Nucleophilic reactivities of hydrazines and amines: the futile search for the α-effect in hydrazine reactivities.
The kinetics of the reactions of amines, hydrazines, hydrazides, and hydroxylamines with benzhydrylium ions and quinone methides were studied in acetonitrile and water by UV-vis spectroscopy, using conventional spectrometers and stopped-flow and laser-flash techniques. From the second-order rate constants k(2) of these reactions, the nucleophilicity parameters N and s(N) were determined according to the linear free energy relationship log k(2) = s(N)(N + E). While methyl groups increase the reactivities of the α-position of hydrazines, they decrease the reactivities of the β-position. Despite the 10(2) times lower reactivities of amines and hydrazines in water than in acetonitrile, the relative reactivities of differently substituted amines and hydrazines are almost identical in the two solvents. In both solvents hydrazine has a reactivity similar to that of methylamine. This observation implies that replacement of one hydrogen in ammonia by Me increases the nucleophilicity more than introduction of an amino group, if one takes into account that hydrazine has two reactive centers. Plots of log k(2) versus the corresponding equilibrium constants (log K) or Brønsted basicities (pK(aH)) do not show enhanced nucleophilicities (α-effect) for either hydrazines or hydroxylamine relative to alkylamines.


Genetic association meets RNA interference: large-scale genomic screens for causation and mechanism of complex diseases.
While the genomic era offers great promise for biomedicine in general and for biomarker discovery in particular, it has yet to significantly impact drug target discovery. Meanwhile, despite improvements over the past 20 years in reducing attrition in clinical trials due to adverse drug responses, the pharmaceutical industry continues to be beset by the high rate of attrition of compounds in late-stage development, primarily due to the lack of drug efficacy. Clearly, even highly potent drugs with ideal safety and pharmacokinetic profiles will fail to survive clinical trials if the drug target itself is not a key point of intervention for most patients. Genetic association studies and RNA interference are two scaleable genomic approaches that together can address the quality as well as quantity of candidate drug targets. Human genetic information has long been used to identify 'molecular bottlenecks' that can highlight the importance of a gene or pathway at the clinical level. The recent availability of the human HapMap and of high-throughput genotyping platforms now enables more systematic genetic screens for novel, clinically-relevant drug targets. In addition, RNA interference can help dissect the molecular role of a candidate drug target in preclinical model systems in vitro and in vivo. Wider applicability of RNA interference methods will closely follow continued progress on efficient delivery into appropriate cell models and target tissues.


Production of Knockout Mutants by CRISPR/Cas9 in the European Honeybee, Apis mellifera L.
The European honeybee (Apis mellifera L.) is used as a model organism in studies of the molecular and neural mechanisms underlying social behaviors and/or advanced brain functions. The entire honeybee genome has been sequenced, which has further advanced molecular biologic studies of the honeybee. Functions of genes of interest, however, remain largely to be elucidated in the honeybee due to the lack of effective reverse genetic methods. Moreover, genetically modified honeybees must be maintained under restricted laboratory conditions due to legal restrictions, further complicating the application of reverse genetics to this species. Here we applied CRISPR/Cas9 to the honeybee to develop an effective reverse genetic method. We targeted major royal jelly protein 1 (mrjp1) for genome editing, because this gene is predominantly expressed in adult workers and its mutation is not expected to affect normal development. By injecting sgRNA and Cas9 mRNA into 57 fertilized embryos collected within 3 h after oviposition, we successfully created six queens, one of which produced genome-edited male offspring. Of the 161 males produced, genotyping demonstrated that the genome was edited in 20 males. All of the processes necessary for producing these genome-edited queens and males were performed in the laboratory. Therefore, we developed essential techniques to create knockout honeybees by CRISPR/Cas9. Our findings also suggested that mrjp1 is dispensable for normal male development, at least till the pupal stage. This new technology could pave the way for future functional analyses of candidate genes involved in honeybee social behaviors.


Shared signals -'alarm calls' from plants increase apparency to herbivores and their enemies in nature.
The attraction of natural enemies of herbivores by volatile organic compounds as an induced indirect defence has been studied in several plant systems. The evidence for their defensive function originates mainly from laboratory studies with trained parasitoids and predators; the defensive function of these emissions for plants in natural settings has been rarely demonstrated. In native populations and laboratory Y-tube choice experiments with transgenic Nicotiana attenuata plants unable to release particular volatiles, we demonstrate that predatory bugs use terpenoids and green leaf volatiles (GLVs) to locate their prey on herbivore-attacked plants. By attracting predators with volatile signals, this native plant reduces its herbivore load - demonstrating the defensive function of herbivore-induced volatile emissions. However, plants producing GLVs are also damaged more by flea beetles. The implications of these conflicting ecological effects for the evolution of induced volatile emissions and for the development of sustainable agricultural practices are discussed.


Anti-hepatitis B virus effects of wogonin isolated from Scutellaria baicalensis.
By using an HBV-producing cell line (MS-G2) in vitro culture system, we found that wogonin isolated from Scutellaria baicalensis can suppress HBV surface antigen production (P < 0.001) without evidence of cytotoxicity. By assaying the endogenous HBV DNA polymerase activity, we found that both the relaxed circular and the linear forms of HBV DNA are significantly reduced in the wogonin-treated group. Wogonin deserves to be further evaluated for the treatment of human HBV infection.


Care Associated With Satisfaction of Bereaved Family Members of Terminally Ill Cancer Patients With Dyspnea: A Cross-sectional Nationwide Survey.
Terminal dyspnea in dying cancer patients is frequent and distressing, and the impact extends to their families. Families are often involved in providing care for terminal dyspnea. This study aimed to describe various care strategies for terminal dyspnea in cancer patients hospitalized in palliative care units (PCUs), evaluate families' satisfaction with care for terminal dyspnea, and explore determinants contributing to families' satisfaction. A nationwide, cross-sectional survey was conducted using a self-reported questionnaire among bereaved families of cancer patients who died in PCUs. The questionnaire consisted of questions on the perceptions of care offered to patients with terminal dyspnea and their families, satisfaction with care for terminal dyspnea, family-perceived intensity of terminal dyspnea, use of oxygen, and background data of patients and families. In total, 533 participants (response rate = 54%) returned the completed questionnaires, and 231 reported that their loved one had experienced terminal dyspnea. Dedicated and compassionate care was perceived by 60%-89% of the participants as the strategy provided for patients. Care for family members was perceived by 58%-69% of the participants. Perception of dedicated and compassionate care for patients and that of care for family members were significantly associated with high satisfaction (odds ratio, 95% confidence interval: 8.64, 3.85-19.36 and 15.37, 5.00-47.25, respectively). Dedicated and compassionate care may be the essential part of the care for terminal dyspnea. Dedicated and compassionate care for patients and care for family members have a potential of improving the care satisfaction among family caregivers.


Frequency of serous tubal intraepithelial carcinoma in various gynecologic malignancies: a study of 300 consecutive cases.
Serous tubal intraepithelial carcinoma (STIC) has been implicated in the pathogenesis of pelvic serous carcinoma. We hypothesized that, if this is the case, the frequency of STIC should be substantially lower in endometrial serous carcinomas, in nonserous gynecologic malignancies, and in benign gynecologic neoplasms than in ovarian or peritoneal serous carcinomas. From 2007 to 2009 the fallopian tubes of 342 consecutive gynecologic cases were entirely submitted for histology using the Sectioning and Extensively Examining the FIMbriated end protocol. This study included 300 of these cases (277 TAH-BSO, 23 BSO) after exclusion. The hematoxylin and eosin-stained slides from the fallopian tubes were independently reviewed by 2 gynecologic pathologists who were blinded to all other findings; disagreements were resolved by a third pathologist. Among 46 cases of ovarian malignancies, STIC was identified in 6 (18.8%) of 32 cases of serous carcinoma, but not in any other subtype. Similarly, STIC coexisted in 4 (14.3%) of 28 cases of endometrial serous carcinoma; however, no STIC was identified in any of the 74 cases of nonserous endometrial malignancies. STIC was identified in 2 (28.6%) of 7 cases of peritoneal serous carcinoma. No STIC was identified among 15 nongynecologic malignancies, 90 cases of benign conditions, and 27 cases of other conditions including 4 cases of cervical adenocarcinoma in situ and high-grade cervical intraepithelial lesions, 8 cases of endometrial atypical complex hyperplasias, and 15 cases of ovarian borderline tumors. In conclusion, the fallopian tube may be the origin of some pelvic serous carcinomas. Other possibilities that may explain the origin of pelvic high-grade serous carcinoma are discussed. Given that STIC coexisted with 14% of endometrial serous carcinomas, a more unifying theory may be that gynecologic serous carcinomas and STIC are multifocal lesions.


Wnt/β-catenin and MAPK signaling: allies and enemies in different battlefields.
Two papers published in Science Signaling reveal extensive crosstalk between Wnt/β-catenin and mitogen-activated protein kinase (MAPK) signaling in cancer. Although both studies describe previously unknown links between these two signaling pathways, the relationship between Wnt/β-catenin and MAPK signaling depends on the specific cellular context. Indeed, in melanoma, hyperactivated MAPK signaling down-regulates the Wnt/β-catenin signal transduction cascade, thereby establishing a negative crosstalk between the two signaling pathways. In contrast, in colorectal cancer, stimulation of the Wnt/β-catenin pathway leads to activation of the MAPK pathway through Ras stabilization, representing an example of positive crosstalk. Moreover, activation of Wnt/β-catenin signaling has context-dependent functions that trigger opposing effects on tumor growth. In melanoma, aberrant activation of Wnt/β-catenin signaling may have anti-oncogenic functions by promoting programmed cell death; by contrast, in the intestine, Wnt/β-catenin signaling drives malignant transformation. Thus, there is no single correct way to target the Wnt/β-catenin pathway for all cancers.


