Mid-ocean ridges: discontinuities, segments and giant cracks.
Geological observations reveal that mid-ocean ridges are segmented by numerous rigid and nonrigid discontinuities. A hierarchy of segmentation, ranging from large, long-lived segments to others that are small, migratory, and transient, determines the pattern and timing of creation of new ocean floor. To the extent that spreading segments behave like giant cracks in a plate, the crack propagation force at segment tips increases with segment length, which may explain why long segments tend to lengthen and prevail over shorter neighboring segments. Partial melting caused by decompression of the upper mantle due to plate separation and changes in the direction of spreading result in the spawning of new short segments so that a balance of long and short segments is maintained.


Assessment of time to clinical response, a proxy for discharge readiness, among hospitalized patients with community-acquired pneumonia who received either ceftaroline fosamil or ceftriaxone in two phase III FOCUS trials.
The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n=562; ceftriaxone, n=554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria (P=0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P=0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.).


Histopathological lesions and DNA adducts in the liver of European flounder (Platichthys flesus) collected in the Seine estuary versus two reference estuarine systems on the French Atlantic coast.
An epidemiological survey was conducted in the Seine estuary and in two smaller and relatively preserved estuaries on the French Atlantic coast in order to estimate the occurrence of liver lesions in European flounder, Platichthys flesus, and also to seek putative risk factors for the recorded pathologies. Four hundred and seventy-eight fish of both sexes and of different size ranges were sampled in the three studied areas, 338 of which in the Seine estuary. All fish were examined for histopathological liver lesions, while DNA adducts and otoliths were analyzed on a subsample. Five categories of hepatic lesions were recorded with the following prevalence for the Seine estuary: 36.7 % inflammations, 8 % parasites (mainly encysted nematodes), 6.5 % foci of cellular alteration (FCA), 5.3 % foci of necrosis or regeneration (FNR), and 1.5 % tumors. Inflammation occurrence increased according to age, contrary to parasitic infestations and FCA which were more prevalent in young fish, notably those of <1 year old (group 0). Tumors were only observed in females of more than two winters. Females exhibited a higher prevalence of tumors (3.0 %) and FCA (6.5 %) than males (0 and 2.6 %, respectively). Parasitic and infectious lesions and FNR were equally distributed in males and females. The prevalence of FNR was also shown to vary according to sampling season, with significantly more occurrences of liver necrosis in the fish collected in summer than in spring. Spatial differences were observed with a higher occurrence of encysted parasites in flounders from the upper Seine estuary, while inflammations predominated in flounders living downstream. Temporal trends were also noted, with an increased prevalence of parasitic infestations, inflammations, and FCA in the 2002-2003 period in comparison to the 1996-1997 one. The three flounder populations from the Seine estuary (Normandy), Ster estuary (Brittany), and Bay of Veys (Normandy) showed different spectra of hepatic lesions. Flounders from the Bay of Veys had relatively few liver lesions as compared to flounders from the two other estuaries. Flounders from the Ster estuary exhibited the highest prevalence of parasites (37.2 %) and inflammations (51.1 %). Finally, FCA and liver tumors occurred at very similar levels in both flounder populations from the Seine and the Ster estuaries. Group 0 flounders inhabiting the upper Seine estuary were more prone to parasitic and pre-neoplastic hepatic lesions and had higher levels of liver DNA adducts than the older ones living downstream. It was postulated that group 0 European flounders may serve as valuable bioindicators for assessing the quality of estuarine waters and the health status of euryhaline fish populations.


A mandible from the Middle Pleistocene Hexian site and its significance in relation to the variability of Asian Homo erectus.
This study presents the first detailed morphological description and comparison of a Middle Pleistocene hominin mandibular fragment (PA 831) and associated teeth from the Hexian site in Eastern China. We aim to investigate where the Hexian mandible fits within the genus Homo variability in the light of an increased and better characterized Asian fossils record. Comparative samples include Pleistocene Homo mandibles and teeth from Africa, Asia, and Europe, as well as earlier African hominins (Australopithecus and early Homo) and Holocene recent humans. Both conventional morphological description and metric analysis were used. In addition, virtual reconstructions of the enamel dentine junction (EDJ) surface, pulp cavity, and roots with micro-CT were used to the mandible and teeth. The Hexian mandible is characterized by a plesiomorphic structural pattern for the Homo clade, with strong corpus robustness and a subparallel and low-positioned mylohyoid line that differentiates the swollen subalveolar planum from the shallow subalveolar fossa. Features that are derived compared to early Homo include a moderately curved dental arcade, a well-developed lateral prominence placed at the M2 -M3 level, and multiple mental foramina. The Hexian mandible's complex enamel surface and strong, stout root structure are primitive traits for the Homo clade. Finally, the highly crenulated "dendrite-like" EDJ found in the molars may represent a dental feature specific to the continental Asian Homo erectus, but more data is needed to confirm this. Mandibular and dental features indicate that the Hexian mandible and teeth differ from northern Chinese H. erectus and European Middle Pleistocene hominins, but show some affinities with the Early Pleistocene specimens from Africa (Homo ergaster) and Java (H. erectus), as well as the Middle-Late Pleistocene mandible from Penghu, Taiwan. Compared to contemporaneous continental Asian hominin populations, the Hexian fossils may represent the survival of a primitive hominin, with more primitive morphologies than other contemporaneous or some chronologically older Asian hominin specimens.


Inhibitory antimicrobial concentrations against Campylobacter pylori in gastric mucosa.
Gastric mucosal concentrations of erythromycin, amoxycillin, ampicillin and ciprofloxacin were determined in patients at upper gastrointestinal endoscopy 38-480 min after a 500 mg dose of erythromycin ethyl succinate, erythromycin stearate, amoxycillin, pivampicillin or ciprofloxacin. All the agents attained concentrations greater than the MIC 90 for Campylobacter pylori. The macrolides attained the lowest concentrations. There was no significant difference between concentrations attained with erythromycin ethyl succinate and stearate. High concentrations were attained by amoxycillin (range 14.6-322 mg/kg) and pivampicillin (range 47.5-209 mg/kg). Ciprofloxacin attained very high concentrations (range 35-1762 mg/kg); inhibitory concentrations 35 mg/kg) were still present at 6 h after the dose. Ciprofloxacin and erythromycin are ineffective in vivo despite these high gastric mucosal concentrations. Penetration into the gastric mucus and crypts where C. pylori is found will be determined by physicochemical properties of the antimicrobials, such as pKa, stability, activity over a wide range of pH, and lipid solubility.


Severe malnutrition with and without HIV-1 infection in hospitalised children in Kampala, Uganda: differences in clinical features, haematological findings and CD4+ cell counts.
The aim of this study was to describe the clinical features, haematological findings and CD4+ and CD8+ cell counts of severely malnourished children in relation to human immunodeficiency virus (HIV) infection. The study was conducted in the paediatric wards of Mulago hospital, which is Uganda's national referral and teaching hospital. We studied 315 severely malnourished children (presence of oedema and/or weight-for-height: z-score < -3) and have presented our findings. At admission, the CD4+ and CD8+ cells were measured by the flow cytometry and HIV serology was confirmed by Enzyme linked Immunoassay for children >18 months of age, and RNA PCR was performed for those < or =18 months. Complete blood count, including differential counts, was determined using a Beckman Coulter counter. Among the 315 children, 119 (38%) were female; the median age of these children was 17 months (Interquartile range 12-24 months), and no difference was observed in the HIV status with regard to gender or age. The children showed a high prevalence of infections: pneumonia (68%), diarrhoea (38%), urinary tract infection (26%) and bacteraemia (18%), with no significant difference with regard to the HIV status (HIV-positive versus HIV-negative children). However, the HIV-positive children were more likely to have persistent diarrhoea than the HIV-uninfected severely malnourished children (odds ratio (OR) 2.0, 95% confidence interval (CI) 1.2-3.6). When compared with the HIV-negative children, the HIV-positive children showed a significantly lower median white blood cell count (10700 versus 8700) and lymphocyte count (4033 versus 2687). The CD4+ cell percentages were more likely to be lower in children with non-oedematous malnutrition than in those with oedematous malnutrition even after controlling for the HIV infection. The novel observation of this study is that the CD4+ percentages in both HIV-positive and HIV-negative children without oedema were lower that those in children with oedema. These observations appear to imply that the development of oedema requires a certain degree of immunocompetence, which is an interesting clue to the pathophysiology of oedema in severe malnutrition.


Neonatal outcomes in relation to sex differences: a national cohort survey in Taiwan.
An extensive assessment investigating the association between sex differences and neonatal outcomes is lacking. In the current study, we estimated the correlation of gender with adverse birth outcomes in a large cohort population. National population-based data containing maternal and neonatal information in 2001 to 2010 were derived from the Health Promotion Administration, Taiwan. Singletons without high-risk pregnancy were further analyzed for the sex ratio of live births in relation to neonatal outcomes-including preterm birth, birth weight, neonatal death, delivery mode, and congenital anomaly. A multivariate logistic regression model was used to adjust for possible confounders. In total, 2,123,100 births were valid for the analysis. Overall, the sex ratio at birth (male/female) was 1.096. Compared to multiple births, the sex ratio was significantly higher with singleton births (p < 0.001). Among multiple births, the incidence of stillbirths was significantly higher in males than in females (p < 0.05). The sex ratio at gestational age (GA) <37 weeks was 1.332, and it declined proportionally with a rise in the GA to 0.899 at GA of ≥41 weeks. In contrast, the sex ratio was 0.850 at birth weight <3000 g, and it rose proportionally with a rise in the birth weight to 1.902 at birth weight ≥4000 g (macrosomia). Operative delivery was more common in males than in females (p < 0.001). The regression analysis showed greater risks of preterm birth, macrosomia, operative delivery, neonatal death, and congenital anomaly among male newborns. Male gender carried higher risks of adverse neonatal outcomes, including preterm birth, macrosomia, operative delivery, neonatal death, and congenital anomaly. The data have clinical implications on health surveillance for plotting strategies in response to the unbalanced sex ratio in relation to the boy preference.


