Sustained rhythmic activity in gap-junctionally coupled networks of model neurons depends on the diameter of coupled dendrites.
Gap junctions are known to be important for many network functions such as synchronization of activity and the generation of waves and oscillations. Gap junctions have also been proposed to be essential for the generation of early embryonic activity. We have previously shown that the amplitude of electrical signals propagating across gap-junctionally coupled passive cables is maximized at a unique diameter. This suggests that threshold-dependent signals may propagate through gap junctions for a finite range of diameters around this optimal value. Here we examine the diameter dependence of action potential propagation across model networks of dendro-dendritically coupled neurons. The neurons in these models have passive soma and dendrites and an action potential-generating axon. We show that propagation of action potentials across gap junctions occurs only over a finite range of dendritic diameters and that propagation delay depends on this diameter. Additionally, in networks of gap-junctionally coupled neurons, rhythmic activity can emerge when closed loops (re-entrant paths) occur but again only for a finite range of dendrite diameters. The frequency of such rhythmic activity depends on the length of the path and the dendrite diameter. For large networks of randomly coupled neurons, we find that the re-entrant paths that underlie rhythmic activity also depend on dendrite diameter. These results underline the potential importance of dendrite diameter as a determinant of network activity in gap-junctionally coupled networks, such as network rhythms that are observed during early nervous system development.


STD rapid assessment in Rwandan refugee camps in Tanzania.
To obtain baseline information on sexually transmitted diseases (STDs) in the Rwandan refugees camps in Tanzania, prior to establishment of STD services. The largest camps of Rwandan refugees in the Ngara District of Tanzania (estimated population 300,000). The study was carried out in 8 days in August 1994. A rapid assessment technique was used to measure STD prevalences among: (i) 100 antenatal clinic attenders (ANC); (ii) 239 men from outpatient clinics (OPD); and (iii) 289 men from the community. Interviews (by questionnaire) and genital examination were performed for all participants; sampling for females included genital swabs for the the diagnosis of Neisseria gonorrhoeae (NG), Candida albicans (CA), Trichomonas vaginalis (TV), bacterial vaginosis (BV) and a blood sample for syphilis serology. Men provided urine samples which were screened for leucocytes using the leucocyte esterase (LE) dipstick; urethral swabs for Gram stain were taken from men with a reactive LE test and from those with symptoms or signs of urethritis. OPD males provided a blood sample for syphilis serology. All groups reported frequent experience with STDs and engaging in risky sexual behaviour prior to the survey. During the establishment of the camps, sexual activity was reportedly low. Over 50% of ANC attenders were infected with agents causing vaginitis (TV/BV/CA) and 3% were infected with NG. The prevalence of active syphilis was 4%. In the male outpatients, the prevalence of urethritis was 2.6% and of serological syphilis was 6.1%. Among males in the community, the prevalence of urethritis was 2.9% (the majority being asymptomatic infections). We noted frequent over-reporting of STD symptoms, unconfirmed clinically or biologically. STD case detection and management should be improved by training health workers in using the WHO syndromic approach, and through IEC campaigns encouraging attendance at clinics. Rapid epidemiological methods provide quick and useful information at low cost in refugee camps.


Changes in access to health care in China, 1989-1997.
The post-1979 period in China has seen the implementation of reforms that dismantled much of the Maoist era social welfare system and permitted a significant reallocation of society's resources. The result has been rapid but uneven economic development that has profoundly altered the environment within which consumers make health investment decisions. Many studies report significant and apparently non-random reductions in health care utilization during this period. Scholars have tended to focus on the loss of insurance coverage and the growth of fees for services in explaining such reductions. An alternative explanation is growing inequality in access to care. This possibility has not received much research attention. As a result, our understanding of the patterns of changes in health care access, and of the types of populations that have been most adversely affected, has been rather limited. This research examines the distribution of the changes in several indicators of access to health care across communities during the period 1989 to 1997. We find evidence of relatively uneven changes to these indicators. Money charges for routine services increased consistently, though this trend was less pronounced in lower-income communities. Most communities experienced reductions in travel distance to clinics but increases in distance to hospitals. There were major improvements to the quality of care in wealthier rural areas, but not in poorer villages. Wealthier villages experienced less improvement in waiting time and drug availability. These trends appear to be closely associated with changing economic circumstances during the reform era.


Chalcogen bonding in synthesis, catalysis and design of materials.
Chalcogen bonding is a type of noncovalent interaction in which a covalently bonded chalcogen atom (O, S, Se or Te) acts as an electrophilic species towards a nucleophilic (negative) region(s) in another or in the same molecule. In general, this interaction is strengthened by the presence of an electron-withdrawing group on the electron-acceptor chalcogen atom and upon moving down in the periodic table of elements, from O to Te. Following a short discussion of the phenomenon of chalcogen bonding, this Perspective presents some demonstrative experimental observations in which this bonding is crucial for synthetic transformations, crystal engineering, catalysis and design of materials as synthons/tectons.


Dehydrobufotenin extracted from the Amazonian toad Rhinella marina (Anura: Bufonidae) as a prototype molecule for the development of antiplasmodial drugs.
The resistance against antimalarial drugs represents a global challenge in the fight and control of malaria. The Brazilian biodiversity can be an important tool for research and development of new medicinal products. In this context, toxinology is a multidisciplinary approach on the development of new drugs, including the isolation, purification, and evaluation of the pharmacological activities of natural toxins. The present study aimed to evaluate the cytotoxicity, as well as the antimalarial activity in silico and in vitro of four compounds isolated from Rhinella marina venom as potential oral drug prototypes. Four compounds were challenged against 35 target proteins from P. falciparum and screened to evaluate their physicochemical properties using docking assay in Brazilian Malaria Molecular Targets (BraMMT) software and in silico assay in OCTOPUS® software. The in vitro antimalarial activity of the compounds against the 3D7 Plasmodium falciparum clones were assessed using the SYBR Green I based assay (IC50). For the cytotoxic tests, the LD50 was determined in human pulmonary fibroblast cell line using the [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay. All compounds presented a ligand-receptor interaction with ten Plasmodium falciparum-related protein targets, as well as antimalarial activity against chloroquine resistant strain (IC50 = 3.44 μM to 19.11 μM). Three of them (dehydrobufotenine, marinobufagin, and bufalin) showed adequate conditions for oral drug prototypes, with satisfactory prediction of absorption, permeability, and absence of toxicity. In the cell viability assay, only dehydrobufotenin was selective for the parasite. Dehydrobufotenin revealed to be a potential oral drug prototype presenting adequate antimalarial activity and absence of cytotoxicity, therefore should be subjected to further studies.


Optomechanical coupling in a two-dimensional photonic crystal defect cavity.
Periodically structured materials can sustain both optical and mechanical modes. Here we investigate and observe experimentally the optomechanical properties of a conventional two-dimensional suspended photonic crystal defect cavity with a mode volume of ~3(λ/n)³. Two families of mechanical modes are observed: flexural modes, associated to the motion of the whole suspended membrane, and localized modes with frequencies in the GHz regime corresponding to localized phonons in the optical defect cavity of diffraction-limited size. We demonstrate direct measurements of the optomechanical vacuum coupling rate using a frequency calibration technique. The highest measured values exceed 80 kHz, demonstrating high coupling of optical and mechanical modes in such structures.


Nursing error: an integrated review of the literature.
Nursing errors are complex and take place frequently in the care of patients. However, despite their significance, they have not been properly defined or addressed in the literature. This integrative review of the literature explored the concept of nursing error, explained its definitions and described its attributes and measurements. The databases of Medline, CINAHL, Google Scholar and SID were searched using a number of keywords, including malpractice, adverse events and mistake, with and without the word nurse. The aim was to determine the definition of nursing error, regardless of the contextual aspects, in various scientific systems. After reviewing the relevant literature, content analysis (in MAXQDA) was applied to classify the definitions, attributes and measurements obtained on the basis of their similarities and differences. Ultimately, a definition was established for the concept of nursing error.


Is passive smoking associated with sleep disturbance among pregnant women?
Pregnant women suffer from sleep disturbance, which may be aggravated by passive smoking. In this study we investigated the effects of passive smoking on sleep disturbance during pregnancy. Two cross-sectional questionnaire surveys conducted in 2002 and 2006. Clinical institutions specializing in obstetrics and gynecology that participated in the nationwide surveys: 260 in the 2002 survey and 344 in the 2006 survey. 16,396 and 19,386 pregnant women in Japan surveyed in 2002 and 2006, respectively. N/A. Pregnant women exposed to passive smoking were likely to have sleep disturbances, such as subjective insufficient sleep, difficulty in initiating sleep, short sleep duration, and snoring loudly/breathing uncomfortably. Smoking pregnant women had the same sleep disturbances and also experienced excessive daytime sleepiness and early morning awakening. The prevalence of 5 types of sleep disturbance (insufficient sleep, difficulty in initiating sleep, short sleep duration, excessive daytime sleepiness, and snoring loudly/breathing uncomfortably) among nonsmokers with environmental tobacco smoke showed a mean value intermediate between that of active smokers and that of nonsmokers without environmental tobacco smoke. Passive smoking is independently associated with increased sleep disturbance during pregnancy.


Internal trafficking and surface mobility of a functionally intact beta2-adrenergic receptor-green fluorescent protein conjugate.
The beta2-adrenergic receptor (beta2AR) is prototypic of the large family of G protein-coupled receptors (GPCRs) whose desensitization and resensitization are regulated by intracellular kinases, arrestin proteins, phosphatases, and ill-defined components of the cellular endocytic machinery. The study of beta2AR signal transduction and behavior in living cells is technically difficult because of the relatively low cellular expression of the receptor and a lack of useful biological reagents. Availability of a functional beta2AR tagged with the highly sensitive Green Fluorescent Protein (GFP) could allow measurements of the various properties of the beta2AR. We demonstrate that a fully functional beta2AR/GFP can be engineered. In mammalian cells, beta2AR/S65T/GFP demonstrates strong, diffuse plasma membrane fluorescence when observed with 480 nm excitation. The fluorescent receptor binds agonist and antagonist, stimulates adenylyl cyclase, undergoes phosphorylation, and is internalized in a manner indistinguishable from wild-type receptor. We then show that its internal trafficking and surface mobility can be determined by measuring only the endogenous fluorescence of the conjugate. beta2AR/S65T/GFP was found to be localized on endosomal membranes in living cells within minutes of agonist treatment, and within 15 min it is observed in more complicated structures formed from fusion of multiple endosomes. Finally, its free diffusion (diffusion coefficient, 4.0-12 x 10(-9) cm2/sec) was assessed on living cells using photobleaching recovery measurements. This approach and the fidelity of the biochemical properties of the beta2AR/S65T/GFP demonstrate that real-time optical measurements of beta2AR (as well as other GPCR) interactions and dynamics on living cells are feasible.