Surgeon characteristics and receipt of adjuvant radiotherapy in women with breast cancer.
Adjuvant radiotherapy following breast conservation surgery (BCS) is considered to be an indicator of quality of care for the majority of women with breast cancer, but many women do not receive adjuvant radiotherapy. We investigated the association of surgeon-related factors with receipt of adjuvant radiotherapy after BCS. We used the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database to identify women aged 65 years or older with stage I/II breast cancer who were diagnosed between 1991 and 2002 and underwent BCS. We collected demographic and clinical data from SEER and treatment information from Medicare claims data. The American Medical Association Masterfile was used to obtain information on surgeons' characteristics, including sex, medical school location (United States or elsewhere), and type of degree (MD or Doctorate in Osteopathic Medicine [DO]). The associations of patient (age, race, rural vs urban residence, comorbidities, marital status), tumor (hormone receptor status, grade, stage), and surgeon-related factors with receipt of adjuvant radiotherapy were analyzed using Generalized Estimating Equations to control for clustering. All statistical tests were two-sided. Of 29,760 women in our sample, 22,207 (75%) received radiotherapy. Patients who received adjuvant radiotherapy were younger, had fewer comorbidities, and were more likely to be white, married, from an urban area, and diagnosed in a later year compared with those who did not. They were also more likely to have a surgeon who was female (79% vs 73%), had an MD degree (75% vs 68%), or was US trained (75% vs 70%). The multivariable analysis confirmed the association of radiotherapy with having a surgeon who was female (odds ratio [OR] = 1.13; 95% confidence interval [CI] = 1.06 to 1.27), had an MD degree (OR = 1.55; 95% CI = 1.24 to 1.91), was US trained (OR = 1.12; 95% CI = 1.01 to 1.25), or had more than 15 patients (OR = 1.18; 95% CI = 1.10 to 1.28). Surgeon characteristics were associated with patients' receipt of adjuvant radiotherapy after BCS after controlling for patient and tumor characteristics, although the individual effect sizes were small for surgeon sex, location of training, and type of medical degree. More research is warranted to confirm the associations to determine whether they reflect surgeon behavior, patient response, or physician-patient interactions.


Insecticidal and antifeedant activities of clerodane diterpenoids isolated from the Indian bhant tree, Clerodendron infortunatum, against the cotton bollworm, Helicoverpa armigera.
The Indian bhant tree, Clerodendron infortunatum L. (Lamialus: Lamiaceae), is a well-known medicinal plant, but little information about its bioefficacy against agricultural pests exists. This scarcity was addressed in the present study, in which dried leaves of C. infortunatum were subjected to extraction with hexane and methanol and then partitioned using different solvents of varying polarity. In a preliminary bioassay, the antifeedant effects of the crude extracts and fractions were tested on a highly polyphagous pest, the cotton bollworm, Helicoverpa armigera Hübner (Lepidoptera: Noctuidae), using the no-choice test method with cabbage leaf discs. The methanol fraction resulted in maximum antifeedant activity. This fraction was further subjected to crystallization and column chromatography in order to isolate the compounds responsible for the activity. Three pure compounds were isolated and identified as clerodin (CL), 15-methoxy-14, 15-dihydroclerodin (MD), and 15-hydroxy-14, 15-dihyroclerodin (HD). The antifeedant activity of these compounds was studied using a choice as well as a no-choice test method with 24 and 48 hr observation periods. Insecticidal activity was measured using the topical application method at 0.5, 1, 1.5, 2, 2.5, and 3% concentrations, and data were recorded 24, 48, and 72 hr after treatment. In the no-choice test conditions, compounds CL and MD showed significantly higher antifeedant activity compared to the key ingredient in many commercial pesticides, azadirachtin, at its highest concentration. Compound HD also showed very good antifeedant activity, which did not differ significantly from that of azadirachtin. In the choice test conditions, all three compounds and azadirachtin showed 100% antifeedant activity at the highest concentration. Antifeedant Index (AI50) values of CL, MD, and HD were 6, 6, and 8 ppm in choice tests, and increased to 8, 9, and 11 ppm in the no-choice tests, respectively. Insecticidal activity of the isolated compounds was not significant compared to the control condition, even at the highest con-concentrations of the compounds. These results suggest that extracts of C. infortunatum have very good antifeedant effects against H. armigera due to the presence of specific compounds. These compounds could be utilized in the development of new biopesticides.


Human endogenous retroviruses: from infectious elements to human genes.
Mammalian genomes contain a heavy load (42% in humans) of retroelements, which are mobile sequences requiring reverse transcription for their replicative transposition. A significant proportion of these elements is of retroviral origin, with thousands of sequences resembling the integrated form of infectious retroviruses, with two LTRs bordering internal regions homologous to the gag, prt, pol, and env genes. These elements, named endogenous retroviruses (ERVs), are most probably the proviral remnants of ancestral germ-line infections by active retroviruses, which have thereafter been transmitted in a Mendelian manner. The complete sequencing of the human genome now allows a comprehensive survey of human ERVs (HERVs), which can be grouped according to sequence homologies into approximately 80 distinct families, each containing a few to several hundred elements. As reviewed here, strong similarities between HERVs and present-day retroviruses can be inferred from phylogenetic analyses on the reverse transcriptase (RT) domain of the pol gene or the transmembrane subunit (TM) of the env gene, which disclose interspersion of both classes of elements and suggest a common history and shared ancestors. Similarities are also observed at the functional levels, since despite the fact that most HERVs have accumulated mutations, deletions, and/or truncations, several elements still possess some of the functions of retroviruses, with evidence for viral-like particle formation, and occurrence of envelope proteins allowing cell-cell fusion and even conferring infectivity to pseudotypes. Along this line, a genomewide screening for human retroviral genes with coding capacity has revealed 16 fully coding envelope genes. These genes are transcribed in several healthy tissues including the placenta, three of them at a very high level. Besides their impact in modelling the genome, HERVs thus appear to contain still active genes, which most probably have been subverted by the host for its benefit and should be considered as bona fide human genes. Some of their characteristic features and possible physiological roles, as well as potential pathological effects inherited from their retroviral ancestors are also reviewed.


Regional chemotherapy directed by individual chemosensitivity testing in vitro: a prospective decision-aiding trial.
A prospective decision-aiding trial was performed to select drugs for regional chemotherapy of various liver tumors (n = 36) by individual drug testing. The drugs were chosen for hepatic artery infusion according to the individual chemosensitivity of tumor biopsies in the human tumor colony-forming assay (HTCA). In vitro HTCA sensitivity correlated with complete response (CR) + partial response (PR) + no change (NC) 93% of the time and with CR + PR 55% of the time. The test sensitivity was 90%, and the specificity was 67% for CR + PR + NC versus progressive disease (PD), whereas the sensitivity and specificity were 89% and 28%, respectively, for CR + PR versus NC + PD. The overall predictive accuracy of the test was 86% for CR + PR + NC versus PD and 58% for CR + PR versus NC + PD. Overall, 83% of this heterogenous patient group with various tumors achieved CR + PR + NC and a 50% clinical response (CR + PR). In vitro-sensitive patients showed a significantly lower intrahepatic progression rate (7% PD) than in vitro-resistant patients (57%; P < 0.05). These results indicate that the HTCA could identify active drugs for individualized hepatic artery infusion, and patients may profit from the use of in vitro-sensitive drugs.


Meaningful sounds enhance visual sensitivity to human gait regardless of synchrony.
Previous research demonstrates that meaningfully related sounds enhance visual sensitivity to point-light displays of human movement. Here we report two psychophysical studies that investigated whether, and if so when, this facilitation is modulated by the temporal relationship between auditory and visual stimuli. In Experiment 1, participants detected point-light walkers in masks while listening to footsteps that were either synchronous or out-of-phase with point-light footfalls. The relative timing of auditory and visual walking did not impact performance. Experiment 2 further tested the importance of multisensory timing by disrupting the rhythm of the auditory and visual streams. Participants detected point-light walkers while listening to footstep or tone sounds that were either synchronous or temporally random with regards to point-light footfalls. Heard footsteps improved visual sensitivity over heard tones regardless of timing. Taken together, these results suggest that during the detection of others' actions, the perceptual system makes use of meaningfully related sounds whether or not they are synchronous. These results are discussed in relation to the unity assumption theory as well as recent empirical data that suggest that temporal correspondence is not always a critical factor in multisensory perception and integration.


Factors associated with preservation of facial nerve function after surgical resection of vestibular schwannoma.
Avoidance of facial nerve palsy is one of the major goals of vestibular schwannoma (VS) microsurgery. In this study, we examined the significance of previously implicated prognostic factors (age, tumor size, the extent of resection and the surgical approach) on post-operative facial nerve function. We selected all VS patients from prospectively collected database (1984-2009) who underwent microsurgical resection as their initial treatment for histopathologically confirmed VS. The effect of variables such as surgical approach, tumor size, patient age and extent of resection on rates facial nerve dysfunction after surgery, were analyzed using multivariate logistic regression. Patients with preoperative facial nerve dysfunction (House-Brackman [HB] score 3 or higher) were excluded, and HB grade of 1 or 2 at the last follow-up visit was defined as "facial nerve preservation." A total of 624 VS patients were included in this study. Multivariate logistic regression analysis found that only pre-operative tumor size significantly predicted poorer facial nerve outcome for patients followed-up for ≥6 and ≥12 months (OR 1.27, 95% CI 1.09-1.49, p < 0.01; OR 1.35, 95% CI 1.10-1.67, P < 0.01, respectively). We found no significant relationship between facial nerve function and age, extent of resection, surgical approach, or tumor size (when extent of resection and surgical approach were included in the regression analysis). Because facial nerve palsy is a debilitating and psychologically devastating condition for the patient, we suggest altering surgical aggressiveness in patients with unfavorable tumor anatomy, particularly in cases with large tumors where overaggressive resection might subject the patient to unwarranted risk. Residual disease can be followed and controlled with radiosurgery if interval growth is noted.


