The HLA class II Allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DL(CO)) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease.


Sex on the internet: furthering our understanding of men with online sexual problems.
A survey on the MSNBC Web site identified 384 men as having online sexual problems (OSP). Respondents' reasons for online sexual activity (OSA) and their preferred Internet medium were associated with several online and offline consequences and behaviors, including important aspects of real-time relationships and sexual experimentation. Two broad behavior patterns manifested by men with OSP were identified: Men who use the Internet (a) to further their real-time sex lives and (b) as a substitute for their real-time sex lives. Men who facilitate their offline sex lives with the Internet might do so for any number of reasons, many of which are adaptive (e.g., sex education, to purchase sexual materials). Future research should use samples from a variety of affinity Web portals to further examine the factors that differentiate individuals who show no negative effects of OSA from those who do.


Accidental Fall Rates in Community-Dwelling Adults Compared to Cancer Survivors During and Post-Treatment: A Systematic Review With Meta-Analysis.
To identify whether rates of accidental falls are greater for cancer survivors living in the community during or post-treatment than people with no history of cancer. . In a systematic literature review that was conducted in December 2013, MEDLINE®, EMBASE, PubMed, and Web of Science were searched for cancer or oncology and accidental falls in prospective and retrospective cohort and case-controlled studies. Studies were included if they were conducted in a community-dwelling adult population and excluded if they were conducted in acute hospitals and hospice. . Of 484 articles initially identified, 10 were included in the review. Of these, three included a control or comparator group and had comparable outcome measures to include in a meta-analysis. The risk ratio for falls for the group with cancer was 1.11. . Accidental fall rates in community-dwelling adults with a cancer diagnosis are greater than rates of falls in adults without cancer; this elevated rate remains after acute care is finished. Patients undergoing active treatment have greater rates of falls. Pain, fatigue, and deconditioning may affect fall rates in the longer term. . Nurses have the capacity to reduce risk of falls in community-dwelling cancer survivors during or post-treatment through provision of information, advocacy, and support around pain and fatigue management and promotion of physical activity.


Impact of tumour histological subtype on chemotherapy outcome in advanced oesophageal cancer.
To investigate the impact of histology on outcome in advanced oesophageal cancer treated with first-line fluoropyrimidine-based chemotherapy. Individual patient data were pooled from three randomised phase III trials of fluoropyrimidine-based chemotherapy ± platinum/anthracycline in patients with advanced, untreated gastroesophageal adenocarcinoma or squamous cell carcinoma (SCC) randomised between 1994 and 2005. The primary endpoint was overall survival of oesophageal cancer patients according to histology. Secondary endpoints were response rates and a toxicity composite endpoint. Of the total 1836 randomised patients, 973 patients (53%) were eligible (707 patients with gastric cancer were excluded), 841 (86%) had adenocarcinoma and 132 (14%) had SCC. There was no significant difference in survival between patients with adenocarcinoma and SCC, with median overall survivals of 9.5 mo vs 7.6 mo (HR = 0.85, 95%CI: 0.70-1.03, P = 0.09) and one-year survivals of 38.8% vs 28.2% respectively. The overall response rate to chemotherapy was 44% for adenocarcinoma vs 33% for SCC (P = 0.01). There was no difference in the frequency of the toxicity composite endpoint between the two groups. There was no significant difference in survival between adenocarcinoma and SCC in patients with advanced oesophageal cancer treated with fluoropyrimidine-based chemotherapy despite a trend for worse survival and less chemo-sensitivity in SCC. Tolerance to treatment was similar in both groups. This analysis highlights the unmet need for SCC-specific studies in advanced oesophageal cancer and will aid in the design of future trials of targeted agents.


Race, socioeconomic status, and health. The added effects of racism and discrimination.
Higher disease rates for blacks (or African Americans) compared to whites are pervasive and persistent over time, with the racial gap in mortality widening in recent years for multiple causes of death. Other racial/ethnic minority populations also have elevated disease risk for some health conditions. This paper considers the complex ways in which race and socioeconomic status (SES) combine to affect health. SES accounts for much of the observed racial disparities in health. Nonetheless, racial differences often persist even at "equivalent" levels of SES. Racism is an added burden for nondominant populations. Individual and institutional discrimination, along with the stigma of inferiority, can adversely affect health by restricting socioeconomic opportunities and mobility. Racism can also directly affect health in multiple ways. Residence in poor neighborhoods, racial bias in medical care, the stress of experiences of discrimination and the acceptance of the societal stigma of inferiority can have deleterious consequences for health.