Monitoring screen use: a qualitative exploration of family strategies in Swiss homes.
Background Digital technologies make family managing more complicated, as parents are worried about their children's well-being and want to protect them from excessive Internet use. Objective The objective of this study was to investigate both youths' and parents' views on strategies and rules set at home to regulate and monitor Internet use. Subjects Thirty-five adolescents (19 females), aged between 11 and 18 years, and 27 parents (17 mothers) from the French-speaking part of Switzerland participated in different focus groups. Methods Using a qualitative approach, results were analyzed using the grounded theory. Results Eight different mediation strategies emerged. One relevant finding is that rules regarding problematic content were never mentioned, while rules about screen time and location of use were numerous. This might indicate that parents are more worried about the time spent in front of the screen than about the actual activities their children engage in. Conclusions It could be recommended to parents to keep striving for an environment contributing to open discussion and exchange on Internet use, even if their digital literacy is lower than their youngsters' are.


[Tuberculous lymphadenitis].
In this study, we evaluate tuberculosis (Tbc) lymphadenitis diagnosed patients age, gender, contact history, history of smoking, socioeconomic status, lymphadenitis localization, imaging techniques, fine needle aspiration biopsy (FNAB) and excisional biopsy results. Between February 2006 and February 2008 104 patients were operated to determine the etiology of their neck masses. Twenty-six patients (16 females, 10 males; mean age 36.9 years; range 16 to 52 years) who were diagnosed as Tbc lymphadenitis according to pathology results were included in the study. Ear, nose and throat examinations were performed in all patients routinely. Hemogram, biochemical and serological tests were performed. The patients were evaluated with anterior-posterior chest radiographs and purified protein derivative (PPD) by chest diseases consultation imaging methods and FNAB was performed. All patients diagnosed with excisional biopsy of neck mass. During the operation, tissue culture and Ziehl-Neelsen method for staining was prepared. Out of 26 patients eight had a history of contact with Tbc. One person had previously lung Tbc. Six patients had previously received treatment because of Tbc lymphadenitis, but didn't complete the treatment. Neck ultrasonography and neck computed tomography detected a solid mass in 16 patients and cystic mass in 10 patients. The 24 patients were evaluated as positive PPD (>10 mm). None of the patients had an association between active pulmonary Tbc and Tbc lymphadenitis. Suspicion is the most important step in the diagnosis of Tbc lymphadenitis. In patients with low socioeconomic status, previous Tbc contact, tabacco usage, suppressed immune system, and particularly in those with drainage from neck masses, Tbc lymphadenitis should be considered in the differential diagnosis.


Cervical esophago-gastric anastomosis using linear cutter stapler in esophageal cancer.
Anastomosis in gastrointestinal (GI) surgery is a commonly performed procedure. Irrelevant various methods of intestinal anastomosis were followed - recent advance is the use of a stapler as a device for GI anastomosis. Due to the use of staplers, technical failures are a rarity, anastomosis is more consistent and can be used at difficult locations. : Between 2008 and August 2016, 75 patients with esophagus or gastroesophageal junction carcinoma underwent curative intent resection either via a right posterolateral thoracotomy (TTE) or transhiatal esophagectomy or video-assisted thoracoscopic surgery with linear stapler anastomosis. The average follow-up was approximately 9 months. Anastomotic leakage was observed in three patients. On follow-up, two patients presented with difficulty in swallowing, and on upper GI endoscopy, they were found to have anastomotic site stricture. There was no perioperative mortality. The linear-stapled esophagogastric anastomosis is a safe and effective anastomotic technique, which can decrease the rate of leak, postoperative dysphagia, and anastomotic stricture. As in this technique only two linear staplers are used in comparison to other techniques where three or more staplers are used, it is also cost-effective. The procedure deserves more attention and further application.


Synthesis and in vitro characterization of radioiodinatable benzodiazepines selective for type 1 and type 2 cholecystokinin receptors.
Radiolabeled antagonists of specific peptide receptors identify a higher number of receptor binding sites than agonists and may thus be preferable for in vivo tumor targeting. In this study, two novel radioiodinated 1,4-benzodiazepines, (S)-1-(3-iodophenyl)-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea (9) and (R)-1-(3-iodophenyl)-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea (7), were developed. They were characterized in vitro as high affinity selective antagonists at cholecystokinin types 1 and 2 (CCK(1) and CCK(2)) receptors using receptor binding, calcium mobilization, and internalization studies. Their binding to human tumor tissues was assessed with in vitro receptor autoradiography and compared with an established peptidic CCK agonist radioligand. The (125)I-labeled CCK(1) receptor-selective compound 9 often revealed a substantially higher amount of CCK(1) receptor binding sites in tumors than the agonist (125)I-CCK. Conversely, the radioiodinated CCK(2) receptor-selective compound 7 showed generally weaker tumor binding than (125)I-CCK. In conclusion, compound 9 is an excellent radioiodinated nonpeptidic antagonist ligand for direct and selective labeling of CCK(1) receptors in vitro. Moreover, it represents a suitable candidate to test antagonist binding to CCK(1) receptor-expressing tumors in vivo.


Clinical Text Mining on FHIR.
Semantic standards and human language technologies are key enablers for semantic interoperability across heterogeneous document and data collections in clinical information systems. Data provenance is awarded increasing attention, and it is especially critical where clinical data are automatically extracted from original documents, e.g. by text mining. This paper demonstrates how the output of a commercial clinical text-mining tool can be harmonised with FHIR, the leading clinical information model standard. Character ranges that indicate the origin of an annotation and machine generates confidence values were identified as crucial elements of data provenance in order to enrich text-mining results. We have specified and requested necessary extensions to the FHIR standard and demonstrated how, as a result, important metadata describing processes generating FHIR instances from clinical narratives can be embedded.


Prevalence and prognostic impact of cachexia among older patients with cancer: a nationwide cross-sectional survey (NutriAgeCancer).
Nutritional impairment is common in cancer patients and is associated with poor outcomes. Only few studies focused on cachexia. We assessed the prevalence of cachexia in older cancer patients, identified associated risk factors, and evaluated its impact on 6 month overall mortality. A French nationwide cross-sectional survey (performed in 55 geriatric oncology clinics) of older cancer patients aged ≥70 referred for geriatric assessment prior to treatment choice and initiation. Demographic, clinical, and nutritional data were collected. The first outcome was cachexia, defined as loss of more than 5% of bodyweight over the previous 6 months, or a body mass index below 20 kg/m2 with weight loss of more than 2%, or sarcopenia (an impaired Strength, Assistance with walking, Rise from chair, Climb stairs and Falls score) with weight loss of more than 2%. The second outcome was 6 month overall mortality. Of the 1030 patients included in the analysis [median age (interquartile range): 83 (79-87); males: 48%; metastatic cancer: 42%; main cancer sites: digestive tract (29%) and breast (16%)], 534 [52% (95% confidence interval: 49-55%)] had cachexia. In the multivariate analysis, patients with breast (P < 0.001), gynaecologic (P < 0.001), urinary (P < 0.001), skin (P < 0.001), and haematological cancers (P = 0.006) were less likely to have cachexia than patients with colorectal cancer. Patients with upper gastrointestinal tract cancers (including liver and pancreatic cancers; P = 0.052), with previous surgery for cancer (P = 0.001), with metastases (P = 0.047), poor performance status (≥2; P < 0.001), low food intake (P < 0.001), unfeasible timed up-and-go test (P = 0.002), cognitive disorders (P = 0.03) or risk of depression (P = 0.005), were more likely to have cachexia. At 6 months, 194 (20.5%) deaths were observed. Cachexia was associated with 6 month mortality risk (adjusted hazard ratio = 1.49; 95% confidence interval: 1.05-2.11) independently of age, in/outpatient status, cancer site, metastatic status, cancer treatment, dependency, cognition, and number of daily medications. More than half of older patients with cancer managed in geriatric oncology clinics had cachexia. The factors associated with cachexia were upper gastrointestinal tract cancer, metastases, poor performance status, poor mobility, previous surgery for cancer, cognitive disorders, a risk of depression, and low food intake. Cachexia was independently associated with 6 month mortality.


Assessment of Spatiotemporal Gait Parameters in Patients with Lumbar Disc Herniation and Patients with Chronic Mechanical Low Back Pain.
To assess spatiotemporal gait parameters in patients with lumbar disc herniation (LDH) and chronic mechanical low back pain (CMLBP), and compare with healthy control group. A total of 70 patients was enrolled in this prospective, controlled cross-sectional study, of which 25 with LDH, 25 with CMLBP and 20 healthy individuals as the control group. Participants completed 10 passes on the "WIN-TRACK" Gait Analysis Platform at their self-selected walking speed. The arithmetic mean of the five flawless walking data was used for analysis. Pain intensity is assessed by the Visual Analog Scale (VAS). The spatiotemporal gait parameters were significantly decreased in LDH and CMLBP groups than the healthy control group, particularly in LDH groups (p≥0.001). It was found that pain intensity is negatively correlated to step and stride length, cadence and velocity (p < 0.001). Results of linear regression analysis showed that 10% of the changes in gait cycle duration of the left extremity and 74% of the changes in the velocity were associated with pain intensity. Pain intensity can affect the spatiotemporal gait parameters in patients with Low Back Pain (LBP). Rehabilitation programs with gait optimization should be considered in the management of patients with LDH and CMLBP.