Use of NSAIDs in treating patients with arthritis.
Patients with rheumatic diseases, including rheumatoid arthritis and osteoarthritis, almost universally describe pain and stiffness as important contributors to reduced health-related quality of life. Of the treatment options available, NSAIDs are the most widely used agents for symptomatic treatment. NSAIDs are effective anti-inflammatory and analgesic drugs by virtue of their ability to inhibit biosynthesis of prostaglandins at the level of the cyclooxygenase enzyme. However, many of the adverse effects of NSAIDs are also related to inhibition of prostaglandin production, making their use problematic in some patient populations. For the clinician, understanding the biology of prostaglandin as it relates to gastrointestinal, renal, and cardiovascular physiology and the pharmacologic properties of specific NSAIDs is key to using these drugs safely. Of particular importance is the recognition of co-morbid conditions and concomitant drugs that may increase the risk of NSAIDs in particular patients. In patients with risk factors for NSAID toxicity, using the lowest dose of a drug with a short half-life only when it is needed is likely to be the safest treatment option. For those patients whose symptoms cannot be managed with intermittent treatment, using protective strategies is essential.


Interval mapping of quantitative trait loci controlling humoral immunity to exogenous antigens: evidence that non-MHC immune response genes may also influence susceptibility to autoimmunity.
IgG Ab titers elicited to bovine rhodopsin in CFA differ 8- to 10-fold between H2s identical inbred strains A.SW/snJ (high responder) and SJL/snJ (low responder). This variation in IgG Ab titer resulted from a dramatic difference in the rise in Ab titer occurring during the maturation of the T-dependent humoral immune response. To determine the positions of non-MHC genes controlling this quantitative variation in T-dependent humoral immune responsiveness, 206 reciprocal (A.SW/snJ x SJL/snJ)F2 female progeny were immunized and assayed for anti-rhodopsin responsiveness. The genomes of these progeny were screened with 115 polymorphic simple sequence repeat markers covering >90% of the mouse genome. interval mapping analysis localized the positions of these non-MHC immune response genes to genomic intervals on chromosomes 1, 5, and 13. Interestingly, these three intervals coincide exactly with three intervals recently shown to contain genes contributing to susceptibility to systemic lupus erythematosus and/or the production of autoimmune anti-dsDNA Abs. These results suggest that some genes affecting levels of humoral immune responsiveness to exogenous Ag may also play a role in genetic susceptibility to humoral autoimmune diseases. Analyses of the modes of inheritance demonstrated that high responder alleles were inherited from both parental genomes, indicative of epistatic interactions among genes influencing humoral immune responsiveness.


Videomicroscopy as a tool for investigation of the microcirculation in the newborn.
The perinatal period remains a time of significant risk of death or disability. Increasing evidence suggests that this depends on microcirculatory behavior. Sidestream dark-field orthogonal polarized light videomicroscopy (OPS) has emerged as a useful assessment of adult microcirculation but the values derived are not delineated for the newborn. We aimed to define these parameters in well term newborn infants. Demographic details were collected prospectively on 42 healthy term neonates (n = 20 females, n = 22 males). OPS videomicroscopy (Microscan) was used to view ear conch skin microcirculation at 6, 24, and 72 h of age. Stored video was analyzed by a masked observer using proprietary software. There were no significant differences between the sexes for any structural parameters at any time point. There was a significant increase over time in small vessel perfusion in female infants only (P = 0.009). A number of 6- and 72-h measurements were significantly correlated, but differed from the 24-h values. These observations confirm the utility of the ear conch for neonatal microvascular videomicroscopy. They provide a baseline for studies into the use of OPS videomicroscopy in infants. The changes observed are comparable with previous studies of term infants using these and other microvascular techniques. It is recommended that studies for examining the mature neonatal microvascular structure be delayed until 72 h of life, but studies of the physiology of cardiovascular transition should include the 24-h time point after delivery.


Self-assembly of a peptide amphiphile containing L-carnosine and its mixtures with a multilamellar vesicle forming lipid.
The self-assembly of the peptide amphiphile (PA) hexadecyl-(β-alanine-histidine) is examined in aqueous solution, along with its mixtures with multilamellar vesicles formed by DPPC (dipalmitoyl phosphatidylcholine). This PA, denoted C(16)-βAH, contains a dipeptide headgroup corresponding to the bioactive molecule L-carnosine. It is found to self-assemble into nanotapes based on stacked layers of molecules. Bilayers are found to coexist with monolayers in which the PA molecules pack with alternating up-down arrangement so that the headgroups decorate both surfaces. The bilayers become dehydrated as PA concentration increases and the number of layers in the stack decreases to produce ultrathin nanotapes comprised of 2-3 bilayers. Addition of the PA to DPPC multilamellar vesicles leads to a transition to well-defined unilamellar vesicles. The unique ability to modulate the stacking of this PA as a function of concentration, combined with its ability to induce a multilamellar to unilamellar thinning of DPPC vesicles, may be useful in biomaterials applications where the presentation of the peptide function at the surface of self-assembled nanostructures is crucial.


Ischemia and reperfusion-induced histologic changes in the rat retina. Demonstration of a free radical-mediated mechanism.
Histologic alterations of ischemia- and reperfusion-induced retinal damage are critically dependent on the duration of the period of ischemia. Male Sprague Dawley rats were anesthetized, and a suture was placed behind the globe including the central retinal artery. Because it was desirable that untreated eyes show a great histologic change due to reperfusion-induced damage (in order that maximum scope would exist for demonstration of any protective effect of a drug treatment), a preliminary series of studies established the time-induced characteristics for the retina with transient regional ischemia. Eyes (n = 6-12 in each group) were subjected to 30, 60, or 90 min of ischemia followed by 0.5, 1, 2, 4, and 24 hr of reperfusion, respectively. The 30-min ischemia followed by reperfusion did not result in any histologic changes; 60-min ischemia followed by reperfusion induced a moderate retinal edema which returned to the preischemic value after 24 hr of reperfusion. The 90-min ischemia followed by reperfusion further aggravated retinal edema and increased the migration of neutrophil leukocytes. Even after 24 hr of reperfusion, the retinal edema had not disappeared although an attenuation was observed. In this study, the rats were treated with superoxide dismutase (SOD-PEG, 15 x 10(3) U/kg) or EGB 761 (100 mg/kg) for 10 days (chronic treatment). The SOD and EGB 761 significantly reduced the development of reperfusion-induced retinal edema and significantly prevented the neutrophil leukocyte infiltration. Both also had a protective effect against reperfusion-induced injury when these agents were administered just before reperfusion ("late" administration).(ABSTRACT TRUNCATED AT 250 WORDS)


Polyethylene oxide film coating enhances lithium cycling efficiency of an anode-free lithium-metal battery.
The practical implementation of an anode-free lithium-metal battery with promising high capacity is hampered by dendrite formation and low coulombic efficiency. Most notably, these challenges stem from non-uniform lithium plating and unstable SEI layer formation on the bare copper electrode. Herein, we revealed the homogeneous deposition of lithium and effective suppression of dendrite formation using a copper electrode coated with a polyethylene oxide (PEO) film in an electrolyte comprising 1 M LiTFSI, DME/DOL (1/1, v/v) and 2 wt% LiNO3. More importantly, the PEO film coating promoted the formation of a thin and robust SEI layer film by hosting lithium and regulating the inevitable reaction of lithium with the electrolyte. The modified electrode exhibited stable cycling of lithium with an average coulombic efficiency of ∼100% over 200 cycles and low voltage hysteresis (∼30 mV) at a current density of 0.5 mA cm-2. Moreover, we tested the anode-free battery experimentally by integrating it with an LiFePO4 cathode into a full-cell configuration (Cu@PEO/LiFePO4). The new cell demonstrated stable cycling with an average coulombic efficiency of 98.6% and capacity retention of 30% in the 200th cycle at a rate of 0.2C. These impressive enhancements in cycle life and capacity retention result from the synergy of the PEO film coating, high electrode-electrolyte interface compatibility, stable polar oligomer formation from the reduction of 1,3-dioxolane and the generation of SEI-stabilizing nitrite and nitride upon lithium nitrate reduction. Our result opens up a new route to realize anode-free batteries by modifying the copper anode with PEO to achieve ever more demanding yet safe interfacial chemistry and control of dendrite formation.


Stent versus Coronary Artery Bypass Surgery in Multi-Vessel and Left Main Coronary Artery Disease: A Meta-Analysis of Randomized Trials with Subgroups Evaluation.
Comparison between percutaneous coronary intervention (PCI) using stents and Coronary Artery Bypass Grafting (CABG) remains controversial. To conduct a systematic review with meta-analysis of PCI using Stents versus CABG in randomized controlled trials. Electronic databases were searched to identify randomized trials comparing PCI using Stents versus CABG for multi-vessel and unprotected left main coronary artery disease (LMCAD). 15 trials were found and their results were pooled. Differences between trials were considered significant if p < 0.05. In the pooled data (n = 12,781), 30 days mortality and stroke were lower with PCI (1% versus 1.7%, p = 0.01 and 0.6% versus 1.7% p < 0.0001); There was no difference in one and two year mortality (3.3% versus 3.7%, p = 0.25; 6.3% versus 6.0%, p = 0.5). Long term mortality favored CABG (10.6% versus 9.4%, p = 0.04), particularly in trials of DES era (10.1% versus 8.5%, p = 0.01). In diabetics (n = 3,274) long term mortality favored CABG (13.7% versus 10.3%; p < 0.0001). In six trials of LMCAD (n = 4,700) there was no difference in 30 day mortality (0.6%versus 1.1%, p = 0.15), one year mortality (3% versus 3.7%, p = 0.18), and long term mortality (8.1% versus 8.1%) between PCI and CABG; the incidence of stroke was lower with PCI (0.3% versus 1.5%; p < 0.001). Diabetes and a high SYNTAX score were the subgroups that influenced more adversely the results of PCI. Compared with CABG, PCI using Stents showed lower 30 days mortality, higher late mortality and lower incidence of stroke. Diabetes and a high SYNTAX were the subgroups that influenced more adversely the results of PCI.