Curriculum to enhance pharmacotherapeutic knowledge in family medicine: interprofessional coteaching and web-based learning.
Prescribing is an essential skill for physicians. Despite the fact that prescribing habits are still developing in residency, formal pharmacotherapy curricula are not commonplace in postgraduate programs. To teach first-year and second-year family medicine residents a systematic prescribing process using a medication prescribing framework, which could be replicated and distributed. A hybrid model of Web-based (www.rationalprescribing.com) and in-class seminar learning was used. Web-based modules, consisting of foundational pharmacotherapeutic content, were each followed by an in-class session, which involved applying content to case studies. A physician and a pharmacist were coteachers and they used simulated cases to enhance application of pharmacotherapeutic content and modeled interprofessional collaboration. This systematic approach to prescribing was well received by family medicine residents. It might be important to introduce the process in the undergraduate curriculum-when learners are building their therapeutic foundational knowledge. Incorporating formal pharmacotherapeutic curriculum into residency teaching is challenging and requires further study to identify potential effects on prescribing habits.


Cataracts produced in rats by yogurt.
Rats kept on an exclusive diet of yogurt avidly ate the yogurt, grew at a normal rate, were normally active, mated, conceived, and gave birth to normal, healthy litters. However, all of the rats developed cataracts. Cataracts appeared in young rats 2 to 3 months, and in adult rats 4 to 6 months, after initiation of the yogurt diet. Cataracts first manifested themselves in small vacuoles at the periphery of the lens and then in small striae extending toward the center of the lens. These striae progressively became longer, more coarse, and numerous until they coalesced, finally forming a mature white lens. The high content of galactose in commercially available yogurt could account in full for appearance of cataracts in 100 percent of the experimental animals. The cataracts appear to be the same as those produced by diets with a high content of galactose.


Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer's disease.
Alzheimer's disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer's and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer's disease, we found significantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer's pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine β-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2(-/-) mice and, unlike in Sstr1(-/-) or Sstr4(-/-) genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (<8 months) in Sstr2(-/-) mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer's disease.


Effects of chronic exposure of electromagnetic fields from mobile phones on hearing in rats.
Little attention has been paid to the effects of electromagnetic field (EMF) of mobile phones on hearing. The aim of this study is to investigate the effects of chronic exposure to EMF emitting from mobile phones on the inner ear of adult and developing rats using distortion product otoacoustic emissions (DPOAEs). EMF of mobile phones exposure was scheduled according to a sham-exposure controlled experimental design. Every day seven of 14 adult and four newborn rats were exposed to 1-h mobile phone EMF for 30 days, while the other seven adult rats were assigned to control group. DPOAEs were measured in both groups before and after the chronic exposure to EMF. The newborn rats were tested following similar exposure beginning on the 2nd day after birth. No measurable EMF associated changes in DPOAEs either in adult or developing rat inner ears were determined (P>0.05). It was concluded that chronic exposure of EMF, as long as 30 days 1 h per day, emitting from a mobile phone did not cause any hearing deterioration in adult and developing rats, at least at outer and middle ear and cochlear levels.


Rhizobium leguminosarum bv. trifolii PssP protein is required for exopolysaccharide biosynthesis and polymerization.
Rhizobium leguminosarum bv. trifolii produces an acidic exopolysaccharide (EPS) that is important for the induction of nitrogen-fixing nodules on clover. Recently, three genes, pssN, pssO, and pssP, possibly involved in EPS biosynthesis and polymerization were identified. The predicted protein product of the pssP gene shows a significant sequence similarity to other proteins belonging to the PCP2a family that are involved in the synthesis of high-molecular-weight EPS. An R. leguminosarum bv. trifolii TA1 mutant with the entire coding region of pssP deleted did not produce the EPS. A pssP mutant with the 5' end of the gene disrupted produced exclusively low-molecular-weight EPS. A mutant that synthesized a functional N-terminal periplasmic domain but lacked the C-terminal part of PssP produced significantly reduced amounts of EPS with a slightly changed low to high molecular form ratio. Mutants affected in the PssP protein carrying a stable plasmid with a constitutively expressed gusA gene induced nodules on red clover that were not fully occupied by bacteria. A mutant with the entire pssP gene deleted infected only a few plant cells in the nodule. The pssP promoter-gusA reporter fusion was active in bacteroids during nodule development.


Does tool use extend peripersonal space? A review and re-analysis.
The fascinating idea that tools become extensions of our body appears in artistic, literary, philosophical, and scientific works alike. In the last 15 years, this idea has been reframed into several related hypotheses, one of which states that tool use extends the neural representation of the multisensory space immediately surrounding the hands (variously termed peripersonal space, peri-hand space, peri-cutaneous space, action space, or near space). This and related hypotheses have been tested extensively in the cognitive neurosciences, with evidence from molecular, neurophysiological, neuroimaging, neuropsychological, and behavioural fields. Here, I briefly review the evidence for and against the hypothesis that tool use extends a neural representation of the space surrounding the hand, concentrating on neurophysiological, neuropsychological, and behavioural evidence. I then provide a re-analysis of data from six published and one unpublished experiments using the crossmodal congruency task to test this hypothesis. While the re-analysis broadly confirms the previously reported finding that tool use does not literally extend peripersonal space, the overall effect sizes are small and statistical power is low. I conclude by questioning whether the crossmodal congruency task can indeed be used to test the hypothesis that tool use modifies peripersonal space.


Transiently beneficial insertions could maintain mobile DNA sequences in variable environments.
The maintenance of mobile DNA sequences in clonal organisms has been seen as a paradox. If selfish mobile sequences spread through genomes only by overreplication in transposition, then sexuality is necessary for their spread through populations. The persistence of bacterial transposable elements without obvious dominant selectable markers has previously been explained by horizontal transfer. However, advantageous insertions of mobile DNAs are known in bacteria. Here we model maintenance of an otherwise selfish mobile DNA element in a clonal species in which selection for null mutations occurs during one of two temporally alternating environments. Large areas of parameter space permit maintenance of mobile DNAs where, without selection, they would have gone extinct. Horizontal transfer diminishes, rather than enhances, mean copy number. In finite populations, effective population sizes are greatly reduced by selective sweeps, and mean copy number can be increased as the reduced variance in copy number results in reduced selection.


A practice-based intervention to improve primary care for falls, urinary incontinence, and dementia.
To determine whether a practice-based intervention can improve care for falls, urinary incontinence, and cognitive impairment. Controlled trial. Two community medical groups. Community-dwelling patients (357 at intervention sites and 287 at control sites) aged 75 and older identified as having difficulty with falls, incontinence, or cognitive impairment. Intervention and control practices received condition case-finding, but only intervention practices received a multicomponent practice-change intervention. Percentage of quality indicators satisfied measured using a 13-month medical record abstraction. Before the intervention, the quality of care was the same in intervention and control groups. Screening tripled the number of patients identified as needing care for falls, incontinence, or cognitive impairment. During the intervention, overall care for the three conditions was better in the intervention than the control group (41%, 95% confidence interval (CI)=35-46% vs 25%, 95% CI=20-30%, P<.001). Intervention group patients received better care for falls (44% vs 23%, P<.001) and incontinence (37% vs 22%, P<.001) but not for cognitive impairment (44% vs 41%, P=.67) than control group patients. The intervention was more effective for conditions identified by screening than for conditions identified through usual care. A practice-based intervention integrated into usual clinical care can improve primary care for falls and urinary incontinence, although even with the intervention, less than half of the recommended care for these conditions was provided. More-intensive interventions, such as embedding intervention components into an electronic medical record, will be needed to adequately improve care for falls and incontinence.


Ovarian transposition for stage Ib squamous cell cervical cancer - lack of effects on survival rates?
To investigate the impact of ovarian transposition (OT) on survival rates of the patients with stage Ib squamous cell cervical cancer. Ninety-two subjects who underwent a radical hysterectomy including oophorectomy were evaluated. For nineteen (20.7%) , OT was performed. Patients were divided into two groups, OT versus oophorectomy alone. The primary end-point of this study was to investigate the impact of OT on tumor recurrence rate and time, 5-year disease-free survival (DFS) and overall survival (OS) . These comparisons were performed for subgroups including patients who received radiotherapy versus who did not. Statistical analyses were conducted using the Chi-square test, T-test and Mann-Whitney test. OS was examined using the Kaplan-Meier method. P ≤ 0.05 was considered to be statistically significant. The median follow-up period was 89 months for OT and 81 months for the oophorectomy group (p>0.05). Both groups experienced similar recurrence rates (31.6% vs. 26.4%, p=0.181). The median duration from surgery to recurrence, and surgery to death were also similar between the groups (p>0.05). The 5-year DFS and OS rates were both 68.4% for the OT group, and 73.6% and 77.8% for the oophorectomy group (p=0.457 and p=0.307, respectively). While the 5-year DFS rate was not statistically significant between the OT and oophorectomy groups who did not receive radiotherapy (p=0.148), the 5-year OS rate was significantly higher in the oophorectomy group (95.4% vs 66.7%, respectively) without radiotherapy (p=0.05). The 5-year DFS and OS rates were statistically similar between the groups who received adjuvant radiotherapy (p>0.05). Ovarian transposition has not significantly negative effect on the survival rates when adjuvant radiotherapy will be applied, while 5-year OS may be less in OT group if radiotherapy is not mandatory.