Burnout among U.S. medical students, residents, and early career physicians relative to the general U.S. population.
To compare the prevalence of burnout and other forms of distress across career stages and the experiences of trainees and early career (EC) physicians versus those of similarly aged college graduates pursuing other careers. In 2011 and 2012, the authors conducted a national survey of medical students, residents/fellows, and EC physicians (≤ 5 years in practice) and of a probability-based sample of the general U.S. population. All surveys assessed burnout, symptoms of depression and suicidal ideation, quality of life, and fatigue. Response rates were 35.2% (4,402/12,500) for medical students, 22.5% (1,701/7,560) for residents/fellows, and 26.7% (7,288/27,276) for EC physicians. In multivariate models that controlled for relationship status, sex, age, and career stage, being a resident/fellow was associated with increased odds of burnout and being a medical student with increased odds of depressive symptoms, whereas EC physicians had the lowest odds of high fatigue. Compared with the population control samples, medical students, residents/fellows, and EC physicians were more likely to be burned out (all P < .0001). Medical students and residents/fellows were more likely to exhibit symptoms of depression than the population control samples (both P < .0001) but not more likely to have experienced recent suicidal ideation. Training appears to be the peak time for distress among physicians, but differences in the prevalence of burnout, depressive symptoms, and recent suicidal ideation are relatively small. At each stage, burnout is more prevalent among physicians than among their peers in the U.S. population.


Epidemiological analysis of group A streptococci recovered from patients in China.
Since the mid-1980s, there has been a resurgence of severe forms of invasive group A streptococcal (GAS) disease in many countries and regions. However, there has not been any systemic epidemiologic analysis of GAS disease reported in mainland China. To analyse the molecular epidemiology of GAS disease, 86 strains from patients in different regions of mainland China were collected. The collection sites included blood, pus, wounds, the epipharynx and other sites. A total of 21 different emm types were identified in the isolates. In both invasive and non-invasive isolates, M1 (29.1%) and M12 (23.3%) were the most prevalent types, a different distribution to M type distributions reported in other countries. Furthermore, minor emm gene sequence alterations were noted for six types. Several important GAS virulence factors were detected by PCR using specific primers. The speB and slo genes were detected in all isolates and were species specific. Four superantigen genes, speA, speC, smeZ and ssa, were found in 52% (45/86), 51% (44/86), 82% (71/86) and 23% (27/86) of isolates, respectively. M1 isolates harboured more speA (84%) and fewer speC genes (44%), while M12 isolates had fewer speA (35%) and more speC genes (100%). There was also an association between some virulence genes and isolation sites, perhaps due to the correlation between the emm type distribution and virulence gene occurrence. For two important virulence genes related to necrotizing fasciitis, the sil gene was only carried by 11 of 86 isolates, and no sil gene contained the start codon ATA. The sla gene rarely occurred in GAS isolates, only four of 86 GAS strains being positive, including two isolates obtained from blood. In antimicrobial susceptibility tests, the overall rate of drug resistance in GAS isolates was higher than reported rates in other countries, and the resistance rates to erythromycin, tetracycline and clindamycin were 91.8, 93.4 and 80%, respectively. This epidemiological study may help to understand the pathogenesis of GAS disease and aid in vaccine development.


Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia.
To assess the incidence of amiodarone-mediated aggravation of ventricular tachyarrhythmias or the development of new arrhythmias, such as torsade de pointes, in patients with cardiac disease. A MEDLINE literature search was done to identify articles published during the last 20 years that presented data on amiodarone-associated proarrhythmic events. The articles were divided into three categories: case reports, uncontrolled retrospective studies, and prospective controlled trials. In addition, articles were identified that examined the effects of amiodarone in patients with previously documented drug-induced torsade de pointes. 65 English-language case reports dealing with torsade de pointes during amiodarone therapy were found in the literature. In many of these cases, other predisposing factors for the development of torsade de pointes were reported. Seventeen studies each reported data from at least 50 patients who were treated with amiodarone for at least 6 months. Of 2878 patients included in these trials, 57 were reported to have a proarrhythmic event while exposed to the drug (an overall incidence of 2%). Torsade de pointes was observed in one third of these patients (an overall incidence of 0.7%). In seven placebo-controlled trials in which the drug was given as monotherapy, amiodarone was not associated with the development of a proarrhythmic event in any patient. Finally, in three reports, 31 patients with previous drug-mediated torsade de pointes were exposed to amiodarone during short- and long-term therapy. In none of these patients did a recurrent episode of torsade de pointes develop, despite the amiodarone-induced prolongation of the QTc interval, which was equivalent to that observed at the time of torsade de pointes during exposure to previous drugs. Amiodarone appears to be associated with a remarkably low frequency of proarrhythmic events and an incidence of torsade de pointes of less than 1.0%. This low arrhythmogenicity and the negligible negative inotropic effect of the compound constitute properties that make amiodarone particularly useful in treating high-risk patients prone to sudden cardiac death. Its potential to reduce this risk is currently being evaluated in several large prospective trials.


Underdiagnosis of hypertension in children and adolescents.
Pediatric hypertension is increasing in prevalence with the pediatric obesity epidemic. Diagnosis of hypertension in children is complicated because normal and abnormal blood pressure values vary with age, sex, and height and are therefore difficult to remember. To determine the frequency of undiagnosed hypertension and prehypertension and to identify patient factors associated with this underdiagnosis. A cohort study of 14,187 children and adolescents aged 3 to 18 years who were observed at least 3 times for well-child care between June 1999 and September 2006 in the outpatient clinics in a large academic urban medical system in northeast Ohio. For children and adolescents who met criteria for hypertension or prehypertension at 3 or more well-child care visits, the proportion with a hypertension-related International Classification of Diseases, Ninth Revision code in the diagnoses list, problem list, or past medical history list of any visit was determined. Proportion of children and adolescents with 3 or more elevated age-adjusted and height-adjusted blood pressure measurements at well-child care visits and with a diagnosis of hypertension or prehypertension documented in the electronic medical record. Multivariate logistic regression identified patient factors associated with a correct diagnosis. Of 507 children and adolescents (3.6%) who had hypertension, 131 (26%) had a diagnosis of hypertension or elevated blood pressure documented in the electronic medical record. Patient factors that increased the adjusted odds of a correct diagnosis were a 1-year increase in age over age 3 (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.03-1.16), number of elevated blood pressure readings beyond 3 (OR, 1.77; 95% CI, 1.21-2.57), increase of 1% in height-for-age percentile (OR, 1.02; 95% CI, 1.01-1.03), having an obesity-related diagnosis (OR, 2.61; 95% CI, 1.49-4.55), and number of blood pressure readings in the stage 2 hypertension range (OR, 1.68; 95% CI, 1.29-2.19). Of 485 children and adolescents (3.4%) who had prehypertension, 55 (11%) had an appropriate diagnosis documented in the electronic medical record. Patient factors that increased the adjusted odds of being diagnosed with prehypertension included a 1-year increase in age over age 3 (OR, 1.21; 95% CI, 1.09-1.34) and number of elevated blood pressure readings beyond 3 (OR, 3.07; 95% CI, 2.20-4.28). Hypertension and prehypertension were frequently undiagnosed in this pediatric population. Patient age, height, obesity-related diagnoses, and magnitude and frequency of abnormal blood pressure readings all increased the odds of diagnosis.


Power and limitations of the chloroplast trnL (UAA) intron for plant DNA barcoding.
DNA barcoding should provide rapid, accurate and automatable species identifications by using a standardized DNA region as a tag. Based on sequences available in GenBank and sequences produced for this study, we evaluated the resolution power of the whole chloroplast trnL (UAA) intron (254-767 bp) and of a shorter fragment of this intron (the P6 loop, 10-143 bp) amplified with highly conserved primers. The main limitation of the whole trnL intron for DNA barcoding remains its relatively low resolution (67.3% of the species from GenBank unambiguously identified). The resolution of the P6 loop is lower (19.5% identified) but remains higher than those of existing alternative systems. The resolution is much higher in specific contexts such as species originating from a single ecosystem, or commonly eaten plants. Despite the relatively low resolution, the whole trnL intron and its P6 loop have many advantages: the primers are highly conserved, and the amplification system is very robust. The P6 loop can even be amplified when using highly degraded DNA from processed food or from permafrost samples, and has the potential to be extensively used in food industry, in forensic science, in diet analyses based on feces and in ancient DNA studies.


Modeling of a violaxanthin-chlorophyll b chromophore pair in its LHCII environment using CAM-B3LYP.
Collecting energy for photosystem II is facilitated by several pigments, xanthophylls and chlorophylls, embedded in the light harvesting complex II (LHCII). One xanthophyll, violaxanthin (Vio), is loosely bound at a site close to a chlorophyll b (Chl). No final answer has yet been found for the role of this specific xanthophyll. We study the electronic structure of Vio in the presence of Chl and under the influence of the LHCII environment, represented by a point charge field (PCF). We compare the capability of the long range corrected density functional theory (DFT) functional CAM-B3LYP to B3LYP for the modeling of the UV/vis spectrum of the Vio+Chl pair. CAM-B3LYP was reported to allow for a very realistic reproduction of bond length alternation of linear polyenes, which has considerable impact on the carotenoid structure and spectrum. To account for the influence of the LHCII environment, the chromophore geometries are optimized using an ONIOM(DFT/6-31G(d):PM6) scheme. Our calculations show that the energies of the locally excited states are almost unaffected by the presence of the partner chromophore or the PCF. There are, however, indications for excitonic coupling of the Chl Soret band and Vio. We propose that Vio may accept energy from blue-light excited Chl.