Is having more preapproval data the best way to assure drug safety?
An intensified focus on drug safety often leads to demands for more data collection prior to drug approval. Other approaches can be used, such as enhanced postmarketing surveillance. Many drug benefits and adverse effects are unlikely to become apparent before wide distribution among diverse patients. The best balance of pre- and postapproval data collection may vary by drug. The consequences of alternative strategies are complex and not always immediately apparent, so formal modeling offers the best approach to determine which strategy is optimal in each case.


Using consensus-shape clustering to identify promiscuous ligands and protein targets and to choose the right query for shape-based virtual screening.
Ligand-based shape matching approaches have become established as important and popular virtual screening (VS) techniques. However, despite their relative success, many authors have discussed how best to choose the initial query compounds and which of their conformations should be used. Furthermore, it is increasingly the case that pharmaceutical companies have multiple ligands for a given target and these may bind in different ways to the same pocket. Conversely, a given ligand can sometimes bind to multiple targets, and this is clearly of great importance when considering drug side-effects. We recently introduced the notion of spherical harmonic-based "consensus shapes" to help deal with these questions. Here, we apply a consensus shape clustering approach to the 40 protein-ligand targets in the DUD data set using PARASURF/PARAFIT. Results from clustering show that in some cases the ligands for a given target are split into two subgroups which could suggest they bind to different subsites of the same target. In other cases, our clustering approach sometimes groups together ligands from different targets, and this suggests that those ligands could bind to the same targets. Hence spherical harmonic-based clustering can rapidly give cross-docking information while avoiding the expense of performing all-against-all docking calculations. We also report on the effect of the query conformation on the performance of shape-based screening of the DUD data set and the potential gain in screening performance by using consensus shapes calculated in different ways. We provide details of our analysis of shape-based screening using both PARASURF/PARAFIT and ROCS, and we compare the results obtained with shape-based and conventional docking approaches using MSSH/SHEF and GOLD. The utility of each type of query is analyzed using commonly reported statistics such as enrichment factors (EF) and receiver-operator-characteristic (ROC) plots as well as other early performance metrics.


Issues of under-representation in quantitative DNA metabarcoding weaken the inference about diet of the tundra vole Microtus oeconomus.
During the last decade, methods based on high-throughput sequencing such as DNA metabarcoding have opened up for a range of new questions in animal dietary studies. One of the major advantages of dietary metabarcoding resides in the potential to infer a quantitative relationship between sequence read proportions and biomass of ingested food. However, this relationship's robustness is highly dependent on the system under study, calling for case-specific assessments. Herbivorous small rodents often play important roles in the ecosystem, and the use of DNA metabarcoding for analyses of rodent diets is increasing. However, there has been no direct validation of the quantitative reliability of DNA metabarcoding for small rodents. Therefore, we used an experimental approach to assess the relationship between input plant biomass and sequence reads proportions from DNA metabarcoding in the tundra vole Microtus oeconomus. We found a weakly positive relationship between the number of high-throughput DNA sequences and the expected biomass proportions of food plants. The weak relationship was possibly caused by a systematic under-amplification of one of the three plant taxa fed. Generally, our results add to the growing evidence that case-specific validation studies are required to reliably make use of sequence read abundance as a proxy of relative food proportions in the diet.


Superficial middle cerebral vein connection to the cavernous sinus is not infrequent in brain arteriovenous malformations: an argument against their congenital origin?
The aim of this study was to test the hypothesis that the superficial middle cerebral vein (SMCV) is frequently absent or fails to connect with the cavernous sinus (CS) in the presence of brain arteriovenous malformations (AVMs), a frequently reported argument for the congenital origin of brain AVMs. The SMCV was retrospectively compared between patients with a brain AVM and a control group. The presence or absence of the SMCV, its direct or indirect connection to the CS and its termination in a laterocavernous sinus (LCS), paracavernous sinus (PCS), or directly in the CS was studied on digital subtraction angiography. One hundred twenty-five left or right side carotid angiograms from 70 patients with a brain AVM were compared to 125 angiograms from 74 controls. The SMCV was present in 88 (70.4 %) cases in the brain AVM group and 96 (76.8 %) cases in controls (p = 0.25). The SMCV was connected directly or indirectly to the CS in 65 (52 %) cases in the brain AVM group and 65 (52 %) cases in controls (p = 1). When comparing the subgroup of carotid angiograms ipsilateral to a supratentorial AVM, no statistically significant difference was found with controls. In three of six cases in which a SMCV drained an AVM, the vein terminated directly or indirectly in the CS. No difference of SMCV presence and direct or indirect connection to the CS was found between patients with AVM and a control group. SMCV anatomy does not support the congenital origin of brain AVMs.


Surveillance of health status in minority communities - Racial and Ethnic Approaches to Community Health Across the U.S. (REACH U.S.) Risk Factor Survey, United States, 2009.
Substantial racial/ethnic health disparities exist in the United States. Although the populations of racial and ethnic minorities are growing at a rapid pace, large-scale community-based surveys and surveillance systems designed to monitor the health status of minority populations are limited. CDC conducts the Racial and Ethnic Approaches to Community Health across the U.S. (REACH U.S.) Risk Factor Survey annually in minority communities. The survey focuses on black, Hispanic, Asian (including Native Hawaiian and Other Pacific Islander), and American Indian (AI) populations. 2009. An address-based sampling design was used in the survey in 28 communities located in 17 states (Arizona, California, Georgia, Hawaii, Illinois, Massachusetts, Michigan, New Mexico, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Virginia, West Virginia, and Washington). Self-reported data were collected through telephone, questionnaire mailing, and in-person interviews from an average of 900 residents aged ≥ 18 years in each community. Data from the community were compared with data derived from the Behavioral Risk Factor Surveillance System (BRFSS) for the metropolitan and micropolitan statistical area (MMSA), county, or state in which the community was located and also compared with national estimates. Reported education level and household income were markedly lower in black, Hispanic, and AI communities than that among the general population living in the comparison MMSA, county, or state. More residents in these minority populations did not have health-care coverage and did not see a doctor because of the cost. Substantial variations were identified in self-perceived health status and prevalence of selected chronic conditions among minority populations and among communities within the same racial/ethnic population. In 2009, the median percentage of men who reported fair or poor health was 15.8% (range: 8.3%-29.3%) among A/PI communities and 26.3% (range: 22.3%-30.8%) among AI communities. The median percentage of women who reported fair or poor health was 20.1% (range: 13.3%-37.2%) among A/PI communities, whereas it was 31.3% (range: 19.4%-44.2%) among Hispanic communities. AI and black communities had a high prevalence of self-reported hypertension, cardiovascular disease, and diabetes. For most communities, prevalence was much higher than that in the corresponding MMSA, county, or state in which the community was located. The median percentages of persons who knew the signs and symptoms of a heart attack and stroke were consistently lower in all four minority communities than the national median. Variations were identified among racial/ethnic populations in the use of preventive services. Hispanics had the lowest percentages of persons who had their cholesterol checked, of those with high blood pressure who were taking antihypertensive medication, and of those with diabetes who had a glycosylated hemoglobin (HbA1C) test in the past year. AIs had the lowest mammography screening rate within 2 years among women aged ≥40 years (median: 72.7%; range: 69.4%-76.2%). A/PIs had the lowest Pap smear screening rate within 3 years (median: 74.4%; range: 60.3%-80.8%). The median influenza vaccination rates in adults aged ≥65 years were much lower among black (57.3%) and Hispanic communities (63.3%) than the national median (70.1%) among the 50 states and DC. Pneumococcal vaccination rates also were lower in black (60.5%), Hispanic (58.5%), and A/PI (59.7%) communities than the national median (68.5%). Data from the REACH U.S. Risk Factor Survey demonstrate that residents in most of the minority communities continue to have lower socioeconomic status, greater barriers to health-care access, and greater risks for and burden of disease compared with the general populations living in the same MMSA, county, or state. Substantial variations in prevalence of risk factors, chronic conditions, and use of preventive services among different minority populations and different communities within the same racial/ethnic population provide opportunities for public health intervention. These variations also indicate that different priorities are needed to eliminate health disparities for different communities. These community-level survey data are being used by CDC and community coalitions to implement, monitor, and evaluate intervention programs in each community. Continuous surveillance of health status in minority communities is necessary so that community-specific, culturally sensitive strategies that include system, environmental, and individual-level changes can be tailored to these communities.


Significant understaging is seen in clinically staged T2N0 esophageal cancer patients undergoing esophagectomy.
This study aimed to determine the impact of preoperative staging on the treatment of clinical T2N0 (cT2N0) esophageal cancer patients undergoing esophagectomy. We reviewed a retrospective cohort of 27 patients treated at a single institution between 1999 and 2011. Clinical staging was performed with computed tomography, positron emission tomography, and endoscopic ultrasound. Patients were separated into two groups: neoadjuvant therapy followed by surgery (NEOSURG) and surgery alone (SURG). There were 11 patients (41%) in the NEOSURG group and 16 patients (59%) in the SURG group. In the NEOSURG group, three of 11 patients (27%) had a pathological complete response and eight (73%) were partial or nonresponders after neoadjuvant therapy. In the SURG group, nine of 16 patients (56%) were understaged, 6 (38%) were overstaged, and 1 (6%) was correctly staged. In the entire cohort, despite being clinically node negative, 14 of 27 patients (52%) had node-positive disease (5/11 [45%] in the NEOSURG group, and 9/16 [56%] in the SURG group). Overall survival rate was not statistically significant between the two groups (P = 0.96). Many cT2N0 patients are clinically understaged and show no preoperative evidence of node-positive disease. Consequently, neoadjuvant therapy may have a beneficial role in treatment.