Practice makes transfer of motor skills imperfect.
We investigated the practice-effects on motor skill transfer and the associated representational memory changes that occur during the within-practice and between-practice phases. In two experiments, participants produced extension-flexion movements with their dominant right arm for a limited or prolonged practice session arranged in either a single- or multi-session format. We tested the ability of participants to transfer the original pattern (extrinsic transformation) or the mirrored one (intrinsic transformation) to the non-dominant left arm, 10 min and 24 h after the practice sessions. Results showed that practice induces rapid motor skill improvements that are non-transferable irrespective of the amount of acquisition trials. Furthermore, the extrinsic component of the skill develops early and remains the dominant coding system during practice. Conversely, we found distinct between-practice memory changes: a limited practice induces an off-line development of the extrinsic component, whereas a prolonged practice session subserves the off-line development of the intrinsic component (experiment 2). We provided further evidence that the long-term representation of the motor skill also depends on the nature of the practice session itself: the parsing of practice into multiple sessions narrows the effector-transfer capacities in comparison to a single session (experiment 1). These findings yield theoretical and practical implications that are discussed in the context of recent motor skill learning models.


Pelvic pain and associated characteristics among women in northern Mexico.
Until recently, the reproductive health agenda has focused on a restricted number of morbidity indicators, particularly those associated with life-threatening diseases. However, gynecologic morbidities that are a source of pelvic pain, although not life-threatening, do impose a substantial burden because of their potential to reduce women's overall well-being. In 2005, a cross-sectional population-based study was conducted in Hermosillo, Mexico, to assess self- reported pelvic pain conditions in a random sample of 1,307 women aged 25-54. The 12-month prevalence of each condition was calculated, and logistic regression was used to assess the association between pelvic pain and social, demographic, anthropometric and reproductive characteristics, and other medical conditions. The 12-month prevalence of pelvic pain during menstruation among 1,007 menstruating women was 40%. Pelvic pain during or after sexual intercourse was reported by 12% of the 1,183 sexually active respondents. Among 1,201 nonpregnant women, 6% reported chronic pelvic pain. In adjusted analyses, younger age (25-34 years) and having a history of STIs or pelvic inflammatory disease (PID) were associated with an increased risk of pain during menstruation and chronic pelvic pain (odds ratios, 1.6-3.1). An interaction term for younger age and history of STIs or PID was associated with an elevated risk of intercourse-related pelvic pain (6.4). Chronic pelvic pain and pain during menstruation were more frequently reported as interfering with daily activities than was intercourse-related pelvic pain. The proportion of women who had talked with a physician about their condition was highest among those with chronic pelvic pain (40%). Pelvic pain associated with menstruation, pelvic pain during or after sexual intercourse, and chronic pelvic pain are common complaints among Mexican women of reproductive age. Health care providers should pay greater attention to these conditions.


Integration of nodal and BMP signals in the heart requires FoxH1 to create left-right differences in cell migration rates that direct cardiac asymmetry.
Failure to properly establish the left-right (L/R) axis is a major cause of congenital heart defects in humans, but how L/R patterning of the embryo leads to asymmetric cardiac morphogenesis is still unclear. We find that asymmetric Nodal signaling on the left and Bmp signaling act in parallel to establish zebrafish cardiac laterality by modulating cell migration velocities across the L/R axis. Moreover, we demonstrate that Nodal plays the crucial role in generating asymmetry in the heart and that Bmp signaling via Bmp4 is dispensable in the presence of asymmetric Nodal signaling. In addition, we identify a previously unappreciated role for the Nodal-transcription factor FoxH1 in mediating cell responsiveness to Bmp, further linking the control of these two pathways in the heart. The interplay between these TGFβ pathways is complex, with Nodal signaling potentially acting to limit the response to Bmp pathway activation and the dosage of Bmp signals being critical to limit migration rates. These findings have implications for understanding the complex genetic interactions that lead to congenital heart disease in humans.


Clinical Practice Guideline: Chiropractic Care for Low Back Pain.
The purpose of this article is to provide an update of a previously published evidence-based practice guideline on chiropractic management of low back pain. This project updated and combined 3 previous guidelines. A systematic review of articles published between October 2009 through February 2014 was conducted to update the literature published since the previous Council on Chiropractic Guidelines and Practice Parameters (CCGPP) guideline was developed. Articles with new relevant information were summarized and provided to the Delphi panel as background information along with the previous CCGPP guidelines. Delphi panelists who served on previous consensus projects and represented a broad sampling of jurisdictions and practice experience related to low back pain management were invited to participate. Thirty-seven panelists participated; 33 were doctors of chiropractic (DCs). In addition, public comment was sought by posting the consensus statements on the CCGPP Web site. The RAND-UCLA methodology was used to reach formal consensus. Consensus was reached after 1 round of revisions, with an additional round conducted to reach consensus on the changes that resulted from the public comment period. Most recommendations made in the original guidelines were unchanged after going through the consensus process. The evidence supports that doctors of chiropractic are well suited to diagnose, treat, co-manage, and manage the treatment of patients with low back pain disorders.


Constitutive expression of steel factor gene by human stromal cells.
Steel factor (SF), the ligand for c-kit, is an essential regulator of normal hematopoiesis, melanogenesis, gametogenesis, and mast-cell growth and development. Hematopoietic stromal cells are important sources of SF, because inactivation of SF in mice results in defects in the support function of hematopoietic stromal cells. To identify specific cells that produce, and factors that govern the expression of the different isoforms of SF in human hematopoiesis, we quantified levels of SF mRNA and membrane-bound protein in human stromal cells before and after exposure to recombinant human interleukin (IL)-1 alpha, a cytokine known to induce the expression of a variety of hematopoietic growth factors. In addition, because stromal cells in longterm bone marrow cultures (LTBMC) are supportive of hematopoietic progenitor cell survival in vitro, while umbilical vein endothelial cells (EC) and diploid fibroblasts (DF) are not, we also sought to test the hypothesis that SF gene expression would differ in cells from LTBMC when compared with EC or DF. Using reverse-transcription polymerase chain reaction amplification (RT-PCR), ribonuclease protection assays (RPA), and Northern blot analysis, SF was found to be constitutively transcribed in EC, DF, and LTBMC. IL-1 alpha neither induced accumulation of SF mRNA nor altered the ratio of exon 6+ to exon 6- transcripts in these stromal cells. By Northern blot analysis, the predominant SF mRNA species was shown to be 5.6 kb; a minor population of 3.6 kb was also found. Low levels of membrane-bound SF protein were found to be constitutively expressed by all three types of stromal cells, and were not regulated by IL-1 alpha. We conclude that the unique capacity of LTBMC to support in vitro hematopoiesis, when compared with EC or DF, cannot be explained on the basis of qualitative or quantitative differences in SF gene expression in these cells.


Clinical characteristics of psychogenic nonepileptic seizures across the lifespan: An international retrospective study.
Previous studies from a few countries have reported semiological differences in younger children compared with adolescents or adults with psychogenic nonepileptic seizures (PNESs). This study tested the hypothesis that semiological, demographic, and historical risk factors vary with different ages of PNES onset in a large cohort from different countries. In this retrospective study, we investigated patients consecutively referred for PNES, who were admitted to epilepsy monitoring units in Iran, Brazil, Venezuela, Canada, Argentina, and USA. Age, gender, age at seizure onset, seizure semiology, and factors predisposing to PNES (abuse, stressors) were documented according to routine diagnostic practices at each center. Participants were grouped according to their age at onset (i.e., childhood, adolescence, or adulthood). A total of 448 patients were studied. Female predominance was associated with adolescent- (85/122, 70%) and adult-onset (190/270, 70%) but not in childhood-onset PNES (28/56, 50%) (p = 0.011). Event frequency in the month preceding the diagnosis was higher in the childhood- [x¯ = 50, standard deviation (sd) = 82, p = 0.025] versus adolescent- (x¯ = 24, sd = 36) or adult-onset groups (x¯ = 29, sd = 61). Significant between-group differences were observed for generalized body movements (p = 0.0001) and ictal injury (p = 0.027), suggesting more severe ictal presentations in adult-onset PNES compared with younger ages. Adult-onset patients were also more likely to be taking an unnecessary antiepileptic medication (p = 0.010). While PNES may present at any age, there appear to be notable differences across the lifespan with respect to some of the clinical characteristics. Further international and cross-cultural studies may reveal other interesting characteristics of PNES.


