07 z-score, 95% CI 0.002, 0.15), but not height (0.05 z-score, 95% CI -0.01, 0.11), at 13 years, but similar blood pressure. Differences by birth order continue into early adolescence with firstborns being heavier with earlier pubic hair development, which could indicate long-term cardiovascular risk.


Heat-related mortality at the beginning of the twenty-first century in Rio de Janeiro, Brazil.
Temperature record-breaking events, such as the observed more intense, longer-lasting, and more frequent heat waves, pose a new global challenge to health sectors worldwide. These threats are of particular interest in low-income regions with limited investments in public health and a growing urban population, such as Brazil. Here, we apply a comprehensive interdisciplinary climate-health approach, including meteorological data and a daily mortality record from the Brazilian Health System from 2000 to 2015, covering 21 cities over the Metropolitan Region of Rio de Janeiro. The percentage of absolute mortality increase due to summer extreme temperatures is estimated using a negative binomial regression modeling approach and maximum/minimum temperature-derived indexes as covariates. Moreover, this study assesses the vulnerability to thermal stress for different age groups and both genders and thoroughly analyzes four extremely intense heat waves during 2010 and 2012 regarding their impacts on the population. Results showed that the highest absolute mortality values during heat-related events were linked to circulatory illnesses. However, the highest excess of mortality was related to diabetes, particularly for women within the elderly age groups. Moreover, results indicate that accumulated heat stress conditions during consecutive days preferentially preceded by persistent periods of moderate-temperature, lead to higher excess mortality rather than sporadic single hot days. This work may provide directions in human health policies related to extreme climate events in large tropical metropolitan areas from developing countries, contributing to altering the historically based purely reactive response.


Multisensory stimulation for elderly with dementia: a 24-week single-blind randomized controlled pilot study.
Dementia in the elderly is a common, debilitating condition. Residents in long-term care facilities present with a number of challenging behaviors. Pharmacological management is not always helpful. Alternative approaches are needed. Multisensory stimulation (MSS) was developed to address sensory stimulation imbalance. In this pilot 24-week single-blinded, randomized controlled study, the authors examined the effect of MSS when given for 12 weeks in either 1 or 3 sessions per week with a control group. There is a trend for better outcomes as measured by daily observation scales (DOS) or Clinical Global Impression-Improvement (CGI-I) with the increase of sessions of treatment per week. This became statistically significant at weeks 8 (DOS) and 12 (CGI). This difference continued for 12 additional weeks after treatment ended. MSS may be a useful addition to the care of elderly patients with dementia. A larger double-blind randomized control study is required.


Sequential effects of root and foliar herbivory on aboveground and belowground induced plant defense responses and insect performance.
Plants are often simultaneously or sequentially attacked by multiple herbivores and changes in host plants induced by one herbivore can influence the performance of other herbivores. We examined how sequential feeding on the plant Plantago lanceolata by the aboveground herbivore Spodoptera exigua and the belowground herbivore Agriotes lineatus influences plant defense and the performance of both insects. Belowground herbivory caused a reduction in the food consumption by the aboveground herbivore independent of whether it was initiated before, at the same time, or after that of the aboveground herbivore. By contrast, aboveground herbivory did not significantly affect belowground herbivore performance, but significantly reduced the performance of later arriving aboveground conspecifics. Interestingly, belowground herbivores negated negative effects of aboveground herbivores on consumption efficiency of their later arriving conspecifics, but only if the belowground herbivores were introduced simultaneously with the early arriving aboveground herbivores. Aboveground-belowground interactions could only partly be explained by induced changes in an important class of defense compounds, iridoid glycosides (IGs). Belowground herbivory caused a reduction in IGs in roots without affecting shoot levels, while aboveground herbivory increased IG levels in roots in the short term (4 days) but only in the shoots in the longer term (17 days). We conclude that the sequence of aboveground and belowground herbivory is important in interactions between aboveground and belowground herbivores and that knowledge on the timing of exposure is essential to predict outcomes of aboveground-belowground interactions.