Munc13-4 is a limiting factor in the pathway required for platelet granule release and hemostasis.
Activation-dependent platelet granule release is mediated by integral membrane proteins called soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors (SNAREs) and their regulators; however, the mechanisms for this process are ill-defined. To further characterize platelet secretion, we analyzed the function of platelets from Unc13d(Jinx) mice. Platelets from these animals lack the putative vesicle priming factor, Munc13-4, and have a severe secretion defect. Release from dense granules was completely ablated and that from alpha-granules and lysosomes was severely compromised. Unc13d(Jinx) platelets showed attenuated aggregation and, consequently, Unc13d(Jinx) mice had prolonged tail-bleeding times. The secretion defect was not due to altered expression of SNAREs or SNARE regulators, defective granule biogenesis, or faulty platelet activation. The defective release could be rescued by adding recombinant Munc13-4 to permeabilized Unc13d(Jinx) platelets. In wild-type mouse platelets, Munc13-4 levels were lower than those of SNAREs suggesting that Munc13-4 could be a limiting component of the platelets' secretory machinery. Consistently, Munc13-4 levels directly correlated with the extent of granule release from permeabilized platelets and from intact, heterozygous Unc13d(Jinx) platelets. These data highlight the importance of Munc13-4 in platelets and indicate that it is a limiting factor required for platelet secretion and hemostasis.


Potential role of flavonoids in the prevention of intestinal neoplasia: a review of their mode of action and their clinical perspectives.
Intestinal neoplasia (adenomas and carcinomas) can possibly be prevented by a diet rich in vegetables and fruits, treatment with aspirin and other nonsteroidal antiinflammatory drugs, and early colonoscopic removal of adenomas. Ballast, fiber, and secondary plant products could play a major role in colon cancer prevention. Recently there has been much experimental work in vitro and in vivo about flavonoids as inducers of bioprevention. Flavonoids are secondary plant products with a wide variety of beneficial biological properties, and they possess anticarcinogenic, antimutagenic, and antioxidative modes of actions. Flavonoids are the main components of a healthy diet containing fruits and vegetables and are concentrated especially in tea, apples, and onions. We will focus this review on flavonoids which are derived from tea products such as proanthocyanidins (green tea) and flavons (camomille tea). Oral supplementation with bioflavonoids derived from tea could be used in humans to prevent growth of intestinal neoplasia such as adenomatous polyps of the colon. Flavonoids are a large group of natural compounds of which only a few have been used in animal models, cell cultures, and enzyme studies to inhibit mutagenic and carcinogenic events. Their clinical mode of action was evaluated by epidemiological studies, but no intervention studies in humans have been performed so far. In vitro flavonoids can bind electrophils, inactivate oxygen radicals, prevent lipid peroxidation, and inhibit DNA oxidation. In cell cultures they increase the rate of apoptosis, inhibit cell proliferation, and angiogenesis. In vivo they can induce the activities of protective enzymes (conjugating enzymes such as glutathione transferases and glucuronosyl transferases) of the intestine and the liver. In models of intestinal polyposis, flavonoids suppress polyp formation. Some epidemiological studies show a protective effect of flavonoids contained in fruits, vegetables, and tea. Flavonoid mixtures of tea origin supplied as nutritional supplements could be studied as a new way of bioprevention of intestinal neoplasia (colon adenomas and cancer). Therefore, a controlled, randomized clinical study should be performed to evaluate the efficacy of flavonoids.


Dietary exclusions for improving established atopic eczema in adults and children: systematic review.
Atopic eczema is the most common inflammatory skin disease of childhood in developed countries. We performed a systematic review of randomized controlled trials to assess the effects of dietary exclusions for the treatment of established atopic eczema. Nine trials (421 participants) were included, most of which were poorly reported. Six were studies of egg and milk exclusion (n = 288), one was a study of few foods (n = 85) and two were studies of an elemental diet (n = 48). There appears to be no benefit of an egg- and milk-free diet in unselected participants with atopic eczema. There is also no evidence of benefit in the use of an elemental or few-foods diet in unselected cases of atopic eczema. There may be some benefit in using an egg-free diet in infants with suspected egg allergy who have positive specific IgE to eggs - one study found 51% of the children had a significant improvement in body surface area with the exclusion diet as compared with normal diet (95% CI 1.07-2.11) and change in surface area and severity score was significantly improved in the exclusion diet as compared with the normal diet at the end of 6 weeks (MD 5.50, 95% CI 0.19-10.81) and end of treatment (MD 6.10, 95% CI 0.06-12.14). Despite their frequent use, we find little good quality evidence to support the use of exclusion diets in atopic eczema.


Strength Training Improves Body Image and Physical Activity Behaviors Among Midlife and Older Rural Women.
The effect of strength training on body image is understudied. The Strong Women Program, a 10-week, twice weekly strength-training program, was provided by Extension agents to 341 older rural women (62±12 years); changes in body image and other psychosocial variables were evaluated. Paired-sample t-test analyses were conducted to assess mean differences pre- to post-program. Strength training was associated with significant improvements in several dimensions of body image, health-related quality of life, and physical activity behaviors, satisfaction, and comfort among rural aging women-an often underserved population that stands to benefit considerably from similar programs.


1,25(OH)2vitamin D3 stimulates myogenic differentiation by inhibiting cell proliferation and modulating the expression of promyogenic growth factors and myostatin in C2C12 skeletal muscle cells.
Skeletal muscle wasting is an important public health problem associated with aging, chronic disease, cancer, kidney dialysis, and HIV/AIDS. 1,25-Dihydroxyvitamin D (1,25-D3), the active form of vitamin D, is widely recognized for its regulation of calcium and phosphate homeostasis in relation to bone development and maintenance and for its calcemic effects on target organs, such as intestine, kidney, and parathyroid glands. Emerging evidence has shown that vitamin D administration improves muscle performance and reduces falls in vitamin D-deficient older adults. However, little is known of the underlying mechanism or the role 1,25-D3 plays in promoting myogenic differentiation at the cellular and/or molecular level. In this study, we examined the effect of 1,25-D3 on myoblast cell proliferation, progression, and differentiation into myotubes. C(2)C(12) myoblasts were treated with 1,25-D3 or placebo for 1, 3, 4, 7, and 10 d. Vitamin D receptor expression was analyzed by quantitative RT-PCR, Western blottings and immunofluorescence. Expression of muscle lineage, pro- and antimyogenic, and proliferation markers was assessed by immunocytochemistry, PCR arrays, quantitative RT-PCR, and Western blottings. Addition of 1,25-D3 to C(2)C(12) myoblasts 1) increased expression and nuclear translocation of the vitamin D receptor, 2) decreased cell proliferation, 3) decreased IGF-I expression, and 4) promoted myogenic differentiation by increasing IGF-II and follistatin expression and decreasing the expression of myostatin, the only known negative regulator of muscle mass, without changing growth differentiation factor 11 expression. This study identifies key vitamin D-related molecular pathways for muscle regulation and supports the rationale for vitamin D intervention studies in select muscle disorder conditions.


Thrombin-induced inositol phosphate production by platelets from rats with diet-induced or genetically determined hypercholesterolemia.
Platelets from rats with diet-induced or genetically determined hypercholesterolemia are hypersensitive to thrombin through a pathway that is independent of the effects of released ADP or formation of thromboxane A2. We examined production of inositol phosphates by platelets from these hypercholesterolemic rats to determine whether the enhanced responsiveness to thrombin is associated with increased production of inositol trisphosphate (IP3). The opportunity to study rats with hypercholesterolemia determined genetically or induced by diet makes it possible to determine whether any differences in inositol phosphate production are caused by hypercholesterolemia alone rather than to any other effect of the diet used to induce hypercholesterolemia. Platelets were prelabeled with [3H]inositol so that increases in inositol phosphates (IP, IP2, and IP3) upon stimulation with thrombin could be assessed by measuring the amount of label in these compounds. Platelets were preincubated with CP/CPK, to inhibit effects of released ADP, and aspirin, to inhibit formation of thromboxane A2/endoperoxides. In platelets from rats with either form of hypercholesterolemia, the percentage increase in labeling of IP3 was significantly greater 30 seconds after stimulation with low concentrations of thrombin than in platelets from control rats. Increased IP3 formation in platelets from hypercholesterolemic rats indicates that there is increased activity of a pathway(s) leading to IP3 formation and that this may be a mechanism responsible for the thrombin-induced hypersensitivity of these platelets.


The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations.
Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).


Evaluation of the gluteus medius muscle after a pelvic support osteotomy to treat congenital dislocation of the hip.
Many authors have reported that the pelvic support osteotomy prevents a Trendelenburg gait by restoring the biomechanics of the abductor muscle in patients with congenital dislocation of the hip. However, we are not aware of any studies in which the hip abductor muscles were examined following pelvic support osteotomy. The purpose of this study was, first, to use magnetic resonance imaging to measure alterations in the length and volume of the gluteus medius muscle after pelvic support osteotomy and, second, to determine which factors influence the results of the Trendelenburg test. Eleven patients with a history of congenital hip dislocation who had been treated with a pelvic support osteotomy were examined clinically with the Harris hip score and the Trendelenburg test, radiographically to measure limb-length discrepancy and valgus angulation of the proximal part of the femur, and with magnetic resonance imaging to measure changes in the gluteus medius length and volume. The pelvic support osteotomy achieved a functional and painless hip in all eleven patients. Five of the eleven patients had a persistently positive Trendelenburg gait at the time of the last follow-up visit, at an average of three years after the osteotomy. The muscle volumes were restored to 43% to 89% of the muscle volumes on the normal contralateral side, and the postoperative muscle volume correlated significantly with the result of the Trendelenburg test (r = -0.63; p = 0.03). There was a positive association between age and the result of the Trendelenburg test (p = 0.01): four of the five patients who had a positive test were at least thirty-one years of age at the time of the operation. There was no correlation between the Trendelenburg test and the change in the length of the gluteus medius muscle, which averaged 19.2 mm in the patients with a positive test and 19.3 mm in those with a negative test. Patient age at the time of the operation and the postoperative change in the volume of the gluteus medius muscle have a significant influence on the result of the Trendelenburg test after a pelvic support osteotomy. Moreover, our study demonstrated that restoration of the muscle volume after a pelvic support osteotomy is not sufficient to prevent a Trendelenburg gait in older patients with congenital dislocation of the hip. Therapeutic Level IV.