Green tea catechins, caffeine and body-weight regulation.
The global prevalence of obesity has increased considerably in the last decade. Tools for obesity management including caffeine, and green tea have been proposed as strategies for weight loss and weight maintenance. These ingredients may increase energy expenditure and have been proposed to counteract the decrease in metabolic rate that is present during weight loss. Positive effects on body-weight management have been shown using green tea mixtures. Green tea, by containing both tea catechins and caffeine, may act through inhibition of catechol O-methyl-transferase, and inhibition of phosphodiesterase. Here the mechanisms may also operate synergistically. A green tea-caffeine mixture improves weight maintenance, through thermogenesis, fat oxidation, and sparing fat free mass. The sympathetic nervous system is involved in the regulation of lipolysis, and the sympathetic innervation of white adipose tissue may play an important role in the regulation of total body fat in general. Taken together, these functional ingredients have the potential to produce significant effects on metabolic targets such as thermogenesis, and fat oxidation. An ethnic or genetic effect, and habitual caffeine or green tea catechin intake may act as confounders; this remains to be revealed.


Cool echidnas survive the fire.
Fires have occurred throughout history, including those associated with the meteoroid impact at the Cretaceous-Palaeogene (K-Pg) boundary that eliminated many vertebrate species. To evaluate the recent hypothesis that the survival of the K-Pg fires by ancestral mammals was dependent on their ability to use energy-conserving torpor, we studied body temperature fluctuations and activity of an egg-laying mammal, the echidna (Tachyglossus aculeatus), often considered to be a 'living fossil', before, during and after a prescribed burn. All but one study animal survived the fire in the prescribed burn area and echidnas remained inactive during the day(s) following the fire and substantially reduced body temperature during bouts of torpor. For weeks after the fire, all individuals remained in their original territories and compensated for changes in their habitat with a decrease in mean body temperature and activity. Our data suggest that heterothermy enables mammals to outlast the conditions during and after a fire by reducing energy expenditure, permitting periods of extended inactivity. Therefore, torpor facilitates survival in a fire-scorched landscape and consequently may have been of functional significance for mammalian survival at the K-Pg boundary.


Causes of death and characteristics of decedents with viral hepatitis, United States, 2010.
Previous research indicates that the mortality burden from viral hepatitis is growing, particularly among middle-aged persons. To monitor progress toward prevention goals, it is important to continue to document characteristics and comortalities of these deaths. This study sought to examine demographic characteristics and the most frequent causes of death among decedents with a viral hepatitis-related death. A cross-sectional study was performed on approximately 2.4 million death records from 2010. We calculated mortality rates for decedents with and without hepatitis A, B, and C virus (HAV, HBV, and HCV) and relative risks for the most frequently cited conditions in decedents with and without HBV and HCV. In 2010, there were 18 473 (0.7%) deaths with HAV, HBV, and HCV listed among causes of death, disproportionately in those aged 45-64 years. Among the 10 frequent causes of death, decedents listing HBV or HCV died, on average, 22-23 years earlier than decedents not listing these infections. HBV- and HCV-infected decedents aged 45-64 years had an increased risk of having the following conditions reported than decedents without these infections: cancer of liver and intrahepatic bile duct; fibrosis, cirrhosis, and other liver diseases; alcohol-related liver disease; gastrointestinal hemorrhage; human immunodeficiency infection; acute and unspecified renal failure; and septicemia (HCV only). Decedents with other causes of death that include HBV or HCV died 22-23 years earlier than decedents not listing these infections. These data suggest and support the need for prevention, early identification, and treatment of HBV and HCV.


Behavioral and Health Outcomes for HIV+ Young Transgender Women (YTW) Linked To and Engaged in Medical Care.
We describe health and psychosocial outcomes of HIV+ young transgender women (YTW) engaged in care across the United States. When compared to other behaviorally infected youth (BIY), YTW reported higher rates of unemployment (25% vs. 19%), limited educational achievement (42% vs 13%), and suboptimal ART adherence (51% vs. 30%). There was no difference in likelihood of having a detectable viral load (38% vs. 39%) between groups. However, particular isolating psychosocial factors (unstable housing, depression, and lack of social support for attending appointments) increased predicted probability of viral detection to a greater extent among YTW that may have important health implications for this marginalized youth population.


Inflammation in the lungs of rats after deposition of dust collected from the air of wool mills: the role of epithelial injury and complement activation.
In a previous study assessing respiratory symptoms in individuals employed in wool textile mills in the north of England relations between symptoms of chronic bronchitis, breathlessness and wheeze, and rhinitis and current exposure to airborne mass concentration of dust were shown. As preliminary steps in defining the potential hazard associated with dust from the air of wool mills the ability of inspirable dust, collected from the air of wool textile mills, to cause inflammation when injected into the lungs of rats was determined. Dusts were collected from the beginning of wool processing (opening) in one factory and from the middle (combing) and late (backwinding) stages of the process in two other factories. Ability of the dusts to cause inflammation was assessed by instillation into the lungs of rats followed by bronchoalveolar lavage. All the dusts caused some inflammation which peaked on day 1 and did not persist beyond one week. A distinctive aggregation response of mononuclear cells in the lavage, however, had a different time course, peaking at day 7. An attempt was made to determine how the wool mill dusts caused inflammation and experiments showed that the dusts themselves had no inherent chemotactic activity but that they did have a pronounced ability to generate chemotaxins in serum and so could activate complement in lung fluid. In addition, dust collected from ledges in the mills had the ability to injure epithelial cells in vitro which could also contribute to inflammation. A role for endotoxin in the inflammatory activity of the dusts was not discounted and a leachate of the dust had the ability to cause inflammation when injected into the lungs of rats. Wool mill dust is likely to be a complex mixture of materials and these experiments represent a preliminary approach to understanding the biological activity of the whole unfractionated dust and further studies are in progress to define more accurately the toxic material(s) in the dust.


Rapid diagnostic tests for diagnosing uncomplicated non-falciparum or Plasmodium vivax malaria in endemic countries.
In settings where both Plasmodium vivax and Plasmodium falciparum infection cause malaria, rapid diagnostic tests (RDTs) need to distinguish which species is causing the patients' symptoms, as different treatments are required. Older RDTs incorporated two test lines to distinguish malaria due to P. falciparum, from malaria due to any other Plasmodium species (non-falciparum). These RDTs can be classified according to which antibodies they use: Type 2 RDTs use HRP-2 (for P. falciparum) and aldolase (all species); Type 3 RDTs use HRP-2 (for P. falciparum) and pLDH (all species); Type 4 use pLDH (fromP. falciparum) and pLDH (all species).More recently, RDTs have been developed to distinguish P. vivax parasitaemia by utilizing a pLDH antibody specific to P. vivax. To assess the diagnostic accuracy of RDTs for detecting non-falciparum or P. vivax parasitaemia in people living in malaria-endemic areas who present to ambulatory healthcare facilities with symptoms suggestive of malaria, and to identify which types and brands of commercial test best detect non-falciparum and P. vivax malaria. We undertook a comprehensive search of the following databases up to 31 December 2013: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; MEDION; Science Citation Index; Web of Knowledge; African Index Medicus; LILACS; and IndMED. Studies comparing RDTs with a reference standard (microscopy or polymerase chain reaction) in blood samples from a random or consecutive series of patients attending ambulatory health facilities with symptoms suggestive of malaria in non-falciparum endemic areas. For each study, two review authors independently extracted a standard set of data using a tailored data extraction form. We grouped comparisons by type of RDT (defined by the combinations of antibodies used), and combined in meta-analysis where appropriate. Average sensitivities and specificities are presented alongside 95% confidence intervals (95% CI). We included 47 studies enrolling 22,862 participants. Patient characteristics, sampling methods and reference standard methods were poorly reported in most studies. RDTs detecting 'non-falciparum' parasitaemiaEleven studies evaluated Type 2 tests compared with microscopy, 25 evaluated Type 3 tests, and 11 evaluated Type 4 tests. In meta-analyses, average sensitivities and specificities were 78% (95% CI 73% to 82%) and 99% (95% CI 97% to 99%) for Type 2 tests, 78% (95% CI 69% to 84%) and 99% (95% CI 98% to 99%) for Type 3 tests, and 89% (95% CI 79% to 95%) and 98% (95% CI 97% to 99%) for Type 4 tests, respectively. Type 4 tests were more sensitive than both Type 2 (P = 0.01) and Type 3 tests (P = 0.03).Five studies compared Type 3 tests with PCR; in meta-analysis, the average sensitivity and specificity were 81% (95% CI 72% to 88%) and 99% (95% CI 97% to 99%) respectively. RDTs detecting P.vivax parasitaemiaEight studies compared pLDH tests to microscopy; the average sensitivity and specificity were 95% (95% CI 86% to 99%) and 99% (95% CI 99% to 100%), respectively. RDTs designed to detect P. vivax specifically, whether alone or as part of a mixed infection, appear to be more accurate than older tests designed to distinguish P. falciparum malaria from non-falciparum malaria. Compared to microscopy, these tests fail to detect around 5% ofP. vivax cases. This Cochrane Review, in combination with other published information about in vitro test performance and stability in the field, can assist policy-makers to choose between the available RDTs.


Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts.
Folate fortification of food aims to reduce the number of babies born with neural tube defects, but has been associated with cognitive impairment when vitamin B12 levels are deficient. Given the prevalence of low vitamin B12 levels among the elderly, and the global deployment of food fortification programs, investigation of the associations between cognitive impairment, vitamin B12, and folate are needed. To investigate the associations of serum vitamin B12, red cell folate, and cognitive impairment. Data were collected on 1,354 subjects in two studies investigating cognitive impairment, and from patients attending for assessment or management of memory problems in the Barwon region of south eastern Australia between 2001 and 2011. Eligible subjects who had blood measurements of vitamin B12 and red cell folate taken within six months of cognitive testing were included. Subjects with stroke or neurodegenerative diseases other than Alzheimer's disease were excluded. A Mini-Mental State Examination score of <24 was used to define impaired cognitive function. Participants with low serum vitamin B12 (<250 pmol/L) and high red cell folate (>1,594 nmol/L) levels were more likely to have impaired cognitive performance (adjusted odds ratio (AOR) 3.45, 95% confidence interval (CI): 1.60-7.43, p = 0.002) when compared to participants with biochemical measurements that were within the normal ranges. Participants with high folate levels, but normal serum vitamin B12, were also more likely to have impaired cognitive performance (AOR 1.74, 95% CI: 1.03-2.95, p = 0.04). High folate or folic acid supplements may be detrimental to cognition in older people with low vitamin B12 levels. This topic is of global significance due to the wide distribution of food fortification programs, so prospective studies should be a high priority.