Continuous measurement of cerebral blood flow in anesthetized cats and dogs.
We have developed a method for virtually continuous measurement of changes in cerebral blood flow (CBF) in cats and dogs. CBF was computed by multiplying cross-sectional area (CSA) and mean blood velocity in a pial artery. CSA was determined by measuring pial artery diameter with an electronic micrometer every 2-4 s through a cranial window. Velocity was measured continuously with a pulsed Doppler crystal positioned under a pial artery. CBF was determined in 12 anesthetized cats during 1) control, 2) hypocapnia, 3) hypercapnia, and 4) hypercapnia plus hypertension. Microspheres were injected under steady-state conditions to compare the two methods. During control, the diameter of the cerebral arteries observed was 388 +/- 28 (SE) micrometers, and CBF measured with microspheres was 40 +/- 4 ml.min-1.100 g-1. CBF decreased 18 +/- 2% during hypocapnia and increased 152 +/- 36% during hypercapnia. During steady-state conditions, the correlation coefficient between changes in CBF (CSA X velocity and microspheres) was 0.94, and the slope of the regression line was 1.02. In similar studies on seven anesthetized dogs, the correlation coefficient between CSA X velocity and microspheres was 0.98, and the slope of the regression line was 0.94. We conclude that the product of CSA and blood velocity of a pial artery provides accurate on-line measurement of changes in CBF.


Diagnostic Accuracy of a Host Gene Expression Signature That Discriminates Clinical Severe Sepsis Syndrome and Infection-Negative Systemic Inflammation Among Critically Ill Children.
SeptiCyte Lab (Immunexpress, Seattle, WA), a molecular signature measuring the relative expression levels of four host messenger RNAs, was developed to discriminate critically ill adults with infection-positive versus infection-negative systemic inflammation. The objective was to assess the performance of Septicyte Lab in critically ill pediatric patients. Prospective observational study. Pediatric and Cardiac ICUs, Seattle Children's Hospital, Seattle, WA. A cohort of 40 children with clinically overt severe sepsis syndrome and 30 children immediately postcardiopulmonary bypass surgery was recruited. The clinically overt severe sepsis syndrome children had confirmed or highly suspected infection (microbial culture orders, antimicrobial prescription), two or more systemic inflammatory response syndrome criteria (including temperature and leukocyte criteria), and at least cardiovascular ± pulmonary organ dysfunction. None (observational study only). Next-generation RNA sequencing was conducted on PAXgene blood RNA samples, successfully for 35 of 40 (87.5%) of the clinically overt severe sepsis syndrome patients and 29 of 30 (96.7%) of the postcardiopulmonary bypass patients. Forty patient samples (~ 60% of cohort) were reanalyzed by reverse transcription-quantitative polymerase chain reaction, to check for concordance with next-generation sequencing results. Postcardiopulmonary bypass versus clinically overt severe sepsis syndrome descriptors included the following: age, 7.3 ± 5.5 versus 9.0 ± 6.6 years; gender, 41% versus 49% male; Pediatric Risk of Mortality, version III, 7.0 ± 4.6 versus 8.7 ± 6.4; Pediatric Logistic Organ Dysfunction, version II, 5.1 ± 2.2 versus 4.8 ± 2.8. SeptiCyte Lab strongly differentiated postcardiopulmonary bypass and clinically overt severe sepsis syndrome patients by receiver operating characteristic curve analysis, with an area-under-curve value of 0.99 (95% CI, 0.96-1.00). Equivalent performance was found using reverse transcription-quantitative polymerase chain reaction. There was no significant correlation between the score produced by the SeptiCyte Lab test and measures of illness severity, immune compromise, or microbial culture status. SeptiCyte Lab is able to discriminate clearly between clinically well-defined and homogeneous postcardiopulmonary bypass and clinically overt severe sepsis syndrome groups in children. A broader investigation among children with more heterogeneous inflammation-associated diagnoses and care settings is warranted.