Border health in the shadow of the Hispanic paradox: issues in the conceptualization of health disparities in older Mexican Americans living in the Southwest.
Mexican Americans have demonstrated lower than what would be expected mortality rates and disease prevalence, given their overrepresentation among those living in poverty. However, Mexican Americans living along the US-Mexico border have been documented as carrying a higher burden of disease and disability that seems to contradict or at least challenge evidence in support of a "Hispanic Paradox". The purpose of this paper is to evaluate the concept of border health as it relates to the conceptualization and measurement of health outcomes in older Mexican Americans living in the Southwest United States. Data for this study comes from the Hispanic Established Populations for the Epidemiologic Studies of the Elderly (Hispanic EPESE) wave 1 and mortality files up to wave 5. Border residence was determined using La Paz Agreement county and distance from a port of entry classifications. Statistical analysis was conducted to assess border versus non-border differences in cause of death, disability, disease prevalence and premature mortality. Adjusted regression models were used to predict cause of death, disability and disease-free life expectancy and premature mortality (i.e. occurring before life expectancy). Interaction models between border/non-border and median income were also performed. Finally, distance from the US-Mexico border was used to determine the effect of distance to the US-Mexico border in border-residing participants. The findings from this study indicate that participants in the HEPESE were more likely to be alive at Wave 5 if they resided in a border county, however more likely to transition into ADL disability status. These findings were not explained by behaviors, duration in the US or sociocultural characteristics of where they lived. Additionally, Hispanic EPESE subjects that lived in the border region were more likely to have died from old age and were less likely to be lost to follow up. Interaction models revealed significant effects for diabetes as a cause of death. Moreover, distance from a US-Mexico port of entry was significant for being alive at wave 5 for border-residing participants. Relative to non-border residing participants, border residing Mexican Americans in the Hispanic EPESE did not carry a uniformly higher burden of disease, however had a significantly greater odds of 10 year survival. These findings bring up issues of measurement and the importance of geographic location when it comes to evaluating disease burden and mortality in Mexican Americans.


Relative breed contributions to neutral genetic diversity of a comprehensive representation of Iberian native cattle.
This study is aimed at establishing priorities for the optimal conservation of genetic diversity among a comprehensive group of 40 cattle breeds from the Iberian Peninsula. Different sets of breed contributions to diversity were obtained with several methods that differ in the relative weight attributed to the within- and between-breed components of the genetic variation. The contributions to the Weitzman diversity and the expected heterozygosity (He) account for between- and within-breed variation only, respectively. Contributions to the core set obtained for several kinship matrices, incorporate both sources of variation, as well as the combined contributions of Ollivier and Foulley and those of Caballero and Toro. In general, breeds that ranked high in the different core set applications also ranked high in the contribution to the global He, for example, Sayaguesa, Retinta, Monchina, Berrenda en Colorado or Marismeña. As expected, the Weitzman method prioritised breeds with low contributions to the He, like Mallorquina, Menorquina, Berrenda en Negro, Mostrenca, Vaca Palmera or Mirandesa, all showing highly negative contributions to He - that is, their removal would significantly increase the average He. Weighing the within- and between-breed components with the FST produced a balanced set of contributions in which all the breeds ranking high in both approaches show up. Unlike the other methods, the contributions to the diversity proposed by Caballero and Toro prioritised a good number of Portuguese breeds (Arouquesa, Barrosã, Mertolenga and Preta ranking highest), but this might be caused by a sample size effect. Only Sayaguesa ranked high in all the methods tested. Considerations with regard to the conservation scheme should be made before adopting any of these approaches: in situ v. cryoconservation, selection and adaptation within the breeds v. crossbreeding or the creation of synthetic breeds. There is no general consensus with regard to balancing within- and between-breed diversity and the decision of which source to favour will depend on the particular scenario. In addition to the genetic information, other factors, such as geographical, historical, economic, cultural, etc., also need to be considered in the formulation of a conservation plan. All these aspects will ultimately influence the distribution of resources by the decision-makers.


The inflammatory response of primary bovine mammary epithelial cells to Staphylococcus aureus strains is linked to the bacterial phenotype.
Staphylococcus aureus is a major mastitis-causing pathogen in dairy cows. The latex agglutination-based Staphaurex test allows bovine S. aureus strains to be grouped into Staphaurex latex agglutination test (SLAT)-negative [SLAT(-)] and SLAT-positive [SLAT(+)] isolates. Virulence and resistance gene profiles within SLAT(-) isolates are highly similar, but differ largely from those of SLAT(+) isolates. Notably, specific genetic changes in important virulence factors were detected in SLAT(-) isolates. Based on the molecular data, it is assumed that SLAT(+) strains are more virulent than SLAT(-) strains. The objective of this study was to investigate if SLAT(-) and SLAT(+) strains can differentially induce an immune response with regard to their adhesive capacity to epithelial cells in the mammary gland and in turn, could play a role in the course of mastitis. Primary bovine mammary epithelial cells (bMEC) were challenged with suspensions of heat inactivated SLAT(+) (n = 3) and SLAT(-) (n = 3) strains isolated from clinical bovine mastitis cases. After 1, 6, and 24 h, cells were harvested and mRNA expression of inflammatory mediators (TNF-α, IL-1β, IL-8, RANTES, SAA, lactoferrin, GM-CSF, COX-2, and TLR-2) was evaluated by reverse transcription and quantitative PCR. Transcription (ΔΔCT) of most measured factors was induced in challenged bMEC for 6 and 24 h. Interestingly, relative mRNA levels were higher (P<0.05) in response to SLAT(+) compared to SLAT(-) strains. In addition, adhesion assays on bMEC also showed significant differences between SLAT(+) and SLAT(-) strains. The present study clearly shows that these two S. aureus strain types cause a differential immune response of bMEC and exhibit differences in their adhesion capacity in vitro. This could reflect differences in the severity of mastitis that the different strain types may induce.


Epitaxial and large area Sb2Te3 thin films on silicon by MOCVD.
Antimony telluride (Sb2Te3) thin films were prepared by a room temperature Metal-Organic Chemical Vapor Deposition (MOCVD) process using antimony chloride (SbCl3) and bis(trimethylsilyl)telluride (Te(SiMe3)2) as precursors. Pre-growth and post-growth treatments were found to be pivotal in favoring out-of-plane and in-plane alignment of the crystallites composing the films. A comprehensive suite of characterization techniques were used to evaluate their composition, surface roughness, as well as to assess their morphology, crystallinity, and structural features, revealing that a quick post-growth annealing triggers the formation of epitaxial-quality Sb2Te3 films on Si(111).


A Culturally Adapted Cognitive Behavioral Internet-Delivered Intervention for Depressive Symptoms: Randomized Controlled Trial.
Internet-delivered treatments for depressive symptoms have proved to be successful in high-income Western countries. There may be potential for implementing such treatments in low- and middle-income countries such as Colombia, where access to mental health services is limited. The objective of this study was to assess the efficacy of a culturally adapted cognitive behavioral internet-delivered treatment for college students with depressive symptoms in Colombia. This was a randomized controlled trial with a 3-month follow-up. The program comprised seven modules. A total of 214 Colombian college students were recruited. They were assessed and randomly assigned to either the treatment group (n=107) or a waiting list (WL) control group (n=107). Participants received weekly support from a trained supporter. The primary outcome was symptoms of depression, as measured by the Patient Health Questionnaire - 9, and the secondary outcomes were anxiety symptoms assessed by the Generalized Anxiety Disorder questionnaire - 7. Other measures, including satisfaction with treatment, were evaluated after 7 weeks. Research attrition and treatment dropouts were high in this study. On average, 7.6 sessions were completed per user. The mean time spent on the program was 3 hours and 18 min. The linear mixed model (LMM) showed significant effects after treatment (t197.54=-5.189; P<.001) for the treatment group, and these effects were maintained at the 3-month follow-up (t39.62=4.668; P<.001). Within-group results for the treatment group yielded a large effect size post treatment (d=1.44; P<.001), and this was maintained at the 3-month follow-up (d=1.81; P<.001). In addition, the LMM showed significant differences between the groups (t197.54=-5.189; P<.001). The results showed a large effect size between the groups (d=0.91; P<.001). In the treatment group, 76.0% (16/107) achieved a reliable change, compared with 32.0% (17/107) in the WL control group. The difference between groups was statistically significant (X22=10.5; P=.001). This study was the first contribution to investigating the potential impact of a culturally adapted internet-delivered treatment on depressive symptoms for college students as compared with a WL control group in South America. Future research should focus on identifying variables associated both with premature dropout and treatment withdrawal at follow-up. ClinicalTrials.gov NCT03062215; https://clinicaltrials.gov/ct2/show/NCT03062215.


A Model Analysis of Mechanisms for Radial Microtubular Patterns at Root Hair Initiation Sites.
Plant cells have two main modes of growth generating anisotropic structures. Diffuse growth where whole cell walls extend in specific directions, guided by anisotropically positioned cellulose fibers, and tip growth, with inhomogeneous addition of new cell wall material at the tip of the structure. Cells are known to regulate these processes via molecular signals and the cytoskeleton. Mechanical stress has been proposed to provide an input to the positioning of the cellulose fibers via cortical microtubules in diffuse growth. In particular, a stress feedback model predicts a circumferential pattern of fibers surrounding apical tissues and growing primordia, guided by the anisotropic curvature in such tissues. In contrast, during the initiation of tip growing root hairs, a star-like radial pattern has recently been observed. Here, we use detailed finite element models to analyze how a change in mechanical properties at the root hair initiation site can lead to star-like stress patterns in order to understand whether a stress-based feedback model can also explain the microtubule patterns seen during root hair initiation. We show that two independent mechanisms, individually or combined, can be sufficient to generate radial patterns. In the first, new material is added locally at the position of the root hair. In the second, increased tension in the initiation area provides a mechanism. Finally, we describe how a molecular model of Rho-of-plant (ROP) GTPases activation driven by auxin can position a patch of activated ROP protein basally along a 2D root epidermal cell plasma membrane, paving the way for models where mechanical and molecular mechanisms cooperate in the initial placement and outgrowth of root hairs.