Caspase-independent cell engulfment mirrors cell death pattern in Drosophila embryos.
Programmed cell death plays an essential role during Drosophila embryonic development. A stereotypic series of cellular changes occur during apoptosis, most of which are initiated by a caspase cascade that is triggered by a trio of proteins, RPR, HID and GRIM. The final step in apoptosis is engulfment of the cell corpse. To monitor cell engulfment in vivo, we developed a fluorogenic beta-galactosidase substrate that is cleaved by an endogenous, lysosomal beta-galactosidase activity. The pattern of cell engulfment in wild-type embryos correlated well with the known pattern of apoptosis. Surprisingly, the pattern of cell engulfment persisted in apoptosis-deficient embryos. We provide evidence for a caspase-independent engulfment process that affects the majority of cells expected to die in developing Drosophila embryos.


Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway.
Insulin receptor substrate (IRS) proteins are important intracellular molecules that mediate insulin receptor tyrosine kinase signaling. A decreased content of IRS proteins has been found in insulin-resistant states in animals, humans, and cultured cells under various conditions. However, the molecular mechanism that controls cellular levels of IRS proteins is unknown. We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells. The insulin-induced degradation of IRS-1 can be prevented by pretreatment with lactacystin, a specific inhibitor for proteasome degradation. These data demonstrate, for the first time, that insulin-induced degradation of IRS-1 is mediated by the proteasome degradation pathway. IRS-2 can escape from the insulin-induced proteasome degradation, suggesting the existence of specific structural requirements for this degradation process.


First Report of Recombinant Potato virus Y Strains in Potato in Jalisco, Mexico.
Potato virus Y (PVY) is a serious problem for potato production worldwide. The virus reduces both tuber yield and quality, and recent spread of recombinant strains of PVY in potato production areas is largely credited with the spread of potato tuber necrotic ringspot disease (PTNRD) (1). In Mexico, recombinant strains of PVY were reported in at least two states, Chihuahua (4) and the State of Mexico (3); however, no surveys have been conducted in other potato-producing areas, and the spectrum of PVY isolates circulating in the country has remained uncharacterized. In October 2011, a small-scale survey of seed potato was conducted in the state of Jalisco, Mexico, to identify PVY isolates present in fields. Twelve seed potato fields were inspected visually. These represented various generations of seed potato, from nuclear to G2. Leaf samples were collected from plants displaying mosaic, crinkling, and yellowing symptoms, and were tested for PVY. Fifty samples were collected from cultivars Fabula, Mondial, Fianna, Gigant, Caesar, and Adora. Of the 50 leaf samples collected, seven were PVY-positive using the Immuno-strip Kit (Agdia, Elkhart, IN), and six of these were determined to have a N-serotype according to the typing by the Pocket Diagnostics lateral flow kit (Forsite Diagnostics, Ltd., York, UK). PVY-positive samples came from cultivars Fabula (2 with N serotype), Mondial (4 with N serotype), and Fianna (1 with O serotype). Extracts of the seven PVY-positive leaf samples were applied to Whatman FTA cards (Sigma, St. Louis, MO), dried, and transported to the Plant Virology Laboratory at the University of Idaho for further characterization. All samples immobilized on FTA cards were subjected to RNA extraction and standard reverse transcriptase (RT)-PCR typing using a set of PVY-specific primers (2) to determine the strain type. All PVY isolates were recombinant. The six N-serotype samples were found to contain recombinant PVYNTN isolates and produced characteristic bands of 181 and 452 bp in RT-PCR, which indicated the presence of two recombination junctions in the HC-Pro/P3 and VPg regions typical of European PVYNTN isolates. The one O-serotype sample was identified as a recombinant PVYN-Wi/N:O isolate, and produced 181 and 689 bp bands in RT-PCR, which indicated the presence of one recombination junction in the HC-Pro/P3 region. Sequence analysis of RT-PCR products amplified from five samples with N serotype identified them as PVYNTN isolates, and from the one with O serotype identified it as PVYN-Wi/N:O isolate. Sequence comparisons confirmed that N serotype samples contained PVY isolates most closely related to typical PVYNTN sequences (Accession No. EF026075), while the O serotype sample contained the PVY isolate most closely related to PVYN-Wi from Europe (HE608963). The data obtained suggest the presence of two different types of PVY recombinants, PVYNTN and PVYN-Wi, in seed potato in Jalisco. Additional surveillance for these recombinant isolates may be needed, as well as a survey of their effects on tuber quality in production areas. This is the first report of recombinant isolates of PVY often associated with PTNRD circulating in seed potato in Jalisco, Mexico. References: (1) S. M. Gray et al. Plant Dis. 94:1384, 2010. (2) J. H. Lorenzen et al. Plant Dis. 90:935, 2006. (3) V. R. Ramirez-Rodriguez et al. Virol. J. 6:48, 2009. (4) L. Robles-Hernandez et al. Plant Dis. 94:1262, 2010.


Spatial distribution of aerosol pollution based on MODIS data over Beijing, China.
With the help of regression analysis, the relationships were detected between aerosol's contribution to apparent reflectance (ACR) derived from Moderate Resolution Imaging Spectroradiometer (MODIS) on board Terra and hourly PM10 mass concentration measured at 30 ground-based locations in Beijing for the August of 2003 and 2004. It was shown that there was a good correlation between the ACR and PM10 (linear correlation coefficient, R = 0.56). On the basis of this relationship, spatial distribution and possible sources of PM10 derived from MODIS were analyzed and two frequently heavily-polluted regions were found, namely downtown of the city and the district near Xishan Mountain. These two regions coincidently are also urban heat island centers. The foundings of this paper will be greatly useful for environmental monitoring and urban planning for Beijing, especially for the 2008 Olympic game to be held in Beijing.


A small GTPase molecular switch regulates epigenetic centromere maintenance by stabilizing newly incorporated CENP-A.
Epigenetic mechanisms regulate genome activation in diverse events, including normal development and cancerous transformation. Centromeres are epigenetically designated chromosomal regions that maintain genomic stability by directing chromosome segregation during cell division. The histone H3 variant CENP-A resides specifically at centromeres, is fundamental to centromere function and is thought to act as the epigenetic mark defining centromere loci. Mechanisms directing assembly of CENP-A nucleosomes have recently emerged, but how CENP-A is maintained after assembly is unknown. Here, we show that a small GTPase switch functions to maintain newly assembled CENP-A nucleosomes. Using functional proteomics, we found that MgcRacGAP (a Rho family GTPase activating protein) interacts with the CENP-A licensing factor HsKNL2. High-resolution live-cell imaging assays, designed in this study, demonstrated that MgcRacGAP, the Rho family guanine nucleotide exchange factor (GEF) Ect2, and the small GTPases Cdc42 and Rac, are required for stability of newly incorporated CENP-A at centromeres. Thus, a small GTPase switch ensures epigenetic centromere maintenance after loading of new CENP-A.


Low-dose effects of bisphenol A on early sexual development in male and female rats.
Bisphenol A (BPA) is widely detected in human urine and blood. BPA has been reported to impair many endpoints for reproductive and neurological development; however, it is controversial whether BPA has effects in the microgram per kilogram dose range. The aim of the current study was to examine the influence of BPA on early sexual development in male and female rats at dose levels covering both regulatory no observed adverse effect levels (NOAELs) (5 and 50 mg/kg bw per day) as well as doses in the microgram per kilogram dose range (0.025 and 0.25 mg/kg bw per day). Time-mated Wistar rats (n=22) were gavaged during pregnancy and lactation from gestation day 7 to pup day 22 with 0, 0.025, 0.25, 5 or 50 mg/kg bw per day BPA. From 0.250 mg/kg and above, male anogenital distance (AGD) was significantly decreased, whereas decreased female AGD was seen from 0.025 mg/kg bw per day and above. Moreover, the incidence of nipple retention in males appeared to increase dose relatedly and the increase was statistically significant at 50 mg/kg per day. No significant changes in reproductive organ weights in the 16-day-old males and females and no signs of maternal toxicity were seen. The decreased AGD at birth in both sexes indicates effects on prenatal sexual development and provides new evidence of low-dose adverse effects of BPA in rats in the microgram per kilogram dose range. The NOAEL in this study is clearly below 5 mg/kg for BPA, which is used as the basis for establishment of the current tolerable daily intake (TDI) by EFSA; thus a reconsideration of the current TDI of BPA appears warranted.


Potential reporting bias in fMRI studies of the brain.
Functional magnetic resonance imaging (fMRI) studies have reported multiple activation foci associated with a variety of conditions, stimuli or tasks. However, most of these studies used fewer than 40 participants. After extracting data (number of subjects, condition studied, number of foci identified and threshold) from 94 brain fMRI meta-analyses (k = 1,788 unique datasets) published through December of 2011, we analyzed the correlation between individual study sample sizes and number of significant foci reported. We also performed an analysis where we evaluated each meta-analysis to test whether there was a correlation between the sample size of the meta-analysis and the number of foci that it had identified. Correlation coefficients were then combined across all meta-analyses to obtain a summary correlation coefficient with a fixed effects model and we combine correlation coefficients, using a Fisher's z transformation. There was no correlation between sample size and the number of foci reported in single studies (r = 0.0050) but there was a strong correlation between sample size and number of foci in meta-analyses (r = 0.62, p<0.001). Only studies with sample sizes <45 identified larger (>40) numbers of foci and claimed as many discovered foci as studies with sample sizes ≥ 45, whereas meta-analyses yielded a limited number of foci relative to the yield that would be anticipated from smaller single studies. These results are consistent with possible reporting biases affecting small fMRI studies and suggest the need to promote standardized large-scale evidence in this field. It may also be that small studies may be analyzed and reported in ways that may generate a larger number of claimed foci or that small fMRI studies with inconclusive, null, or not very promising results may not be published at all.