Social Media-Delivered Patient Education to Enhance Self-management and Attitudes of Patients with Type 2 Diabetes During the COVID-19 Pandemic: Randomized Controlled Trial.
The use of mobile health technologies has been necessary to deliver patient education to patients with diabetes during the COVID-19 pandemic. This open-label randomized controlled trial evaluated the effects of a diabetes educational platform-Taipei Medical University-LINE Oriented Video Education-delivered through a social media app. Patients with type 2 diabetes were recruited from a clinic through physician referral. The social media-based program included 51 videos: 10 about understanding diabetes, 10 about daily care, 6 about nutrition care, 21 about diabetes drugs, and 4 containing quizzes. The intervention group received two or three videos every week and care messages every 2 weeks through the social media platform for 3 months, in addition to usual care. The control group only received usual care. Outcomes were measured at clinical visits through self-reported face-to-face questionnaires at baseline and at 3 months after the intervention, including the Simplified Diabetes Knowledge Scale (true/false version), the Diabetes Care Profile-Attitudes Toward Diabetes Scales, the Summary of Diabetes Self-Care Activities, and glycated hemoglobin (HbA1c) levels. Health literacy was measured at baseline using the Newest Vital Sign tool. Differences in HbA1c levels and questionnaire scores before and after the intervention were compared between groups. The associations of knowledge, attitudes, and self-care activities with health literacy were assessed. Patients with type 2 diabetes completed the 3-month study, with 91 out of 181 (50.3%) patients in the intervention group and 90 (49.7%) in the control group. The change in HbA1c did not significantly differ between groups (intervention group: mean 6.9%, SD 0.8% to mean 7.0%, SD 0.9%, P=.34; control group: mean 6.7%, SD 0.6% to mean 6.7%, SD 0.7%, P=.91). Both groups showed increased mean knowledge scores at 12 weeks, increasing from 68.3% (SD 16.4%) to 76.7% (SD 11.7%; P<.001) in the intervention group and from 64.8% (SD 18.2%) to 73.2% (SD 12.6%; P<.001) in the control group. Positive improvements in attitudes and self-care activities were only observed in the intervention group (attitudes: mean difference 0.2, SD 0.5, P=.001; self-care activities: mean difference 0.3, SD 1.2, P=.03). A 100% utility rate was achieved for 8 out of 21 (38%) medication-related videos. Low health literacy was a significant risk factor for baseline knowledge scores in the intervention group, with an odds ratio of 2.80 (95% CI 1.28-6.12; P=.01); this became insignificant after 3 months. The social media-based program was effective at enhancing the knowledge, attitudes, and self-care activities of patients with diabetes. This intervention was also helpful for patients with low health literacy in diabetes knowledge. The program represents a potentially useful tool for delivering diabetes education to patients through social media, especially during the COVID-19 pandemic. ClinicalTrials.gov NCT04876274; https://clinicaltrials.gov/ct2/show/results/NCT04876274.


Time-dependent formation of 8-oxo-deoxyguanosine in the lungs of mice exposed to cigarette smoke.
Active and passive smoking are major risk factors for lung cancer. Pro-oxidants in tobacco smoke have been implicated in smoking-associated disease development due to their potential role in inducing oxidative stress. Previous studies have failed to associate increased levels of oxidative damage to DNA with the formation of the potentially mutagenic lesion, 8-oxo-2-deoxyguanosine (8-oxodG), probably due to repair of this lesion. However, no systematic studies have been performed to assess the dose- and time-dependent formation and removal of this lesion by cigarette smoke exposure. In the present study, female A/J mice were exposed to side-stream cigarette smoke in a whole body exposure chamber for 6 h a day, 5 days a week for up to 6 weeks. Age-matched controls were maintained in filtered ambient air. Lung tissues were harvested from 2, 4, and 6 weeks smoke-exposed mice after 1, 3, 6, and 20 h, following the cessation of smoking. A significant increase in the levels of 8-oxodG in lung DNA was observed in 10 day smoke-exposed mice at 1 (11.5+/-1.1/10(6) nucleotides), 3 (20.2+/-2.7/10(6) nucleotides; p=0.0008), and 6 h (17.2+/-1.0/10(6) nucleotides; p<0.005) postcessation, as compared with age-matched sham treatment (8.8+/-2.3/10(6) nucleotides) (mean+/-SD). The levels significantly declined 20 h after the cessation of smoke exposure (14.0+/-1.6/10(6) nucleotides), although they were still higher than the control. Our results strongly suggest that there is a significant increase in the 8-oxodG levels immediately after the cessation of smoking, which is repaired over time. This initial increase in 8-oxodG levels may lead to gene mutations, and accumulation of such mutations over time can eventually lead to malignant transformation of the cells.


Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study.
Seizures commonly complicate cerebral malaria and are associated with an increased risk of death and neurological sequelae. We undertook a randomised study to assess the efficacy of intramuscular phenobarbital in preventing seizures in childhood cerebral malaria. Children with cerebral malaria admitted to one hospital in Kilifi, Kenya, were randomly assigned a single intramuscular dose of phenobarbital (20 mg/kg) or identical placebo. Clinical tolerance was assessed at the start of the trial, with particular reference to respiratory depression and hypotension. Seizures were timed and recorded, and treated in a standard way. Plasma phenobarbital concentrations were measured. Analyses were by intention to treat. 440 children with cerebral malaria were admitted to the hospital; 100 were not recruited to the study. Of the remaining 340, 170 received phenobarbital and 170 placebo. The drug was adequately absorbed and well tolerated. Seizure frequency was significantly lower in the phenobarbital group than in the placebo group (18 [11%] vs 46 [27%] children had three or more seizures of any duration; odds ratio 0.32 [95% CI 0.18-0.58]) but mortality was doubled (30 [18%] vs 14 [8%] deaths; 2.39 [1.28-4.64]). The frequency of respiratory arrest was higher in the phenobarbital group than in the placebo group, and mortality was greatly increased in children who received phenobarbital plus three or more doses of diazepam (odds ratio 31.7 [1.2-814]). In children with cerebral malaria, phenobarbital 20 mg/kg provides highly effective seizure prophylaxis but is associated with an unacceptable increase in mortality. Use of this dose cannot, therefore, be recommended.


Forensic utility of cranial measurements in stature reconstruction in South Africans of European descent.
The height of an individual (stature) is one of the biological profiles that is estimated as part of human identification process from various components of the human skeleton. The anatomical method is often used for this purpose when a complete and intact skeleton is available for forensic analysis because it is accurate. Since complete skeletons are seldom present in most forensic cases, the mathematical method, which shows linear relationship between stature and bone measurements, becomes the method of choice. Population and sex-specific regression equations for stature estimation have been formulated using intact and fragmentary long bones amongst South African whites and blacks. Individual and combinations of measurements of other skeletal elements including bones of the feet have also been used in the formulation of regression equations. However, few studies have utilized measurements of the skull for stature reconstruction. Skeletal height, calculated from a suite of measurements, was regressed on six cranial measurements. Basibregmatic height and basion-nasion length presented with the highest correlation coefficient for an individual variable in males (0.50) and females (0.48), respectively. The range of correlation coefficient from multivariate analyses in males (0.58-0.63) is similar to that obtained in females (0.55-0.62). The standard error of estimates of the equations, a measure of the accuracy of the equations, for male sample (6.74-7.09) was slightly higher than that for females (5.47-5.89). Regression equations presented in this study should be used with caution in forensic cases when only the skull is available for human identification. Significance of main findings: 1. Skull measurements show low to moderate correlation with stature. 2. Use of skull dimensions is advised only in the absence of intact long bones and other skeletal elements in South Africa.


Whole-genome sequences of DA and F344 rats with different susceptibilities to arthritis, autoimmunity, inflammation and cancer.
DA (D-blood group of Palm and Agouti, also known as Dark Agouti) and F344 (Fischer) are two inbred rat strains with differences in several phenotypes, including susceptibility to autoimmune disease models and inflammatory responses. While these strains have been extensively studied, little information is available about the DA and F344 genomes, as only the Brown Norway (BN) and spontaneously hypertensive rat strains have been sequenced to date. Here we report the sequencing of the DA and F344 genomes using next-generation Illumina paired-end read technology and the first de novo assembly of a rat genome. DA and F344 were sequenced with an average depth of 32-fold, covered 98.9% of the BN reference genome, and included 97.97% of known rat ESTs. New sequences could be assigned to 59 million positions with previously unknown data in the BN reference genome. Differences between DA, F344, and BN included 19 million positions in novel scaffolds, 4.09 million single nucleotide polymorphisms (SNPs) (including 1.37 million new SNPs), 458,224 short insertions and deletions, and 58,174 structural variants. Genetic differences between DA, F344, and BN, including high-impact SNPs and short insertions and deletions affecting >2500 genes, are likely to account for most of the phenotypic variation between these strains. The new DA and F344 genome sequencing data should facilitate gene discovery efforts in rat models of human disease.


Early invasive versus conservative strategies for unstable angina & non-ST-elevation myocardial infarction in the stent era.
In patients with unstable angina and non-ST-elevation myocardial infarction (UA/NSTEMI) two strategies are possible: a routine invasive strategy where all patients undergo coronary angiography shortly after admission and, if indicated, coronary revascularization; or a conservative strategy where medical therapy alone is used initially with selection of patients for angiography based on clinical symptoms or investigational evidence of persistent myocardial ischemia. To determine the benefits of an invasive compared to a conservative strategy for treating UA/NSTEMI in the stent era. The Cochrane Central Register of Controlled Trials (Issue 3 2005), MEDLINE and EMBASE were searched from 1996 to September 2005 with no language restrictions. Included studies were prospective trials comparing invasive with conservative strategies in UA/NSTEMI. We identified 5 studies (7818 participants). Using intention-to-treat analysis with random effects models, summary estimates of relative risk (95% confidence interval [CI]) were determined for primary end-points of all-cause death, fatal and non-fatal myocardial infarction; all-cause death or non-fatal myocardial infarction; and refractory angina. Further analysis of included studies was undertaken based on whether glycoprotein IIb/IIIa receptor antagonists were used routinely. Heterogeneity was assessed using chi-square and variance (I(2)) methods. In the all-study analysis, mortality during initial hospitalization showed a trend to hazard with an invasive strategy; relative risk 1.59 (95% CI 0.96 to 2.64). Mortality and myocardial infarction assessed at 2-5 years in two trials were significantly decreased by an invasive strategy with relative risk of 0.75 (95% CI 0.62 to 0.92) and 0.75 (95% CI 0.61 to 0.91) respectively. The composite end-point of death or non-fatal myocardial infarction was significantly decreased by an invasive strategy at several time points after initial hospitalization. The incidence of early (<4 months) and intermediate (6-12 months) refractory angina were both significantly decreased by an invasive strategy; relative risk 0.47 (95% CI 0.32 to 0.68) and 0.67 (95% CI 0.55 to 0.83) respectively, as were early and intermediate rehospitalization rates with relative risk 0.60 (95% CI 0.41 to 0.88) and 0.67 (95% CI 0.61 to 0.74) respectively. The invasive strategy was associated with a two-fold increase in the relative risk of peri-procedural myocardial infarction (as variably defined) and a 1.7-fold increase in the relative risk of bleeding. An early invasive strategy is preferable to a conservative strategy in the treatment of UA/NSTEMI.