Sense of mastery and metabolic risk: moderating role of the local fast-food environment.
To test the moderating role of the extent of fast-food restaurants in one's immediate environment in the association between mastery and metabolic risk. Higher sense of mastery (perceived control over one's circumstances) has been associated with better metabolic outcomes. Mastery may be instrumental in resisting unhealthful environmental food cues when these become ubiquitous, resulting in a greater health impact of mastery. Blood samples were obtained from 344 individuals (50% men), aged 18 to 57 years (mean, 34.9 years), sampled from seven census tracts representing the spectrum of census tract-level socioeconomic status and language (French/English) in Montreal. Risk factors based on standards for high-density lipoprotein and total cholesterol, waist circumference, body mass index, triglycerides, and glycated hemoglobin were summed to obtain a cumulative metabolic risk score. Mastery was self-reported, using a validated scale. The proportion of restaurants classified as fast-food within 500 m of participants' residences was determined, using a geographic information system. Main and interactive effects were tested with Poisson regression, accounting for clustering of observations and participants' age, gender, education, and income. Mastery interacted with fast-food exposure in relation to metabolic risk (p = .03). Higher mastery was significantly associated with lower metabolic risk for participants surrounded by a high proportion of fast food (relative risk, 0.80; 95% confidence interval, 0.76-0.84; p < .0001), but not for those living in areas with low proportion of fast-food restaurants (relative risk, 0.94; 95% confidence interval, 0.82-1.08; p = .37). A positive relationship between mastery and lower metabolic risk was most apparent in environments with higher fast-food exposure.


Bis(dipyrrinato)metal(ii) coordination polymers: crystallization, exfoliation into single wires, and electric conversion ability.
One-dimensional coordination polymers (1D-CPs) tend either to dissociate into constitutive ligands and metals readily in solution, or to aggregate randomly and amorphously, which prevents them from widespread application. In the present research, 1D-CPs comprising bridging dipyrrin ligands and divalent metal ions (Zn2+, Ni2+, and Cu2+) are synthesized. A liquid/liquid interfacial reaction gives rise to single crystals suitable for X-ray diffraction analysis: A dichloromethane solution of the ligand is layered with aqueous metal(ii) acetate, such that the coordination reaction proceeds at the liquid/liquid interface. Isolated single fibers of the zinc coordination polymer may be exfoliated from the single crystal or bulk solid upon ultrasonication. Atomic force microscopy (AFM) detects the isolated fibers with lengths of more than several μm. The exfoliated 1D-CP wires feature good processability, realizing a conjugate with single-wall carbon nanotubes (SWCNTs), and a thin film on a transparent SnO2 electrode. The processed materials show electric conversion ability: For example, the modified SnO2 electrode serves as a photoanode for a photoelectric conversion system. The designability and tunability of the present 1D-CPs is demonstrated by a ligand modification, affording a luminescent property and an extension of the photoelectric conversion response to longer wavelengths.


Cloud cover amplifies the sleep-suppressing effect of artificial light at night in geese.
In modern society the night sky is lit up not only by the moon but also by artificial light devices. Both of these light sources can have a major impact on wildlife physiology and behaviour. For example, a number of bird species were found to sleep several hours less under full moon compared to new moon and a similar sleep-suppressing effect has been reported for artificial light at night (ALAN). Cloud cover at night can modulate the light levels perceived by wildlife, yet, in opposite directions for ALAN and moon. While clouds will block moon light, it may reflect and amplify ALAN levels and increases the night glow in urbanized areas. As a consequence, cloud cover may also modulate the sleep-suppressing effects of moon and ALAN in different directions. In this study we therefore measured sleep in barnacle geese (Branta leucopsis) under semi-natural conditions in relation to moon phase, ALAN and cloud cover. Our analysis shows that, during new moon nights stronger cloud cover was indeed associated with increased ALAN levels at our study site. In contrast, light levels during full moon nights were fairly constant, presumably because of moonlight on clear nights or because of reflected artificial light on cloudy nights. Importantly, cloud cover caused an estimated 24.8% reduction in the amount of night-time NREM sleep from nights with medium to full cloud cover, particularly during new moon when sleep was unaffected by moon light. In conclusion, our findings suggest that cloud cover can, in a rather dramatic way, amplify the immediate effects of ALAN on wildlife. Sleep appears to be highly sensitive to ALAN and may therefore be a good indicator of its biological effects.


Suppression of histamine signaling by probiotic Lac-B: a possible mechanism of its anti-allergic effect.
It has been shown that probiotic bacteria are effective for the treatment of allergic diseases. As histamine plays a central role in allergic diseases, it is possible that probiotic bacteria affect the allergy-related histamine signaling. Here, we investigated the effect of Lac-B, a mixture of freeze-dried Bifidobacterium infantis and Bifidobacterium longum, on the allergy-related histamine signaling. In the nasal allergy model rats made by sensitization and provocation with toluene 2,4-diisocyanate (TDI) for 3 weeks, TDI provocation caused acute allergy-like behaviors along with significant up-regulation of histamine H(1) receptor (H1R) and histidine decarboxylase (HDC) mRNA expression, increased HDC activity, histamine content, and [(3)H]mepyramine binding activity in nasal mucosa. Prolonged treatment with Lac-B (40 mg/rat, p.o.) significantly suppressed both the allergy-like behaviors and all of the above mentioned factors involved in histamine signaling. Our findings indicate that oral administration of Lac-B showed significant anti-allergic effect through suppression of both H1R and HDC gene expression followed by decrease in H1R, HDC protein level, and histamine content. Suppression of histamine signaling may be a novel target of probiotics in preventing allergic diseases.


Genetic variation and phylogenetic relationship between two species of yellow catfish, Horabagrus brachysoma and H. nigricollaris (Teleostei: Horabagridae) based on RAPD and microsatellite markers.
The two species of yellow catfish, Horabagrus brachysoma and H. nigricollaris are categorized as 'endangered' and 'critically endangered' respectively in their wild habitat. Proper knowledge of genetic structure and variability of these endangered species are highly essential for the management, conservation and improvement of fish stocks. Therefore, genetic variation and phylogenetic relationships between these species of yellow catfish sampled from Chalakkudy River in the hot spot of biodiversity-Western Ghats region, Kerala, India were analyzed by using Random amplified polymorphic DNA (RAPD) and microsatellite markers. 85 RAPD and five microsatellites loci were detected to analyze the genetic variation and phylogenetic relationships among these species. Out of 85 RAPD loci produced only 52.94% were polymorphic whereas in microsatellite, all 5 loci were polymorphic (100%). Species-specific RAPD bands were found in both species studied. In microsatellite, the number of alleles across the five loci ranged from 1 to 8. The observed heterozygosities in H. brachysoma and H. nigricollaris were 0.463 and 0.443, respectively. Here, both RAPD and microsatellite methods reported a low degree of gene diversity and lack of genetic heterogeneity in both species of Horabagrus which strongly emphasize the need of fishery management, conservation and rehabilitation of these species.


Knowledge of ghostwriting and financial conflicts-of-interest reduces the perceived credibility of biomedical research.
While the impact of conflicts-of-interest (COI) is of increasing concern in academic medicine, there is little research on the reaction of practicing clinicians to the disclosure of such conflicts. We developed two research vignettes presenting a fictional antidepressant medication study, one in which the principal investigator had no COI and another in which there were multiple COI disclosed. We confirmed the face validity of the COI vignette through consultation with experts. Hospital-based clinicians were randomly assigned to read one of these two vignettes and then administered a credibility scale. Perceived credibility ratings were much lower in the COI group, with a difference of 11.00 points (31.42%) on the credibility scale total as calculated through the Mann-Whitney U test (95% CI = 6.99 - 15.00, p < .001). Clinicians in the COI group were also less likely to recommend the antidepressant medication discussed in the vignette (Odds Ratio = 0.163, 95% CI = .03 = 0.875). In this study, increased disclosure of COI resulted in lower credibility ratings.


Sneeze to leave: African wild dogs (Lycaon pictus) use variable quorum thresholds facilitated by sneezes in collective decisions.
In despotically driven animal societies, one or a few individuals tend to have a disproportionate influence on group decision-making and actions. However, global communication allows each group member to assess the relative strength of preferences for different options among their group-mates. Here, we investigate collective decisions by free-ranging African wild dog packs in Botswana. African wild dogs exhibit dominant-directed group living and take part in stereotyped social rallies: high energy greeting ceremonies that occur before collective movements. Not all rallies result in collective movements, for reasons that are not well understood. We show that the probability of rally success (i.e. group departure) is predicted by a minimum number of audible rapid nasal exhalations (sneezes), within the rally. Moreover, the number of sneezes needed for the group to depart (i.e. the quorum) was reduced whenever dominant individuals initiated rallies, suggesting that dominant participation increases the likelihood of a rally's success, but is not a prerequisite. As such, the 'will of the group' may override dominant preferences when the consensus of subordinates is sufficiently great. Our findings illustrate how specific behavioural mechanisms (here, sneezing) allow for negotiation (in effect, voting) that shapes decision-making in a wild, socially complex animal society.


Predictive value of various Doppler-derived parameters of atrial conduction time for successful atrial fibrillation ablation.
Various Doppler-derived parameters of left atrial electrical remodeling have been demonstrated to predict recurrence of atrial fibrillation (AF) after AF ablation. The aim of this study was to compare three Doppler-derived measures of atrial conduction time in patients undergoing AF ablation, and to investigate their predictive value for successful procedure. In 32 prospectively enrolled patients undergoing the first AF ablation, atrial conduction time was estimated by measuring the time delay between the onset of P-wave on the surface ECG to the peak of the a'-wave on the pulsed-wave Doppler and color-coded tissue Doppler imaging of the left atrial lateral wall, and to the peak of the A-wave on the pulsed-wave Doppler of the mitral inflow. There was a significant difference in the baseline atrial conduction time measured by different echocardiographic techniques. Most (88%) patients had normal or only mildly dilated left atrium. At 6 months, 12 patients (38%) had recurrent AF/atrial tachycardia. The duration of history of AF was the only predictor of AF/atrial tachycardia recurrence following the first AF ablation (P=0.024; OR 1.023, CI 1.003-1.044). A combination of normal left atrial volume and history of paroxysmal AF of ≤48 months was associated with the best outcome. Predictive value of the Doppler derived parameters of atrial conduction time may be reduced in the early stages of left atrial remodeling. Future studies may determine which echocardiographic parameter correlates best with the extent of left atrial remodeling and is most predictive of successful AF ablation.