Patient casemix classification for medicare psychiatric prospective payment.
For a proposed Medicare prospective payment system for inpatient psychiatric facility treatment, the authors developed a casemix classification to capture differences in patients' real daily resource use. Primary data on patient characteristics and daily time spent in various activities were collected in a survey of 696 patients from 40 inpatient psychiatric facilities. Survey data were combined with Medicare claims data to estimate intensity-adjusted daily cost. Classification and Regression Trees (CART) analysis of average daily routine and ancillary costs yielded several hierarchical classification groupings. Regression analysis was used to control for facility and day-of-stay effects in order to compare hierarchical models with models based on the recently proposed payment system of the Centers for Medicare & Medicaid Services. CART analysis identified a small set of patient characteristics strongly associated with higher daily costs, including age, psychiatric diagnosis, deficits in daily living activities, and detox or ECT use. A parsimonious, 16-group, fully interactive model that used five major DSM-IV categories and stratified by age, illness severity, deficits in daily living activities, dangerousness, and use of ECT explained 40% (out of a possible 76%) of daily cost variation not attributable to idiosyncratic daily changes within patients. A noninteractive model based on diagnosis-related groups, age, and medical comorbidity had explanatory power of only 32%. A regression model with 16 casemix groups restricted to using "appropriate" payment variables (i.e., those with clinical face validity and low administrative burden that are easily validated and provide proper care incentives) produced more efficient and equitable payments than did a noninteractive system based on diagnosis-related groups.


Simulating the effects of common and specific abilities on test performance: an evaluation of factor analysis.
Factor analysis is a useful technique to aid in organizing multivariate data characterizing speech, language, and auditory abilities. However, knowledge of the limitations of factor analysis is essential for proper interpretation of results. The present study used simulated test scores to illustrate some characteristics of factor analysis. Linear models were used to simulate test scores that were determined by multiple latent variables. These simulated test scores were evaluated with principal components analysis and, in certain cases, structural equation modeling. In addition, a subset of simulated individuals characterized by poor test performance was examined. The number of factors recovered and their identity do not necessarily correspond to the structure of the latent variables that generated the test scores. The first principal component may represent variance from multiple uncorrelated sources. Practices such as correction or control for general cognitive ability may produce misleading results. Inferences from the results of factor analysis should be primarily about the structure of test batteries rather than the structure of human mental abilities. Researchers and clinicians should consider multiple sources of evidence to evaluate hypotheses about the processes generating test results.


Prolonged eradication of urogenital mycoplasmas after administration of tetracycline to men in the Antarctic.
Meatal swabs were obtained at intervals over 1 year from 23 men in the Antarctic. A 5-day course of tetracycline was given to twelve of them. In retrospect it was found that the antibiotic had been received by two men who were harbouring ureaplasmas, one of whom also had M. hominis. After treatment, these organisms were not found in any of the swabs taken over the next year, except in a swab from one of the men following sexual contact after this time. One of the twelve men developed N.S.U. just before arriving in the Antarctic. He responded clinically to a shorter course of tetracycline and ureplasmas were not recovered from a meatal swab immediately thereafter. However, without further sexual contact, ureaplasmas and disease recurred about a month later. This time, after a 5-day course of tetracycline, disease was not seen, and ureaplasmas were not isolated, over the next year. In contrast, ureaplasmas were isolated consistently over a year from two men who were not given the antibiotic. The evidence strongly suggests that, under natural conditions, the most likely cause of mycoplasmas, particularly ureaplasmas, recurring in the genital tract after apparently adequate tetracycline therapy, is re-infection as a result of sexual re-exposure.


Activation of Drosophila heat shock factor: conformational change associated with a monomer-to-trimer transition.
The induction of heat shock genes in eukaryotic cells is regulated by the transcription factor heat shock factor (HSF). Activation of HSF occurs at two independent levels, DNA binding and the acquisition of transcriptional competence. The binding of HSF to DNA is accomplished by a stress-induced oligomeric switch of HSF protein. We have defined the oligomeric state of the latent and induced forms of HSF by measuring the sedimentation coefficient and the Stokes radius of the protein in Drosophila cell extracts. Calculation of the native molecular mass indicates that the two forms of Drosophila HSF are best described as a monomer and trimer, respectively, of the 77-kDa HSF polypeptide. The monomeric and trimeric states of HSF were verified by chemical cross-linking experiments. The finding of a monomeric composition for the latent form of HSF is incompatible with speculative models which suggest that molecular chaperones such as hsp70 feed back to inhibit trimerization of HSF by forming a stable heteromeric complex. We also found that both HSF monomers and HSF trimers exhibit unusually high frictional ratios, indicating that they have asymmetric shapes. The degree of asymmetry is significantly greater for the HSF trimer, suggesting that the monomer undergoes a conformational change to a more extended structure upon trimerization. These findings are consistent with a model for the inert HSF protein that is based on a monomer constrained by intramolecular coiled-coil interactions between amino- and carboxy-terminal domains.


Perfluoroalkylphosphinic Acids in Northern Pike (Esox lucius), Double-Crested Cormorants (Phalacrocorax auritus), and Bottlenose Dolphins (Tursiops truncatus) in Relation to Other Perfluoroalkyl Acids.
Perfluoroalkyl phosphinic acids (PFPIAs) are perfluoroalkyl acids (PFAAs) that are used for their surfactant properties in a variety of applications, resulting in their presence in environmental waters; however, they have not been widely studied in biota. A survey of PFPIAs was conducted in fish, dolphins, and birds from various locations in North America. Northern pike (Esox lucius) were collected at two locations in 2011 near Montréal Island in the St. Lawrence River, Canada, double-crested cormorants (Phalacrocorax auritus) were collected from bird colonies in the Great Lakes in 2010-2012, and bottlenose dolphins (Tursiops truncatus) from Sarasota Bay, FL and Charleston Harbor, SC were sampled in 2004-2009. PFPIAs had a detection frequency of 100% in all animals. This is the first report of PFPIAs in fish, dolphin, and bird plasma. Total PFPIA levels (mean ± standard deviation, 1.87 ± 2.17 ng/g wet weight (ww), range of 0.112-15.3 ng/g ww) were 1-2 orders of magnitude lower than those of perfluoroalkyl carboxylates (PFCA) and perfluoroalkanesulfonates (PFSA) in the same samples. The predominant congeners were 6:8 PFPIA (cormorants and pike) and 6:6 PFPIA (dolphins). Total PFPIAs in cormorants from Hamilton Harbour (5.02 ± 2.80 ng/g ww) were statistically higher than in other areas and taxonomic groups. The ubiquity of PFPIAs warrants further research on sources and effects of these unique compounds.


A subclass of archaeal U8-tRNA sulfurases requires a [4Fe-4S] cluster for catalysis.
Sulfuration of uridine 8, in bacterial and archaeal tRNAs, is catalyzed by enzymes formerly known as ThiI, but renamed here TtuI. Two different classes of TtuI proteins, which possess a PP-loop-containing pyrophosphatase domain that includes a conserved cysteine important for catalysis, have been identified. The first class, as exemplified by the prototypic Escherichia coli enzyme, possesses an additional C-terminal rhodanese domain harboring a second cysteine, which serves to form a catalytic persulfide. Among the second class of TtuI proteins that do not possess the rhodanese domain, some archaeal proteins display a conserved CXXC + C motif. We report here spectroscopic and enzymatic studies showing that TtuI from Methanococcus maripaludis and Pyrococcus furiosus can assemble a [4Fe-4S] cluster that is essential for tRNA sulfuration activity. Moreover, structural modeling studies, together with previously reported mutagenesis experiments of M. maripaludis TtuI, indicate that the [4Fe-4S] cluster is coordinated by the three cysteines of the CXXC + C motif. Altogether, our results raise a novel mechanism for U8-tRNA sulfuration, in which the cluster is proposed to catalyze the transfer of sulfur atoms to the activated tRNA substrate.


Derivation of a clinical decision-making aid to improve the insertion of clinically indicated peripheral intravenous catheters and promote vessel health preservation. An observational study.
It is well established that the idle peripheral intravenous catheter (PIVC) provides no therapeutic value and is a clinical, economic and above all, patient concern. This study aimed to develop a decision aid to assist with clinical decision making to promote clinically indicated peripheral intravenous catheter (CIPIVC) insertion in the emergency department (ED) setting. Providing evidence for a uniform process could assist clinicians in a decision-making process for PIVC insertion. This could enable patients receive appropriate vascular access healthcare. We performed a secondary analysis of data from a multicentre cohort of emergency department clinicians who performed PIVC insertion. We defined CIPIVC a priori as one used for a specific clinical treatment and or procedure such as prescribed intravenous (IV) fluids; prescribed IV medication; or IV contrast (for computerized tomography scans). We sought to refute or validate an assumption if the clinician performing or requesting the insertion decided the patient was >80% likely to need a PIVC. Using logistic regression, we derived a decision aid for CIPIVCs. In 817 patients undergoing PIVC insertion, we observed 68% of these to be CIPIVCs. Admitted patients were significantly more likely to have a CIPIVC, Odds Ratio (OR) = 3.05, 95% confidence interval (CI) = 2.17-4.30, p = <0.0001. Before insertion, patients who definitely needed IV fluids/medicines OR = 3.30, 95% CI = 2.02-5.39, p = <0.0001 and who definitely needed a contrast scan OR = 3.04, 95% CI = 1.15-8.03, p = 0.0250 were significantly more likely to have a device inserted for a clinical indication. Patients who presented with an existing vascular access device were more likely to have a new CIPIVC inserted for use OR = 4.35, 95% CI = 1.58-11.95, p = 0.0043. The clinician's pre-procedural judgment of the likelihood of therapeutic use >80% was independently associated with CIPIVC; OR 3.16, 95% CI = 2.06-4.87, p<0.0001. The area under the receiver operating characteristic curve was 0.81, and at the best cut-off, the model had a specificity of 0.81, sensitivity of 0.71, a positive predictive value of 0.89 and negative predictive value of 0.57. Using the derived decision aid, clinicians could ask:- "Does this patient need A-PIVC?" Clinicians can decide to insert a CIPIVCs when: (i) Admission to hospital is anticipated and when (ii) a Procedure requires a PIVC, e.g., computerised tomography scans and where an existing suitable vascular access device is not present and or; (iii) there is an indication for IV fluids and or medicines that cannot be tolerated enterally and are suitable for dilution in peripheral veins; and, (iv) the Clinician's perceived likelihood of use is greater than 80%.