Cohabitation and Children's Externalizing Behavior in Low-Income Latino Families.
We consider the association of cohabitation experience with externalizing behavior among children of Latina mothers whose ethnic origin is in Mexico, Puerto Rico, or the Dominican Republic. Data were drawn from three waves of the Three-City Study (N=656 mother-child pairs). Children of Mexican-origin mothers had higher externalizing problems in childhood and adolescence when their mothers were born in the United States or immigrated as minors. For children of Caribbean-origin mothers, being born to a cohabiting or married mother had a statistically equivalent association with externalizing behavior when mothers were born outside the mainland United States (Dominican and island-born Puerto Rican mothers). Children of mainland-born Puerto Rican mothers had more behavior problems when their mothers cohabited at birth.


Trained assistance dogs for people with dementia: a systematic review.
This systematic review investigated evidence for the effectiveness of trained assistance dogs as an intervention and support for people with dementia. Peer-reviewed articles were retrieved from multiple databases (SCOPUS, Web of Science, and Google Scholar). Reference lists of the articles retrieved were also screened to identify key authors for inclusion. Articles were subject to a quality review, and the results synthesised to address the research questions. Both qualitative and quantitative data were reported. There was evidence of the potential positive effects of dog-assisted interventions in relation to mood, prosocial behaviours, activities of daily living and/or quality of life, cognitive impairment and symptoms specific to dementia, and existential functions. However, the form and quality of the studies varied considerably. It was concluded that further research is needed, particularly for those with younger onset dementia (YOD), for whom there were no specific studies available. Attention needs to be given to establishing adequate-sized samples and designs incorporating control groups. Research would benefit from employing mixed-methods, allowing for the triangulation of qualitative and quantitative data. For deteriorating conditions such as the dementias, studies need to be conducted over time. Furthermore, given the important place family members play in the lives of those with dementia, the effects of dog-assisted interventions on the wider family should also be considered.


Conceptual distinctiveness supports detailed visual long-term memory for real-world objects.
Humans have a massive capacity to store detailed information in visual long-term memory. The present studies explored the fidelity of these visual long-term memory representations and examined how conceptual and perceptual features of object categories support this capacity. Observers viewed 2,800 object images with a different number of exemplars presented from each category. At test, observers indicated which of 2 exemplars they had previously studied. Memory performance was high and remained quite high (82% accuracy) with 16 exemplars from a category in memory, demonstrating a large memory capacity for object exemplars. However, memory performance decreased as more exemplars were held in memory, implying systematic categorical interference. Object categories with conceptually distinctive exemplars showed less interference in memory as the number of exemplars increased. Interference in memory was not predicted by the perceptual distinctiveness of exemplars from an object category, though these perceptual measures predicted visual search rates for an object target among exemplars. These data provide evidence that observers' capacity to remember visual information in long-term memory depends more on conceptual structure than perceptual distinctiveness.


Breast cancer screening disparities among urban immigrants: a population-based study in Ontario, Canada.
Breast cancer is one of the leading cause of mortality and morbidity in Canada. Screening is the most promising approach in identification and treatment of the disease at early stage of its development. Research shows higher rate of breast cancer mortality among ethno-racial immigrant women despite their lower incidence which suggests disparities in mammography screening. This study aimed to compare the prevalence of appropriate mammography screening among immigrant and native borne women and determine predicators of low mammography screening. We conducted secondary data analyses on Ontario linked social and health databases to determine the proportion of women who were screened during the two-year period of 2010-2012 among 1.4 million screening-eligible women living in urban centres in Ontario. We used multivariate Poisson regression to adjust for various socio-demographic, health care-related and migration related variables. 64% of eligible women were appropriately screened. Screening rates were lowest among new and recent immigrants compared to referent group (Canadian-born women and immigrant who arrived before 1985) (Adjusted Rate Ratio (ARR) (0.87, 95% CI 0.85-0.88 for new immigrants and 0.90, 95% CI 0.89-0.91 for recent immigrants. Factors that were associated with lower rates of screening included living in low-income neighborhoods, having a male physician, having internationally-trained physician and not being enrolled in primary care patient enrolment models. Those not enrolled were 22% less likely to be screened compared to those who were (ARR 0.78, 95% CI 0.77-0.79). To enhance immigrant women screening rates efforts should made to increase their access to primary care patient enrolment models and preferably female health professionals. Support should be provided to interventions that address screening barriers like language, acculturation limitations and knowledge deficit. Health professionals need to be educated and take an active role in offering screening guidelines during health encounters.


Personalized one-to-one intervention in agitated individuals with dementia: responders versus non-responders.
The aim of the current study was to explore why some individuals with dementia and agitated behavior showed limited response to a personalized intervention. Ten consistently agitated individuals (i.e., non-responders) were compared with 34 individuals who were more settled during the intervention (i.e., responders). Most participants had severe cognitive deficits; however, non-responders were more impaired. Where responders showed large improvements across conditions, agitated behavior remained equally high in non-responders. Responders and non-responders showed increased interest and engagement during the intervention. Increased agitated behavior was associated with severe cognitive impairment. Although studies have shown that psychosocial interventions can reduce agitated behavior, there does seem to be a point where it becomes more difficult to reduce this behavior. However, non-responders still displayed interest, and the authors believe further personalization of the intervention is possible. Therefore, severe dementia and agitated behavior should not exclude individuals from psychosocial interventions; however, a more detailed and timely implementation plan of such treatments may be warranted.


Analysis of methylation-sensitive transcriptome identifies GADD45a as a frequently methylated gene in breast cancer.
Treatment of the breast cancer cell line, MDAMB468 with the DNA methylation inhibitor, 5-azacytidine (5-AzaC) results in growth arrest, whereas the growth of the normal breast epithelial line DU99 (telomerase immortalized) is relatively unaffected. Comparing gene expression profiles of these two lines after 5-AzaC treatment, we identified 36 genes that had relatively low basal levels in MDAMB468 cells compared to the DU99 line and were induced in the cancer cell line but not in the normal breast epithelial line. Of these genes, 33 have associated CpG islands greater than 300 bp in length but only three have been previously described as targets for aberrant methylation in human cancer. Northern blotting for five of these genes (alpha-Catenin, DTR, FYN, GADD45a, and Zyxin) verified the array results. Further analysis of one of these genes, GADD45a, showed that 5-AzaC induced expression in five additional breast cancer cell lines with little or no induction in three additional lines derived from normal breast epithelial cells. The CpG island associated with GADD45a was analysed by bisulfite sequencing, sampling over 100 CpG dinucleotides. We found that four CpG's, located approximately 700 bp upstream of the transcriptional start site are methylated in the majority of breast cancer cell lines and primary tumors but not in DNA from normal breast epithelia or matched lymphocytes from cancer patients. Therefore, this simple method of dynamic transcriptional profiling yielded a series of novel methylation-sensitive genes in breast cancer including the BRCA1 and p53 responsive gene, GADD45a.


Type A behavior and work situation: associations with burnout and work engagement.
The aim of the present study was to investigate Type A behavior as well as perceived work situation, and associations with burnout and work engagement. The associations in focus were investigated through hierarchical regressions in a sample (N= 329) of Swedish Information Communication Technology consultants. The findings indicated that both work situation and Type A behavior was correlated with work engagement and burnout; however, no interactions between Type A behavior and work situation were elicited. The main conclusion was that the achievement striving aspect of Type A behavior appears as "non-toxic" and is related only to work engagement. However, the irritability/impatience aspect appears to be responsible for burnout complaints among Type A individuals, possibly through negative effects of the mood itself than through perceived stress at work.


The bioconjugation mechanism of purine cross-linkers affects microstructure and cell response to ultra rapidly gelling purine-chitosan sponges.
As a cell carrier, cross-linking is one of the most common approaches used to provide chitosan with greater structural integrity. We introduced a cross-linking strategy by using two purines, guanosine 5'-diphosphate (GDP) or adenosine 5'-diphosphate (ADP), as cross-linkers. The rationale for this approach is that both GDP and ADP have an important physiological role and act as intercellular signaling molecules in numerous biological processes. The slight difference between the chemical structure of guanine and adenosine in GDP and ADP, respectively, affect the cross-linking mechanism. This resulted in a different scaffold microstructure and thus, altered the response of encapsulated cells to the scaffold. FTIR and solid-state 13C-NMR revealed the formation of a quadruplex structure among the four GDP molecules confined between the chitosan backbone. This resulted from the ability of guanine to form intermolecular hydrogen bonds, while adenosine in ADP lacks this capacity. The formation of a more organized structure in GDP-chitosan sponges also increased the crystallinity of the sponge as shown by X-ray diffraction data. Further, physicochemical analyses with SEM and μCT indicated a more open-pore architecture and increased porosity. Although an active population of encapsulated cells was maintained in all chitosan sponges overtime, the GDP-based sponges provided a 6-fold increase in the activity of MC-3T3 cells and significantly enhanced their proliferation due to a more appropriate microstructure. Overall, these findings suggest that slight changes in the chemical structure of the cross-linker in the preparation of chitosan-based biomaterials will have a significant impact on the structural properties of the chitosan. This important parameter can be utilized to modulate cell response and to understand the cell signaling pathway of chitosan-based biomaterials in the context of their applications in tissue engineering.