Postural stability changes during the prism adaptation test in patients with intermittent and constant exotropia.
Computerized static stabilometry is a clinical test in neurologic and muscular diseases to assess postural stability or body sway in a quantitative manner. The purpose of this study was to examine whether postural stability would change in the process of the prism adaptation test in patients with intermittent and constant exotropia. Postural stability was measured before the prism adaptation test and immediately, 15 minutes, and 60 minutes after the prism adaptation test by computerized static stabilometry in 17 consecutive adult patients with exotropia, including 10 patients with intermittent exotropia and seven with constant exotropia. Stabilometric parameters were compared between patients with intermittent and those with constant exotropia for 60 minutes by repeated-measures analysis of variance as statistical analysis. The Romberg quotients for the root mean square areas of the sway path (cm(2)), the area in the condition of the patients' eyes open, divided by that in the condition of the patients' eyes closed, increased significantly in the time course of the prism adaptation test and returned to the pretest level in patients with intermittent exotropia and in patients with constant exotropia (P = 0.0173). No significant difference in the Romberg quotients was noted between the patients with intermittent exotropia and those with constant exotropia. Postural instability became more pronounced by the prism adaptation test in the patients with exotropia. Binocular visual and motor perceptional changes induced by the prism adaptation test could lead to postural instability, with adaptation taking place 60 minutes after the start of the test.


Status of hematopoietic stem cell transplantation in the WHO Eastern Mediterranean Region (EMRO).
Several centers are now performing allogeneic hematopoietic stem cell transplantation (HSCT) in the World Health Organization Eastern Mediterranean Region (EMRO) but the availability is still limited due to high cost and the need for multi-disciplinary team and an advanced laboratory support. Special issues including compatible donor availability, potential for alternate donor programs, differences in pattern of disease, pre-HSCT general status particularly for patients with BM failure, high sero-positivity for CMV, Hepatitis B and C infection and specific observations about GVHD with its relation to genetically homogeneous community are discussed. A total of 17 HSCT programs (performing five or more HSCTs annually) exist in nine countries of the EM region. Only six programs are currently reporting to EBMT or IBMTR. A total of 7617 HSCTs including 5701 allogeneic HSCTs have been performed. Due to low HSCT team density (1.5583 teams/10 million inhabitants versus 14.4333 in Europe) and very low HSCT team distribution (0.2729 teams/10,000 sq km area versus <1 to 6 teams in Europe) only 70.8% of total population has access to such a program in EM region. GNI/capita had no clear association with low HSCT activity; however improvement in infrastructure and establishment of EM regional HSCT registry need prioritization.


Ion-exchanged Er3+/Yb3+ co-doped waveguide amplifiers longitudinally pumped by broad area lasers.
A multimode pumping scheme for Er(3+)/Yb(3+) co-doped waveguide amplifiers based on broad area lasers at around 980 nm is presented. The proposed amplifier is fabricated by ion-exchange (IE) technique on silicate and phosphate glasses. The highly efficient energy transfer from Yb(3+) to Er(3+) ions, combined with the use of low cost and high power broad area laser, allows the realization of high performance and cost-effective integrated amplifiers. The structure has been designed and numerically studied using a 3D finite element modelling tool, and over 3 dB/cm small signal gain has been predicted for an optimized amplifier. Preliminary characterization of an amplifier structure provides a first experimental evidence of the novel multimode longitudinal pumping.


Genetic networks with canalyzing Boolean rules are always stable.
We determine stability and attractor properties of random Boolean genetic network models with canalyzing rules for a variety of architectures. For all power law, exponential, and flat in-degree distributions, we find that the networks are dynamically stable. Furthermore, for architectures with few inputs per node, the dynamics of the networks is close to critical. In addition, the fraction of genes that are active decreases with the number of inputs per node. These results are based upon investigating ensembles of networks using analytical methods. Also, for different in-degree distributions, the numbers of fixed points and cycles are calculated, with results intuitively consistent with stability analysis; fewer inputs per node implies more cycles, and vice versa. There are hints that genetic networks acquire broader degree distributions with evolution, and hence our results indicate that for single cells, the dynamics should become more stable with evolution. However, such an effect is very likely compensated for by multicellular dynamics, because one expects less stability when interactions among cells are included. We verify this by simulations of a simple model for interactions among cells.


Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy.
The blood system is maintained by a small pool of haematopoietic stem cells (HSCs), which are required and sufficient for replenishing all human blood cell lineages at millions of cells per second throughout life. Megakaryocytes in the bone marrow are responsible for the continuous production of platelets in the blood, crucial for preventing bleeding--a common and life-threatening side effect of many cancer therapies--and major efforts are focused at identifying the most suitable cellular and molecular targets to enhance platelet production after bone marrow transplantation or chemotherapy. Although it has become clear that distinct HSC subsets exist that are stably biased towards the generation of lymphoid or myeloid blood cells, we are yet to learn whether other types of lineage-biased HSC exist or understand their inter-relationships and how differently lineage-biased HSCs are generated and maintained. The functional relevance of notable phenotypic and molecular similarities between megakaryocytes and bone marrow cells with an HSC cell-surface phenotype remains unclear. Here we identify and prospectively isolate a molecularly and functionally distinct mouse HSC subset primed for platelet-specific gene expression, with enhanced propensity for short- and long-term reconstitution of platelets. Maintenance of platelet-biased HSCs crucially depends on thrombopoietin, the primary extrinsic regulator of platelet development. Platelet-primed HSCs also frequently have a long-term myeloid lineage bias, can self-renew and give rise to lymphoid-biased HSCs. These findings show that HSC subtypes can be organized into a cellular hierarchy, with platelet-primed HSCs at the apex. They also demonstrate that molecular and functional priming for platelet development initiates already in a distinct HSC population. The identification of a platelet-primed HSC population should enable the rational design of therapies enhancing platelet output.


GPs' decision-making--perceiving the patient as a person or a disease.
The aim of this study was to analyse the clinical decision making strategies of GPs with regard to the whole range of problems encountered in everyday work. A prospective questionnaire study was carried through, where 16 General practitioners in Sweden registered consecutively 378 problems in 366 patients. 68.3% of the problems were registered as somatic, 5.8% as psychosocial and 25.9% as both somatic and psychosocial. When the problem was characterised as somatic the main emphasis was most often on the symptoms only, and when the problem was psychosocial main emphasis was given to the person. Immediate, inductive, decision-making contrary to gradual, analytical, was used for about half of the problems. Immediate decision-making was less often used when problems were registered as both somatic and psychosocial and focus was on both the symptoms and the person. When immediate decision-making was used the GPs were significantly more often certain of their identification of the problem and significantly more satisfied with their consultation. Rules of thumb in consultations registered as somatic with emphasis on symptoms only did not include any reference to the individual patient. In consultations registered as psychosocial with emphasis on the person, rules of thumb often included reference to the patient as a known person. The decision-making (immediate or gradual) registered by the GPs seemed to have been adjusted on the symptom or on the patient as a person. Our results indicate that the GPs seem to recognise immediately both problems and persons, hence the quintessence of the expert skill of the GP as developed through experience.


EMG activities of the quadratus lumborum and erector spinae muscles during flexion-relaxation and other motor tasks.
OBJECTIVE: The aim of this study was to provide new information on the myoelectrical activation of the quadratus lumborum, the deep lateral and the superficial medial lumbar erector spinae, the psoas, and the iliacus muscles in various motor tasks. DESIGN: An intramuscular electromyographic study was performed. BACKGROUND: The contribution of individual deep trunk muscles to the stability of the lumbar spine is relatively unknown in different tasks, including the flexion-relaxation phenomenon. METHODS: Seven healthy subjects participated. Fine-wire electrodes were inserted with a needle guided by ultrasound. RESULTS: The highest activity observed for quadratus lumborum and deep lateral erector spinae occurred in ipsilateral trunk flexion in a side-lying position and for superficial medial erector spinae during bilateral leg lift in a prone position. Quadratus lumborum and deep lateral erector spinae were activated when the flexion-relaxation phenomenon was present for superficial medial erector spinae, i.e. when its activity ceased in the latter part of full forward flexion of the trunk, held relaxed and kyphotic. CONCLUSIONS: In general, the activation of the investigated muscles showed a high degree of task specificity, where activation of a certain muscle was not always predictable from its anatomical arrangement and mechanical advantage.


Mortality study of pathologists and medical laboratory technicians.
Membership lists of professional bodies were used to establish study populations of British pathologists (1955-73) and medical laboratory technicians (1963-73). The standardised mortality ratio (SMR) for pathologists was 60 and for medical laboratory technicians 67. Twenty-seven of the 310 deaths were due to suicide. These numbers gave SMRs of 250 for pathologists and 243 for medical laboratory technicians. Suicide was the commonest cause of death in female technicians. Access to lethal chemicals at work is a possible factor explaining the high proportion of suicide by poisoning compared with the general population. Suicide rates for pathologists exceed those of all medical practitioners; similary medical laboratory have higher rates than all laboratory technicians. Excess deaths from lymphatic and haemopoietic neoplasms were noted in English male pathologists (observed 8, expected 3-3; P less than 0-01). This difference is not due to Hodgkin's disease or leukaemia and remains unexplained. No other neoplastic diseases were noted as causing excess mortality in either occupational group but a small, possibly spurious, excess number of deaths was noted for aortic aneurysm in male pathologists (observed 4, expected 1-8).