Randomized trial assessing the effectiveness of a pharmacist-delivered program for smoking cessation.
As trained and accessible healthcare professionals, pharmacists are in an ideal position to provide tobacco cessation interventions. Of the 15 studies identified in the literature assessing the effectiveness of tobacco cessation interventions delivered by pharmacists, this is the first randomized controlled trial conducted in the US of a pharmacist-delivered program for smoking cessation using biochemical confirmation. To assess the effectiveness on smoking cessation of a face-to-face group program conducted by the pharmacist team compared with a brief standard care session delivered by a pharmacist over the telephone. An open-label, prospective, randomized, controlled trial was conducted at a Veterans Health Administration, community-based outpatient clinic in the Rocky Mountain region. Participants were randomly assigned to receive a 3-session face-to-face group program conducted by the pharmacist team or one 5- to 10-minute standard care session delivered by the pharmacist team over the telephone. Participants in both groups were offered either immediate-release bupropion or nicotine patch at no cost. The primary outcome of self-reported abstinence was biochemically confirmed by urinary cotinine at 6 months after the quit date. One hundred one smokers were randomized from October 3, 2005, to March 30, 2007, with the last 6-month follow-up survey completed on November 6, 2007. Analysis of data was completed in December 2007. Using intent-to-treat procedures, confirmed abstinence rates at the end of 6 months were 28% in the pharmacist-delivered face-to-face treatment group and 11.8% in the standard care telephone session control group (p < 0.041). This study demonstrates that pharmacists are effective providers of tobacco cessation interventions. Greater utilization of pharmacists in tobacco cessation efforts could have a significant impact on smoking rates, prevention of tobacco-related diseases, and overall improvement in public health across the US.


Choline Supplementation During Pregnancy Protects Against Gestational Lipopolysaccharide-Induced Inflammatory Responses.
To estimate the effects and mechanisms of choline, an essential nutrient and a selective α7 nicotinic acetylcholine receptor (α7nAChR) agonist, on the prevention of symptoms and the effects on the cholinergic anti-inflammatory pathways (CAP) in a lipopolysaccharide (LPS)-induced inflammatory response in a rat model. Inflammation was induced by LPS treatment (1.0 μg LPS/kg body weight) on gestational day (GD) 14. Nonpregnant and pregnant Sprague Dawley rats were placed on a normal choline diet (1.1 g/kg) or supplemented choline diet (5.0 g/kg) from GDs 1 to 20. Systolic blood pressure (SBP), urinary albumin, and pregnancy outcomes were recorded. On GD 20, serum and placentas were assayed for cytokines. Western blots were used to determine the expression of placenta α7nAChR and components of the α7nAChR-CAP, including nuclear factor-κB (NF-κB) and protein kinase B (AKT). Immunohistochemistry was used to localize placental sites for the p65 subunit of NF-κB. Lipopolysaccharide significantly increased SBP and urinary albumin and decreased pregnancy outcomes, and these effects were partially reversed by higher choline treatment. Choline supplementation also significantly attenuated the LPS-induced increase in serum and placental inflammatory cytokines, decreased the expression of placental α7nAChR, lowered the activation of NF-κB signaling in placenta mononuclear cells, and inhibited placental AKT phosphorylation. This study confirms that LPS induces inflammatory conditions in pregnant rats and shows that choline supplementation protects against the inflammatory symptoms through its action on α7nAChR and CAP. These observations have important implications for the prevention and treatment of inflammatory responses associated with pregnancy.


[Usefulness of fresh wet mount examination in the diagnosis of vaginal candidiasis].
A prospective study was done at the Clinic for Sexually Transmitted Diseases of the Department of Infectology, Instituto Nacional de Perinatología, Mexico City, in order to validate the fresh wet mount examination as a confirmatory test for vaginal candidiasis. Ninety six patients with cervico-vaginal infection were included, 22 of them had clinical candidiasis (22.9%). The fresh wet mount examination showed the presence of yeast and/or pseudomycelium in all 2 samples (100%). The presence of Candida in the cultures was confirmed in 18 of the 22 specimens (81.8). Negative in 71/96 (73.9%) (Three cultures were not processed). The fresh wet mount examination had a sensitivity of 100% and a specificity of 94.8%. The positive predictive value was 88.8% while the negative predictive value was 100%. It can be concluded that the fresh wet mount examination is very recommendable, useful, economic and easy to practice at the physician's office for the confirmation of vaginal candidiasis.