Continuous flow actuation between external reservoirs in small-scale devices driven by surface acoustic waves.
We have designed and characterized a surface acoustic wave (SAW) fluid actuation platform that significantly improves the transmission of sound energy from the SAW device into the fluid in order to obtain enhanced performance. This is in distinct contrast to previous SAW microfluidic devices where the SAW substrate is simply interfaced with a microchannel without due consideration given to the direction in which the sound energy is transmitted into the fluid, thus resulting in considerable reflective and dissipative losses due to reflection and absorption at the channel walls. For the first time, we therefore demonstrate the ability for continuous fluid transfer between independent reservoirs driven by the SAW in a miniature device and report the associated pressure-flow rate relationship, in which a maximum flow rate of 100 μl min(-1) and pressure of 15 Pa were obtained. The pumping efficiency is observed to increase with input power and, at peak performance, offers an order-of-magnitude improvement over that of existing SAW micropumps that have been reported to date.


Top POEMs of 2016 Consistent with the Principles of the Choosing Wisely Campaign.
A challenge in the Choosing Wisely campaign is to identify low-value clinical actions supported by high-quality evidence. We applied a method based on crowdsourcing the Daily POEM (patient-oriented evidence that matters) to identify low-value clinical actions from research studies consistent with the principles of Choosing Wisely. In 2016, we analyzed an average of 1,382 questionnaires on 265 unique POEMs delivered to physician members of the Canadian Medical Association. From these questionnaires, we identified the POEMs ranking highest on one questionnaire item directly linked to reducing overdiagnosis or overtreatment. The recommendations from these POEMs based on primary research or meta-analyses are presented as actions to consider avoiding in clinical practice. These recommendations fall into the categories of musculoskeletal conditions (e.g., degenerative meniscal tears, chronic low back pain), cardiovascular disease (e.g., chronic stable angina, heart failure with preserved ejection fraction), respiratory disease (e.g., pneumonia, asthma exacerbations), and preventive care (e.g., screening for lung, colorectal, or ovarian cancer). Based on the results of the studies, these recommendations describe interventions whose benefits are not superior to other options, are sometimes more expensive, or put patients at increased risk of harm. Knowing more about these POEMs and their connection with the Choosing Wisely campaign will help clinicians and their patients engage in conversations better informed by high-quality evidence.


A rapid protein structure alignment algorithm based on a text modeling technique.
Structural alignment of proteins is widely used in various fields of structural biology. In order to further improve the quality of alignment, we describe an algorithm for structural alignment based on text modelling techniques. The technique firstly superimposes secondary structure elements of two proteins and then, models the 3D-structure of the protein in a sequence of alphabets. These sequences are utilized by a step-by-step sequence alignment procedure to align two protein structures. A benchmark test was organized on a set of 200 non-homologous proteins to evaluate the program and compare it to state of the art programs, e.g. CE, SAL, TM-align and 3D-BLAST. On average, the results of all-against-all structure comparison by the program have a competitive accuracy with CE and TM-align where the algorithm has a high running speed like 3D-BLAST.


Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation.
Human mitochondrial DNA is widely used as tool in many fields including evolutionary anthropology and population history, medical genetics, genetic genealogy, and forensic science. Many applications require detailed knowledge about the phylogenetic relationship of mtDNA variants. Although the phylogenetic resolution of global human mtDNA diversity has greatly improved as a result of increasing sequencing efforts of complete mtDNA genomes, an updated overall mtDNA tree is currently not available. In order to facilitate a better use of known mtDNA variation, we have constructed an updated comprehensive phylogeny of global human mtDNA variation, based on both coding- and control region mutations. This complete mtDNA tree includes previously published as well as newly identified haplogroups, is easily navigable, will be continuously and regularly updated in the future, and is online available at http://www.phylotree.org.


Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.
We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.


Targeting the urokinase plasminogen activator receptor enhances gene transfer to human airway epithelia.
Developing gene therapy for cystic fibrosis has been hindered by limited binding and endocytosis of vectors by human airway epithelia. Here we show that the apical membrane of airway epithelia express the urokinase plasminogen activator receptor (uPAR). Urokinase plasminogen activator (uPA), or a 7-residue peptide derived from this protein (u7-peptide), bound the receptor and stimulated apical endocytosis. Both ligands enhanced gene transfer by nonspecifically bound adenovirus and adeno-associated virus vectors and by a modified adenovirus vector that had been coupled to the u7-peptide. These data provide the first evidence that targeting an apical receptor can circumvent the two most important barriers to gene transfer in airway epithelia. Thus, the uPA/uPAR system may offer significant advantages for delivering genes and other pharmaceuticals to airway epithelia.


Differential accumulation of oocyte nuclear proteins by embryonic nuclei of Xenopus.
Oocyte nuclear proteins of Xenopus are distributed into the cytoplasm of the maturing egg after germinal vesicle breakdown. Later they are found in all cell nuclei of the embryo. At early stages of development, different nuclear proteins behave differently. A class of 'early shifting' antigens is accumulated by pronuclei and cleavage nuclei, whereas others appear to be excluded from the nuclei at early stages but are shifted into the nuclei at blastula or during and after gastrulation. Accumulation of 'late-shifting' nuclear antigens is a gradual process and occurs during a period characteristic of each protein. Multiple artificial pronuclei can be formed after injection of sperm nuclei, erythrocyte nuclei or pure lambda-DNA into unfertilized eggs. The artificial pronuclei accumulate early- but not late-shifting proteins. Early-migrating proteins rapidly accumulate into the germinal vesicle after de novo synthesis in the oocyte, indicating that the efficiency of translocation into nuclei is an intrinsic property of each protein. Artificial extension of the length of the cell cycle before midblastula transition does not lead to accumulation of the late-shifting nuclear antigens investigated.


Enhancement of plant metabolite fingerprinting by machine learning.
Metabolite fingerprinting of Arabidopsis (Arabidopsis thaliana) mutants with known or predicted metabolic lesions was performed by (1)H-nuclear magnetic resonance, Fourier transform infrared, and flow injection electrospray-mass spectrometry. Fingerprinting enabled processing of five times more plants than conventional chromatographic profiling and was competitive for discriminating mutants, other than those affected in only low-abundance metabolites. Despite their rapidity and complexity, fingerprints yielded metabolomic insights (e.g. that effects of single lesions were usually not confined to individual pathways). Among fingerprint techniques, (1)H-nuclear magnetic resonance discriminated the most mutant phenotypes from the wild type and Fourier transform infrared discriminated the fewest. To maximize information from fingerprints, data analysis was crucial. One-third of distinctive phenotypes might have been overlooked had data models been confined to principal component analysis score plots. Among several methods tested, machine learning (ML) algorithms, namely support vector machine or random forest (RF) classifiers, were unsurpassed for phenotype discrimination. Support vector machines were often the best performing classifiers, but RFs yielded some particularly informative measures. First, RFs estimated margins between mutant phenotypes, whose relations could then be visualized by Sammon mapping or hierarchical clustering. Second, RFs provided importance scores for the features within fingerprints that discriminated mutants. These scores correlated with analysis of variance F values (as did Kruskal-Wallis tests, true- and false-positive measures, mutual information, and the Relief feature selection algorithm). ML classifiers, as models trained on one data set to predict another, were ideal for focused metabolomic queries, such as the distinctiveness and consistency of mutant phenotypes. Accessible software for use of ML in plant physiology is highlighted.


Studies on the Correct Length of Nasopharyngeal Airways in Adults: A Literature Review.
The use of a nasopharyngeal airway (NPA) as an adjunct airway device can be critically important in emergency medicine. When placed correctly, the device can prevent upper airway obstruction. The goal of our review was to learn whether there is scientific evidence about the correct length and the insertion depth, and also possible facial landmarks, that can predict the appropriate length of the NPA. There has been no real consensus on how to measure the appropriate tube length for the NPA. Several studies have been able to demonstrate correlations between facial landmarks and body dimensions; however, we did not find any scientific evidence on this matter. The reviewed studies do not indicate evidence to support current recommended guidelines. This could potentially lead to both military and civilian emergency training programs not having the most accurate scientific information for training on anatomic structures and also not having a better overall understanding of intraoral dimensions. Emergency personnel should be taught validated scientific knowledge of NPAs so as to quickly determine the correct tube length and how to use anatomic correlations. This might require further studies on the correlations and perhaps radiographic measurements. A further approach includes adjusting the tube to its correct length according to the sufficient assessment and management of the airway problem.


Psychometric testing of the British-English Long-Term Conditions Job Strain Scale, Long-Term Conditions Work Spillover Scale and Work-Health-Personal Life Perceptions Scale in four rheumatic and musculoskeletal conditions.
The aims were to validate linguistically British-English versions of the Long-Term Conditions Job Strain Scale (LTCJSS), Long-Term Conditions Work Spillover Scale (LTCWSS) and Work-Health-Personal Life Perceptions Scale (WHPLPS) in rheumatoid arthritis, axial spondyloarthritis, osteoarthritis and fibromyalgia (FM). The three scales were forward translated and reviewed by an expert panel prior to cognitive debriefing interviews. Participants completed a postal questionnaire. Construct validity was assessed using Rasch analysis. Concurrent validity included testing between the three scales and work (e.g., Workplace Activity Limitations Scale [WALS]) and condition-specific health scales. Two weeks later, participants were mailed a second questionnaire to measure test-retest reliability. The questionnaire was completed by 831 employed participants: 68% women, 53.5 (SD 8.9) years of age, with condition duration 7.7 (SD 8.0) years. The LTCJSS, LTCWSS and WHPLPS Parts 1 and 2 satisfied Rasch model requirements, but Part 3 did not. A Rasch transformation scale and Reference Metric equating scales with the WALS were created. Concurrent validity was generally good (rs = 0.41-0.85) for the three scales, except the WHPLPS Part 3. Internal consistency (Person Separation Index values) was consistent with group use in all conditions, and individual use except for the LTCWSS and WHPLSP Parts 1 and 2 in FM. Test-retest reliability was excellent, with intraclass coefficients (2,1) of 0.80-0.96 for the three scales in the four conditions. Reliable, valid versions of the British-English LTCJSS, LTCWSS and WHPLPS Parts 1 and 2 are now available for use in the UK.