Opposing motor activities are required for the organization of the mammalian mitotic spindle pole.
We use both in vitro and in vivo approaches to examine the roles of Eg5 (kinesin-related protein), cytoplasmic dynein, and dynactin in the organization of the microtubules and the localization of NuMA (Nu-clear protein that associates with the Mitotic Apparatus) at the polar ends of the mammalian mitotic spindle. Perturbation of the function of Eg5 through either immunodepletion from a cell free system for assembly of mitotic asters or antibody microinjection into cultured cells leads to organized astral microtubule arrays with expanded polar regions in which the minus ends of the microtubules emanate from a ring-like structure that contains NuMA. Conversely, perturbation of the function of cytoplasmic dynein or dynactin through either specific immunodepletition from the cell free system or expression of a dominant negative subunit of dynactin in cultured cells results in the complete lack of organization of microtubules and the failure to efficiently concentrate the NuMA protein despite its association with the microtubules. Simultaneous immunodepletion of these proteins from the cell free system for mitotic aster assembly indicates that the plus end-directed activity of Eg5 antagonizes the minus end-directed activity of cytoplasmic dynein and a minus end-directed activity associated with NuMA during the organization of the microtubules into a morphologic pole. Taken together, these results demonstrate that the unique organization of the minus ends of microtubules and the localization of NuMA at the polar ends of the mammalian mitotic spindle can be accomplished in a centrosome-independent manner by the opposing activities of plus end- and minus end-directed motors.


Meta-Analysis of Massage Therapy on Cancer Pain.
Cancer pain is the most common complaint among patients with cancer. Conventional treatment does not always relieve cancer pain satisfactorily. Therefore, many patients with cancer have turned to complementary therapies to help them with their physical, emotional, and spiritual well-being. Massage therapy is increasingly used for symptom relief in patients with cancer. The current study aimed to investigate by meta-analysis the effects of massage therapy for cancer patients experiencing pain. Nine electronic databases were systematically searched for studies published through August 2013 in English, Chinese, and Korean. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) and Cochrane risk-of-bias scales. Twelve studies, including 559 participants, were used in the meta-analysis. In 9 high-quality studies based on the PEDro scale (standardized mean difference, -1.24; 95% confidence interval, -1.72 to -0.75), we observed reduction in cancer pain after massage. Massage therapy significantly reduced cancer pain compared with no massage treatment or conventional care (standardized mean difference, -1.25; 95% confidence interval, -1.63 to -0.87). Our results indicate that massage is effective for the relief of cancer pain, especially for surgery-related pain. Among the various types of massage, foot reflexology appeared to be more effective than body or aroma massage. Our meta-analysis indicated a beneficial effect of massage for relief of cancer pain. Further well-designed, large studies with longer follow-up periods are needed to be able to draw firmer conclusions regarding the effectiveness.


Physicians' perceptions of shared decision-making behaviours: a qualitative study demonstrating the continued chasm between aspirations and clinical practice.
Shared Decision Making (SDM) is a process of engaging patients in health decisions that involve multiple medically appropriate treatment options. Despite growing public and policy support for patient engagement in health decisions, SDM is not widely practiced in clinical settings. The purpose of our study was to explore clinicians' attitudes, beliefs and perceived social norms about engaging in SDM behaviours. Semi-structured qualitative interviews were conducted with physicians in five practice areas. This study was conducted at an academic medical centre in St. Louis, MO. The final sample included 20 physicians: five surgeons, five OB/GYNs, four medical oncologists, five internists and one emergency medicine physician. Clinicians described a number of beliefs and cultural- and system-level obstacles to the widespread implementation of SDM, such as how to engage in discussions of cost, uncertainty and clinical equipoise and how to engage patients across various socioeconomic backgrounds. Although a large number of participants expressed general support for incorporating SDM into practice, most held fundamentally inconsistent beliefs about practicing specific SDM behaviours. More extensive training of physicians at all levels (pre- and post-licensure) can help increase clinicians' confidence in SDM skills. Developing methods of integrating SDM into the institutional framework of hospitals and training programmes could also increase clinicians' motivation to practice SDM and work to change the culture of medicine such that SDM behaviours are supported.


A model of crosslink kinetics in the expanding plant cell wall: yield stress and enzyme action.
The plant primary cell wall is a composite material containing stiff cellulose microfibrils that are embedded within a pectin matrix and crosslinked through a network of hemicellulose polymers. This microstructure endows the wall with nonlinear anisotropic mechanical properties and allows enzymatic regulation of expansive cell growth. We present a mathematical model of hemicellulose crosslink dynamics in an expanding cell wall incorporating strain-enhanced breakage and enzyme-mediated crosslink kinetics. The model predicts the characteristic yielding behaviour in the relationship between stress and strain-rate seen experimentally, and suggests how the effective yield and extensibility of the wall depend on microstructural parameters and on the action of enzymes of the XTH and expansin families. The model suggests that the yielding behaviour encapsulated in the classical Lockhart equation can be explained by the strongly nonlinear dependence of crosslink breakage rate on crosslink elongation. The model also demonstrates how enzymes that target crosslink binding can be effective in softening the wall in its pre-yield state, whereas its post-yield extensibility is determined primarily by the pectin matrix.


Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis.
Systemic sclerosis (SSc) is an autoimmune disease with unknown pathogenesis manifested by inflammation, vasculopathy and fibrosis in skin and internal organs. Type I interferon signature found in SSc propelled us to study plasmacytoid dendritic cells (pDCs) in this disease. We aimed to identify candidate pathways underlying pDC aberrancies in SSc and to validate its function on pDC biology. In total, 1193 patients with SSc were compared with 1387 healthy donors and 8 patients with localised scleroderma. PCR-based transcription factor profiling and methylation status analyses, single nucleotide polymorphism genotyping by sequencing and flow cytometry analysis were performed in pDCs isolated from the circulation of healthy controls or patients with SSc. pDCs were also cultured under hypoxia, inhibitors of methylation and hypoxia-inducible factors and runt-related transcription factor 3 (RUNX3) levels were determined. To study Runx3 function, Itgax-Cre:Runx3f/f mice were used in in vitro functional assay and bleomycin-induced SSc skin inflammation and fibrosis model. Here, we show downregulation of transcription factor RUNX3 in SSc pDCs. A higher methylation status of the RUNX3 gene, which is associated with polymorphism rs6672420, correlates with lower RUNX3 expression and SSc susceptibility. Hypoxia is another factor that decreases RUNX3 level in pDC. Mouse pDCs deficient of Runx3 show enhanced maturation markers on CpG stimulation. In vivo, deletion of Runx3 in dendritic cell leads to spontaneous induction of skin fibrosis in untreated mice and increased severity of bleomycin-induced skin fibrosis. We show at least two pathways potentially causing low RUNX3 level in SSc pDCs, and we demonstrate the detrimental effect of loss of Runx3 in SSc model further underscoring the role of pDCs in this disease.


Older Adults' Experiences With the Visual Physio-Feedback Technology and Peer-Led Combined Group and Home-Based Exercises.
This study aimed to explore older adults' experience with an in-home Physio-feEdback and Exercise pRogram and explore whether the Physio-feEdback and Exercise pRogram intervention influenced their physical activity adherence. A qualitative study approach was employed, and data were collected using exercise logs, observations, focus groups, and open-ended questions after the program completion. Nineteen participants who engaged in an 8-week Physio-feEdback and Exercise pRogram intervention participated in this study. Thematic analysis was used. Three major concepts of the self-determination theory, including competence, relatedness, and autonomy, were used as guidelines for coding. Results reveal three themes, including: (a) competence-alignment of body and mind and increased awareness about fall risk, (b) relatedness-relationship with peer coach and having fun with friends, and (c) autonomy-integration of exercise into daily activities for staying physically and socially active. Individuals' need for competence and autonomy can be supported by giving physio-feedback, cognitive reframing, and peer-led exercise, which can enhance physical activity and prevent falls.


Deleterious effects of criminal victimization on women's health and medical utilization.
The long-term consequences of criminal victimization on physical health were examined among 390 adult women (74 nonvictims and 316 victims of crime). Data included health status self-ratings and objective service utilization. Findings indicated that severely victimized women, compared with nonvictims, reported more distress and less well-being, made physician visits twice as frequently in the index year, and had outpatient costs that were 2.5 times greater. Criminal victimization severity was the most powerful predictor of physician visits and outpatient costs. Utilization data across 5 years preceding and following crime were obtained from 15 rape victims, 26 physical assault victims, and 27 noncontact crime victims and were compared with five continuous years of utilization among 26 nonvictims. Victims' physician visits increased 15% to 24% during the year of the crime compared with less than 2% change among nonvictims. We conclude that these long-term deleterious effects suggest that criminally victimized women's needs for medical treatment transcend the traditional focus on emergency care and forensic evaluation.