Socio-economic burden of rare diseases: A systematic review of cost of illness evidence.
Cost-of-illness studies, the systematic quantification of the economic burden of diseases on the individual and on society, help illustrate direct budgetary consequences of diseases in the health system and indirect costs associated with patient or carer productivity losses. In the context of the BURQOL-RD project ("Social Economic Burden and Health-Related Quality of Life in patients with Rare Diseases in Europe") we studied the evidence on direct and indirect costs for 10 rare diseases (Cystic Fibrosis [CF], Duchenne Muscular Dystrophy [DMD], Fragile X Syndrome [FXS], Haemophilia, Juvenile Idiopathic Arthritis [JIA], Mucopolysaccharidosis [MPS], Scleroderma [SCL], Prader-Willi Syndrome [PWS], Histiocytosis [HIS] and Epidermolysis Bullosa [EB]). A systematic literature review of cost of illness studies was conducted using a keyword strategy in combination with the names of the 10 selected rare diseases. Available disease prevalence in Europe was found to range between 1 and 2 per 100,000 population (PWS, a sub-type of Histiocytosis, and EB) up to 42 per 100,000 population (Scleroderma). Overall, cost evidence on rare diseases appears to be very scarce (a total of 77 studies were identified across all diseases), with CF (n=29) and Haemophilia (n=22) being relatively well studied, compared to the other conditions, where very limited cost of illness information was available. In terms of data availability, total lifetime cost figures were found only across four diseases, and total annual costs (including indirect costs) across five diseases. Overall, data availability was found to correlate with the existence of a pharmaceutical treatment and indirect costs tended to account for a significant proportion of total costs. Although methodological variations prevent any detailed comparison between conditions and based on the evidence available, most of the rare diseases examined are associated with significant economic burden, both direct and indirect.


High-Q whispering gallery traveling wave resonators for oscillator frequency stabilization.
Usually a frequency-stabilized standing wave resonator-oscillator incorporating a resonator as a frequency discriminator requires a circulator to separate the injected and reflected wave, A ferrite circulator is a noisy device and can limit the phase noise or frequency stability. Moreover, we show that the noise in a circulator varies, and detailed low noise measurements are necessary to choose an appropriate quiet circulator. Thus, by realizing a configuration that does not require a circulator, an improvement in performance and reliability can be obtained. A solution to this problem is to design a high-Q whispering gallery traveling wave (WGTW) resonator. This device naturally separates the injected and reflected wave in the same way as a ring cavity at optical frequencies, without degrading the frequency discrimination. Q-factor measurements of a WGTW sapphire resonator are presented, along with a derivation of critical parameters to maximize the frequency discrimination. New measurements of noise in ferrite circulators and isolators have also been made, which is followed with a discussion on oscillator design.


Tunable two-dimensional photonic crystal couplers made of dielectric elastomer inclusions.
We propose a tunable directional coupler based on a two-dimensional photonic crystal made of dielectric elastomer rods embedded in air background. In the interaction region, the inclusions are a dielectric elastomer cylindrical actuator made of a hollow cylinder sandwiched between two compliant electrodes. By applying a voltage between the compliant electrodes, the radial strain of the silicon-made actuator and the coupling characteristics of the photonic crystal coupler are investigated. The coupling length of the photonic crystal coupler depends on the voltage applied between the electrodes, which is analyzed by the plane wave expansion method. Due to the radial strain of the dielectric elastomer under external voltage, the tunable photonic crystal coupler is realized. Numerical simulations obtained by the finite-difference time-domain method confirmed the feasibility of the tunable photonic crystal coupler.