Bier's block using lignocaine and butorphanol.
Opioids are most commonly used as adjuncts in intravenous regional anesthesia (IVRA) to improve the quality of intraoperative and postoperative analgesia. There is paucity of literature on the use of butorphanol in IVRA. The aim of this study was to evaluate the likely benefits of addition of butorphanol to lignocaine in Bier's block in terms of onset and duration of sensory block and also for analgesic requirement in postoperative period. A randomized double blind study was conducted at Tertiary Care Educational Institute. A total of 40 adult ASA I or II patients scheduled to undergo upper limb surgery were randomized in two groups (n=20). Group I received 3 mg/kg of lignocaine alone and group II received 1 mg butorphanol in addition to 3 mg/kg lignocaine. Sensory block onset time and time to recovery from sensory block after tourniquet deflation were noted using the pin prick method. Duration of postoperative analgesia was noted using a visual analogue scale. All the patients were compared for the time to first rescue analgesic consumption and total analgesic consumption in first 24 hours postoperatively. The statistical analysis was done using unpaired Student's t-test. Our study showed significant prolongation of postoperative analgesia in group II as noted by the time to first analgesic requirement. Total analgesic consumption in first 24 hours postoperatively was less in group II. Sensory block onset time and time to recovery from sensory block after tourniquet deflation, did not show any significant difference between the two groups. Addition of butorphanol to lignocaine in IVRA significantly prolongs the duration of postoperative analgesia and 24 hours analgesic consumption is less in patients receiving butorphanol along with lignocaine in IVRA. However, there is no effect on sensory block onset time and time to recovery from sensory block.


Targeting virological core groups: a new paradigm for controlling herpes simplex virus type 2 epidemics.
Classic modeling of sexually transmitted diseases has focused on modeling behavioral heterogeneity and designing epidemic control strategies targeted at behavioral core groups. We analyzed a new mathematical model of herpes simplex virus type 2 (HSV-2) epidemics that includes virological core groups (i.e., groups of individuals with high rates of viral reactivation) and suggest a new paradigm for epidemic control. We used our model, in conjunction with virological data, to determine the potential role of virological core groups in contributing to transmission and the effect that daily antiviral therapy (DAT) could have on reducing transmission if virological core groups were targeted. We estimated that a virological core group (11% of infected individuals) can cause a disproportionately large percentage (44%) of new infections and that a median of only 6.4 person-years of DAT would be necessary to prevent 1 HSV-2 infection. We determined that relatively few individuals would need to receive DAT to substantially reduce the incidence of HSV-2 infection. Identifying and targeting individuals in the virological core group could be an effective and practical public health strategy for reducing transmission. Treating individuals who are high-frequency viral shedders should be evaluated as a strategy for reducing HSV-2 transmission.


Estimation of effective vaccination rate: pertussis in New Zealand as a case study.
In some cases vaccination is unreliable. For example vaccination against pertussis has comparatively high level of primary and secondary failures. To evaluate efficiency of vaccination we introduce the idea of effective vaccination rate and suggest an approach to estimate it. We consider pertussis in New Zealand as a case study. The results indicate that the level of immunity failure for pertussis is considerably higher than was anticipated.


Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation.
Acute lung injury (ALI) causes high mortality, but its molecular mechanisms are poorly understood. Acid aspiration is a frequent cause of ALI, leading to neutrophil sequestration, increased permeability, and deterioration of gas exchange. We investigated the role of platelet-neutrophil interactions in a murine model of acid-induced ALI. Acid aspiration induced P-selectin-dependent platelet-neutrophil interactions in blood and in lung capillaries. Reducing circulating platelets or blocking P-selectin halted the development of ALI. Bone marrow chimeras showed that platelet, not endothelial, P-selectin was responsible for the injury. The interaction of platelets with neutrophils and endothelia was associated with TXA(2) formation, with detrimental effects on permeability and tissue function. Activated platelets induced endothelial expression of ICAM-1 and increased neutrophil adhesion. Inhibition of platelet-neutrophil aggregation improved gas exchange, reduced neutrophil recruitment and permeability, and prolonged survival. The key findings were confirmed in a sepsis-induced model of ALI. These findings may translate into improved clinical treatments for ALI.


Search performance is better predicted by tileability than presence of a unique basic feature.
Traditional models of visual search such as feature integration theory (FIT; Treisman & Gelade, 1980), have suggested that a key factor determining task difficulty consists of whether or not the search target contains a "basic feature" not found in the other display items (distractors). Here we discriminate between such traditional models and our recent texture tiling model (TTM) of search (Rosenholtz, Huang, Raj, Balas, & Ilie, 2012b), by designing new experiments that directly pit these models against each other. Doing so is nontrivial, for two reasons. First, the visual representation in TTM is fully specified, and makes clear testable predictions, but its complexity makes getting intuitions difficult. Here we elucidate a rule of thumb for TTM, which enables us to easily design new and interesting search experiments. FIT, on the other hand, is somewhat ill-defined and hard to pin down. To get around this, rather than designing totally new search experiments, we start with five classic experiments that FIT already claims to explain: T among Ls, 2 among 5s, Q among Os, O among Qs, and an orientation/luminance-contrast conjunction search. We find that fairly subtle changes in these search tasks lead to significant changes in performance, in a direction predicted by TTM, providing definitive evidence in favor of the texture tiling model as opposed to traditional views of search.


Phototherapy in pediatric patients.
The treatment of children with psoriasis, atopic dermatitis (AD), pityriasis lichenoides, and scleroderma poses a therapeutic problem because all therapeutic options are associated with numerous side effects. Therefore ultraviolet A and B (UVA and UVB) phototherapy is presented as a possible alternative to some of these therapies, primarily topical and systemic corticosteroids, in children. Our results in treating children with phototherapy and psoralen plus UVA (PUVA) bath phototherapy over the past 5 years are reported. UVB therapy (TL01) was used in 20 psoriatic children (6 boys, 14 girls; ages 6-14 years) during the stage of disease exacerbation and in 9 children (3 boys, 6 girls; ages 8-16 years) with pityriasis lichenoides. Combined UVA/UVB phototherapy was applied in 21 AD children (7 boys, 14 girls; ages 4-15 years). Photochemotherapy with local application of a PUVA bath was used in six children (2 boys, 4 girls; ages 9-16 years) with circumscribed scleroderma and in one girl with systemic scleroderma. All children received short courses of phototherapy with either no maintenance or short maintenance. All three therapeutic protocols resulted in a certain degree of improvement in most of the study patients. None of the patients exhibited any early phototherapy side effects. We conclude that phototherapy and PUVA bath are valuable and safe therapeutic options for selected children who do not respond to other treatments.


Secretomes from metastatic breast cancer cells, enriched for a prognostically unfavorable LCN2 axis, induce anti-inflammatory MSC actions and a tumor-supportive premetastatic lung.
Cancer metastasis is responsible for the clear majority of cancer-related deaths. Survival and expansion of cancer cells at secondary sites requires that these premetastatic microenvironments be primed by primary tumor cells and their secreted factors. Efforts to date have been limited by immune-deficient in vivo models and/or the need for finely-tuned analysis time points that reduce contributions from early-disseminating cancer cells. In this regard, we developed a tumor cell-free syngeneic breast cancer model for characterizing tumor cell secretome-mediated reprogramming of premetastatic tissues. We demonstrate that secretomes from metastatic breast cancer cells differentially regulate the lung and brain, promoting a tumor-supportive lung microenvironment with both elevated CD73 expression and decreased TNFα expression. Using in vitro models of CD73-positive mesenchymal stem cells (MSCs) and macrophages/monocytes, we tested whether MSCs can mediate anti-inflammatory effects of metastatic breast cancer cells. Notably, conditioned media from metastatic Py230 cells reprogrammed the secretomes of MSCs toward an anti-inflammatory state. Mining transcriptome data from Py8119 and Py230 cells revealed a lipocalin 2 (LCN2) axis that is selectively expressed in the metastatic Py230 cells, predicts poor breast cancer patient survival and is elevated in circulating serum of mice chronically treated with conditioned media from Py230 cells. Taken together, these results establish the utility of an immune-competent tumor cell-free model for characterizing the mechanisms of breast cancer cell priming of the premetastatic niche, demonstrate that MSCs can mediate the anti-inflammatory effects of metastatic breast cancer cells and substantiate LCN2 as a promising therapeutic target for blocking breast cancer progression.


Monoclonal gammopathies in the adult population of Finistère, France.
Three hundred and thirty-four monoclonal gammopathies were detected in the sera of 30 279 adults from Finistère. Monoclonal gammopathies (MG) are more common in Finistère than in Paris and their distribution is not homogeneous. IgG paraproteins are particularly common in the northeast of Finistère whereas IgM paraproteins are more common in the southwest. Family studies and the high degree of inbreeding would support the hypothesis that there is a genetic predisposition to develop MG but the occurrence of paraproteins among three non-consanguineous couples seems to favour the existence of an environmental factor.