New perspective for third generation percutaneous vertebral augmentation procedures: Preliminary results at 12 months.
The prevalence of osteoporotic vertebral fractures (OVF) increased in the last years. Compression fractures promote a progressive spine kyphosis increase, resulting in a weight shift and anterior column overload, with OVF additional risk (domino effect). The aim of this study is to evaluate the OVF treatment outcome using Spine Jack(®), a titanium device for third generation percutaneous vertebral augmentation procedures (PVAPs). From February 2010, a prospective randomized study was performed examining 300 patients who underwent PVAP due to OVF type A1 according to Magerl/AO spine classification. Patients enrolled in the study were divided in two homogenous groups with regards to age (65-85 years), sex, and general clinical findings. Group A included 150 patients who underwent PVAP using Spine Jack(®) system; the second, group B (control group), included 150 patients treated by conventional balloon kyphoplasty. Patients underwent a clinical (visual analogue scale and Oswestry disability index) and radiographic follow-up, with post-operative standing plain radiogram of the spine at 1, 6, and 12 months. The radiographic parameters that were taken into account were: Post-operative anterior vertebral body height, pre-operative anterior vertebral body height, cephalic anterior vertebral body height, and caudal anterior vertebral body height. Compared to the Spine Jack(®) group, the kyphoplasty group required a little longer operation time (an average of 40 min-group A vs. 45 min-group B, P < 0.05) and a greater amount of polymethylmethacrylate (4.0 mL-group A vs. 5.0 mL-group B, P < 0.05;). The post-operative increase in vertebral body height was greater in the Spine Jack(®) group than in the kyphoplasty group (P < 0.05). PVAP are based on the cement injection into the vertebral body. Vertebroplasty does not allow the vertebral body height recovery. Balloon kyphoplasty allows a temporary height restoration. Spine Jack(®) has some new features compared to other systems: It is equipped with a mechanical and not a hydraulic opening control; this ensures a gradual and controlled vertebral fracture reduction. In our study, we demonstrated that the third generation PVAP with Spine Jack(®) is able to determine a safe vertebral body height restoration compared to the conventional balloon kyphoplasty.


Antibodies against donor human leukocyte antigens and the outcome of cardiac allografts in adults and children.
Mismatched histocompatibility antigens between donor organ and host stimulate the immune response that causes allograft rejection. Antibodies against human leukocyte antigen (HLA) are known to appear in the serum of heart transplant recipients. We have tested stored sera with HLA bound to polystyrene microbeads in a retrospective analysis of heart recipients transplanted in our center to better understand the impact of antibodies against HLA on the posttransplant course. Our analysis included two groups of patients: 113 adults and 31 children who received consecutive heart transplants performed between 1996 and 2003. Presence of HLA antibodies, especially when donor-specific, as determined with single HLA class I or class II beads, was associated with more frequent occurrence of acute rejection, development of transplant-related coronary artery disease and decreased graft survival. Recipients having antibodies only to HLA not in the transplant and those without any HLA antibodies had similar outcomes, suggesting that antibodies against antigens not present on the donor organ did not harm the graft. The results showed that presence of antibodies against HLA of the donor correlated with graft loss and suggested that testing for these antibodies may help in the management of heart transplant patients.


The Thoracic Lordosis Correction Improves Sacral Slope and Walking Ability in Neuromuscular Scoliosis.
Retrospective study. To report on neuromuscular patients with preserved walking ability, but forward bending of the body due to thoracic lordosis, and to suggest thoracic lordosis correction as the surgical treatment. It is an established fact that lumbar lordosis or pelvic parameter is directly related to thoracic sagittal balance. However, the reverse relationship has not been fully defined yet. Loss of thoracic kyphosis results in positive sagittal balance, which causes walking difficulty. Neuromuscular patients with thoracic lordosis have not been reported yet, and there have been no reports on their surgical treatments. This study analyzed 8 patients treated with thoracic lordosis correction surgery. Every patient was diagnosed with muscular dystrophy. In thoracic lordosis correction surgery, anterior release was performed in the first stage and posterior segmental instrumentation was performed in the second stage. Radiographic parameters were compared and walking ability was evaluated with gait analysis. All patients were classified according to the modified Rancho Los Amigos Hospital system preoperatively and 2 years postoperatively to evaluate functional ability. The average follow-up period was 2.9 years. Before surgery, the mean thoracic sagittal alignment was -2.1-degree lordosis, the mean Cobb angle and sacral slope increased to 36.3 and 56.6 degrees, respectively. The anterior pelvic tilt in gait analysis was 29.3 degrees. At last follow-up after surgery, the mean thoracic sagittal alignment changed to 12.6-degree kyphosis, and the Cobb angle and sacral slope decreased to 18.9 and 39.5 degrees, respectively. Lumbar lordosis and the sacral slope showed significant positive correlation (P<0.001). The improvement in thoracic lordosis showed a significant correlation to the preoperative flexibility of the major curve (P=0.028). The anterior pelvic tilt in gait analysis improved to 15.4 degrees. The functional ability improved in 2 (50%) of 4 patients in class 2 and maintained in remaining 6 patients 2 years after surgery. Thoracic lordosis correction surgery in neuromuscular scoliosis patients with thoracic lordosis improved the sacral slope in the standing position and the anterior pelvic tilt in gait. Sagittal imbalance was compensated by the spinopelvic mechanism, and back and hip extensor muscles seem to play a major role in this compensation.


50years of oral lipid-based formulations: Provenance, progress and future perspectives.
Lipid based formulations (LBF) provide well proven opportunities to enhance the oral absorption of drugs and drug candidates that sit close to, or beyond, the boundaries of Lipinski's 'rule-of-five' chemical space. Advantages in permeability, efflux and presystemic metabolism are evident; however, the primary benefit is in increases in dissolution and apparent intestinal solubility for lipophilic, poorly water soluble drugs. This review firstly details the inherent advantages of LBF, their general properties and classification, and provides a brief retrospective assessment of the development of LBF over the past fifty years. More detailed analysis of the ability of LBF to promote intestinal solubilisation, supersaturation and absorption is then provided alongside review of the methods employed to assess formulation performance. Critical review of the ability of simple dispersion and more complex in vitro digestion methods to predict formulation performance subsequently reveals marked differences in the correlative ability of in vitro tests, depending on the properties of the drug involved. Notably, for highly permeable low melting drugs e.g. fenofibrate, LBF appear to provide significant benefit in all cases, and sustained ongoing solubilisation may not be required. In other cases, and particularly for higher melting point drugs such as danazol, where re-dissolution of crystalline precipitate drug is likely to be slow, correlations with ongoing solubilisation and supersaturation are more evident. In spite of their potential benefits, one limitation to broader use of LBF is low drug solubility in the excipients employed to generate formulations. Techniques to increase drug lipophilicity and lipid solubility are therefore explored, and in particular those methods that provide for temporary enhancement including lipophilic ionic liquid and prodrug technologies. The transient nature of these lipophilicity increases enhances lipid solubility and LBF viability, but precludes enduring effects on receptor promiscuity and off target toxicity. Finally, recent efforts to generate solid LBF are briefly described as a means to circumvent the need to encapsulate in soft or hard gelatin capsules, although the latter remain popular with consumers and a proven means of LBF delivery.


Behavioral idiosyncrasy reveals genetic control of phenotypic variability.
Quantitative genetics has primarily focused on describing genetic effects on trait means and largely ignored the effect of alternative alleles on trait variability, potentially missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study the genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used Drosophila inbred lines and measured the spontaneous locomotor behavior of flies walking individually in Y-shaped mazes, focusing on variability in locomotor handedness, an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals, whereas lines with low variability behaved as although they tossed a coin at each left/right turn decision. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicates a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. Our study reveals the constellation of phenotypes that can arise from a single genotype and shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variabililty. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype.


Orthogonality in main group compounds: a direct one-step synthesis of air- and moisture-stable cyclophosphazanes by mechanochemistry.
Mechanochemistry has been established to be an environmentally-friendly way of conducting reactions in a solvent-free manner. The development of mechanochemical orthogonal reactions, in which multiple reagents are milled together, can be a powerful strategy to selectively yield the desired product. Such orthogonal syntheses are rare, especially those involving main group frameworks - based on bonds other than carbon - which are yet to be reported. Herein, we demonstrate the direct formation of air- and moisture-stable cyclophosph(v)azanes enabled by an orthogonal "one-step one-pot" mechanochemical reaction. In addition, detailed hydrolytic- and air-stability studies, conducted over one and 12 months, respectively, revealed high robustness of these compounds.


The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT.
Costimulatory molecules on antigen-presenting cells (APCs) play an important role in T cell activation and expansion. However, little is known about the surface molecules involved in direct T-T cell interaction required for their activation and expansion. LIGHT, a newly discovered TNF superfamily member (TNFSF14), is expressed on activated T cells and immature dendritic cells. Here we demonstrate that blockade of LIGHT activity can reduce anti-CD3-mediated proliferation of purified T cells, suggesting that T cell-T cell interaction is essential for this proliferation. To test the in vivo activity of T cell-derived LIGHT in immune homeostasis and function, transgenic (Tg) mice expressing LIGHT in the T cell lineage were generated. LIGHT Tg mice have a significantly enlarged T cell compartment and a hyperactivated peripheral T cell population. LIGHT Tg mice spontaneously develop severe autoimmune disease manifested by splenomegaly, lymphadenopathy, glomerulonephritis, elevated autoantibodies, and severe infiltration of various peripheral tissues. Furthermore, the blockade of LIGHT activity ameliorates the severity of T cell-mediated diseases. Collectively, these findings establish a crucial role for this T cell-derived costimulatory ligand in T cell activation and expansion; moreover, the dysregulation of T cell-derived LIGHT leads to altered T cell homeostasis and autoimmune disease.


Humans differ in their personal microbial cloud.
Dispersal of microbes between humans and the built environment can occur through direct contact with surfaces or through airborne release; the latter mechanism remains poorly understood. Humans emit upwards of 10(6) biological particles per hour, and have long been known to transmit pathogens to other individuals and to indoor surfaces. However it has not previously been demonstrated that humans emit a detectible microbial cloud into surrounding indoor air, nor whether such clouds are sufficiently differentiated to allow the identification of individual occupants. We used high-throughput sequencing of 16S rRNA genes to characterize the airborne bacterial contribution of a single person sitting in a sanitized custom experimental climate chamber. We compared that to air sampled in an adjacent, identical, unoccupied chamber, as well as to supply and exhaust air sources. Additionally, we assessed microbial communities in settled particles surrounding each occupant, to investigate the potential long-term fate of airborne microbial emissions. Most occupants could be clearly detected by their airborne bacterial emissions, as well as their contribution to settled particles, within 1.5-4 h. Bacterial clouds from the occupants were statistically distinct, allowing the identification of some individual occupants. Our results confirm that an occupied space is microbially distinct from an unoccupied one, and demonstrate for the first time that individuals release their own personalized microbial cloud.