Effect of chemotherapy on health-related quality of life among early-stage ovarian cancer survivors: a study from the population-based PROFILES registry.
There is wide variation in the application of adjuvant chemotherapy in early-stage epithelial ovarian cancer. Our aim was to assess differences in health-related quality of life (hrqol) between patients with early-stage ovarian cancer who did or did not receive chemotherapy as adjuvant treatment. All patients diagnosed with early-stage ovarian cancer between 2000 and 2010 within the population-based Eindhoven Cancer Registry (n = 191) were enrolled in this study. Patients were requested to complete questionnaires, including the cancer-specific (qlq-C30) and ovarian cancer-specific (qlq-OV28) quality of life measures from the European Organisation for Research and Treatment of Cancer. Primary outcome measures were the generic-and cancer-specific domain scores for hrqol in ovarian cancer survivors. Of the 107 patients (56%) who returned the questionnaires, 57 (53.3%) had received adjuvant chemotherapy and 50 (46.7%) had been treated with surgery alone. Significant differences in hrqol between those groups were found in the symptom scales for peripheral neuropathy, attitude toward sickness, and financial situation, with worse scores in the chemotherapy group. Results of our study show that patients who receive adjuvant chemotherapy have a significantly worse score for 3 aspects of hrqol. Efforts should be made to reduce use of adjuvant chemotherapy in early-stage ovarian cancer. Moreover, preventive strategies to improve long-term quality of life for those who need adjuvant chemotherapy should be explored.


Local topographic wetness indices predict household malaria risk better than land-use and land-cover in the western Kenya highlands.
Identification of high-risk malaria foci can help enhance surveillance or control activities in regions where they are most needed. Associations between malaria risk and land-use/land-cover are well-recognized, but these environmental characteristics are closely interrelated with the land's topography (e.g., hills, valleys, elevation), which also influences malaria risk strongly. Parsing the individual contributions of land-cover/land-use variables to malaria risk requires examining these associations in the context of their topographic landscape. This study examined whether environmental factors like land-cover, land-use, and urban density improved malaria risk prediction based solely on the topographically-determined context, as measured by the topographic wetness index. The topographic wetness index, an estimate of predicted water accumulation in a defined area, was generated from a digital terrain model of the landscape surrounding households in two neighbouring western Kenyan highland communities. Variables determined to best encompass the variance in this topographic wetness surface were calculated at a household level. Land-cover/land-use information was extracted from a high-resolution satellite image using an object-based classification method. Topographic and land-cover variables were used individually and in combination to predict household-level malaria in the communities through an iterative split-sample model fitting and testing procedure. Models with only topographic variables were compared to those with additional predictive factors related to land-cover/land-use to investigate whether these environmental factors improved prediction of malaria based on the shape of the land alone. Variables related to topographic wetness proved most useful in predicting the households of individuals contracting malaria in this region of rugged terrain. Other variables related to human modification of the environment also demonstrated clear associations with household malaria. However, these land-cover/land-use variables failed to produce unambiguous improvements in statistical predictive models controlling for important topographic factors, with none improving prediction of household-level malaria more than 75% of the time. Topographic wetness values in this region of highly varied terrain more accurately predicted houses at greater risk of malaria than did consideration of land-cover/land-use characteristics. As such, those planning control or local elimination strategies in similar highland regions may use topographic and geographic characteristics to effectively identify high-receptivity regions that may require enhanced vigilance.


Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications.
Biogenic amines are a collection of endogenous molecules that play pivotal roles as neurotransmitters and hormones. In addition to the "classical" biogenic amines resulting from decarboxylation of aromatic acids, including dopamine (DA), norepinephrine, epinephrine, serotonin (5-HT), and histamine, other biogenic amines, present at much lower concentrations in the central nervous system (CNS), and hence referred to as "trace" amines (TAs), are now recognized to play significant neurophysiological and behavioral functions. At the turn of the century, the discovery of the trace amine-associated receptor 1 (TAAR1), a phylogenetically conserved G protein-coupled receptor that is responsive to both TAs, such as β-phenylethylamine, octopamine, and tyramine, and structurally-related amphetamines, unveiled mechanisms of action for TAs other than interference with aminergic pathways, laying the foundations for deciphering the functional significance of TAs and its mammalian CNS receptor, TAAR1. Although, its molecular interactions and downstream targets have not been fully elucidated, TAAR1 activation triggers accumulation of intracellular cAMP, modulates PKA and PKC signaling and interferes with the β-arrestin2-dependent pathway via G protein-independent mechanisms. TAAR1 is uniquely positioned to exert direct control over DA and 5-HT neuronal firing and release, which has profound implications for understanding the pathophysiology of, and therefore designing more efficacious therapeutic interventions for, a range of neuropsychiatric disorders that involve aminergic dysregulation, including Parkinson's disease, schizophrenia, mood disorders, and addiction. Indeed, the recent development of novel pharmacological tools targeting TAAR1 has uncovered the remarkable potential of TAAR1-based medications as new generation pharmacotherapies in neuropsychiatry. This review summarizes recent developments in the study of TAs and TAAR1, their intricate neurochemistry and pharmacology, and their relevance for neurodegenerative and neuropsychiatric disease.


Validating a multifactorial falls risk assessment.
Reducing risk of falls has been identified as a national safety goal by The Joint Commission (TJC). The purpose was to determine if the total score on the multifactorial Falls Risk Assessment accurately identifies the risk of falls in a homebound client. In addition, the study examined if any individual item had a higher predictive power with the incidence of falls. One hundred clients (> 65 years old) who sustained an avoidable fall during a home care episode of care, plus 25 home care clients in the same age range and time period, who did not fall. A retrospective chart review, including Falls Risk Assessment (FRA) performed at start of care, demographic information, specific physical therapy (PT) evaluation, and visit notes if necessary to determine if the fall met the inclusion criteria. Scores for each individual area of the assessment were collected for statistical analysis. Data were analyzed by a biostatistician using simple linear regression, t-tests, and regression of variable combinations. The total score on the multifactorial risk assessment tool was shown to have a strong relationship with incidence of falls. The average scores of individuals who fell after assessment were significantly higher than those of individuals who did not fall. No single factors were found to be highly predictive. A single approach to decreasing falls is likely to be less effective than a multipronged approach. Caregivers and providers are advised to consider the entirety of the falls risk and direct comprehensive interventions to address the multiple factors that lead to falls.


The somatostatin 2A receptor is enriched in migrating neurons during rat and human brain development and stimulates migration and axonal outgrowth.
The neuropeptide somatostatin has been suggested to play an important role during neuronal development in addition to its established modulatory impact on neuroendocrine, motor and cognitive functions in adults. Although six somatostatin G protein-coupled receptors have been discovered, little is known about their distribution and function in the developing mammalian brain. In this study, we have first characterized the developmental expression of the somatostatin receptor sst2A, the subtype found most prominently in the adult rat and human nervous system. In the rat, the sst2A receptor expression appears as early as E12 and is restricted to post-mitotic neuronal populations leaving the ventricular zone. From E12 on, migrating neuronal populations immunopositive for the receptor were observed in numerous developing regions including the cerebral cortex, hippocampus and ganglionic eminences. Intense but transient immunoreactive signals were detected in the deep part of the external granular layer of the cerebellum, the rostral migratory stream and in tyrosine hydroxylase- and serotonin- positive neurons and axons. Activation of the sst2A receptor in vitro in rat cerebellar microexplants and primary hippocampal neurons revealed stimulatory effects on neuronal migration and axonal growth, respectively. In the human cortex, receptor immunoreactivity was located in the preplate at early development stages (8 gestational weeks) and was enriched to the outer part of the germinal zone at later stages. In the cerebellum, the deep part of the external granular layer was strongly immunoreactive at 19 gestational weeks, similar to the finding in rodents. In addition, migrating granule cells in the internal granular layer were also receptor-positive. Together, theses results strongly suggest that the somatostatin sst2A receptor participates in the development and maturation of specific neuronal populations during rat and human brain ontogenesis.


Mechanical ventilation-induced oxidative stress in the diaphragm.
Prolonged mechanical ventilation (MV) results in oxidative damage in the diaphragm; however, it is unclear whether this MV-induced oxidative injury occurs rapidly or develops slowly over time. Furthermore, it is unknown whether both soluble (cytosolic) and insoluble (myofibrillar) proteins are equally susceptible to oxidation during MV. These experiments tested two hypotheses: 1). MV-induced oxidative injury in the diaphragm occurs within the first 6 h after the initiation of MV; and 2). MV is associated with oxidative modification of both soluble and insoluble proteins. Adult Sprague-Dawley rats were randomly divided into one of seven experimental groups: 1) control (n = 8); 2) 3-h MV (n = 8); 3). 6-h MV (n = 6); 4). 18-h MV (n = 8); 5). 3-h anesthesia-spontaneous breathing (n = 8); 6). 6-h anesthesia-spontaneous breathing (n = 6); and 7). 18-h anesthesia-spontaneous breathing (n = 8). Markers of oxidative injury in the diaphragm included the measurement of reactive (protein) carbonyl derivatives (RCD) and total lipid hydroperoxides. Three hours of MV did not result in oxidative injury in the diaphragm. In contrast, both 6 and 18 h of MV promoted oxidative injury in the diaphragm, as indicated by increases in both protein RCD and lipid hydroperoxides. Electrophoretic separation of soluble and insoluble proteins indicated that the MV-induced accumulation of RCD was limited to insoluble proteins with molecular masses of approximately 200, 120, 80, and 40 kDa. We conclude that MV results in a rapid onset of oxidative injury in the diaphragm and that insoluble proteins are primary targets of MV-induced protein oxidation.