Quantification of compensatory eye movements in light and darkness.
A broad frequency-band rotatory test has been used to quantify compensatory eye movements in 13 healthy subjects during light and darkness conditions. Eye movements were recorded by EOG. Head movements were recorded either by a potentiometer attached to the chair's axis of rotation or by an angular rate sensory attached to a bite-board. Gain and phase values between eye and head velocity were calculated. A systematic error in the higher frequency range is introduced in the results by assuming head movement equal to chair movement. Different instructions in the dark can alter the gain values at lower frequencies (up to 2 Hz) during sinusoidal stimulation. During pseudorandom stimulation no such differences can be obtained. During all test conditions with the rate sensor the gain values approach unity at about 3 Hz.


The role of Drosophila Lamin C in muscle function and gene expression.
The inner side of the nuclear envelope (NE) is lined with lamins, a meshwork of intermediate filaments that provides structural support for the nucleus and plays roles in many nuclear processes. Lamins, classified as A- or B-types on the basis of biochemical properties, have a conserved globular head, central rod and C-terminal domain that includes an Ig-fold structural motif. In humans, mutations in A-type lamins give rise to diseases that exhibit tissue-specific defects, such as Emery-Dreifuss muscular dystrophy. Drosophila is being used as a model to determine tissue-specific functions of A-type lamins in development, with implications for understanding human disease mechanisms. The GAL4-UAS system was used to express wild-type and mutant forms of Lamin C (the presumed Drosophila A-type lamin), in an otherwise wild-type background. Larval muscle-specific expression of wild type Drosophila Lamin C caused no overt phenotype. By contrast, larval muscle-specific expression of a truncated form of Lamin C lacking the N-terminal head (Lamin C DeltaN) caused muscle defects and semi-lethality, with adult 'escapers' possessing malformed legs. The leg defects were due to a lack of larval muscle function and alterations in hormone-regulated gene expression. The consequences of Lamin C association at a gene were tested directly by targeting a Lamin C DNA-binding domain fusion protein upstream of a reporter gene. Association of Lamin C correlated with localization of the reporter gene at the nuclear periphery and gene repression. These data demonstrate connections among the Drosophila A-type lamin, hormone-induced gene expression and muscle function.


Motivations for caregiving in adult intimate relationships: influences on caregiving behavior and relationship functioning.
This study identified and examined the correlates of specific motivations for caregiving in romantic couples (N = 194 couples). At Time 1, couple members completed measures assessing motivations for caregiving, the quality of caregiving that occurs in the relationship, and personal and relationship characteristics that might influence caregiving motivations. Relationship functioning was then assessed 2 to 3 months later. Results revealed that (a) there are a number of distinct motivations for providing and for not providing care to one's partner, (b) the motivations are associated with various personal features of the caregiver and the recipient, (c) the caregiver's perceptions of the relationship influence his or her caregiving motives, (d) different motivations for caregiving predict different patterns of caregiving behavior, and (e) responsive caregiving predicts the recipient's perceptions of healthy relationship functioning both immediately and over time. Implications of identifying the motivations that promote or inhibit the provision of responsive support in intimate relationships are discussed.


Histone-derived piRNA biogenesis depends on the ping-pong partners Piwi5 and Ago3 in Aedes aegypti.
The piRNA pathway is of key importance in controlling transposable elements in most animal species. In the vector mosquito Aedes aegypti, the presence of eight PIWI proteins and the accumulation of viral piRNAs upon arbovirus infection suggest additional functions of the piRNA pathway beyond genome defense. To better understand the regulatory potential of this pathway, we analyzed in detail host-derived piRNAs in A. aegypti Aag2 cells. We show that a large repertoire of protein-coding genes and non-retroviral integrated RNA virus elements are processed into genic piRNAs by different combinations of PIWI proteins. Among these, we identify a class of genes that produces piRNAs from coding sequences in an Ago3- and Piwi5-dependent fashion. We demonstrate that the replication-dependent histone gene family is a genic source of ping-pong dependent piRNAs and that histone-derived piRNAs are dynamically expressed throughout the cell cycle, suggesting a role for the piRNA pathway in the regulation of histone gene expression. Moreover, our results establish the Aag2 cell line as an accessible experimental model to study gene-derived piRNAs.


Prescribing and the core curriculum for tomorrow's doctors: BPS curriculum in clinical pharmacology and prescribing for medical students.
Prescribing is one of the commonest tasks expected of new doctors and is a complex process involving a mixture of knowledge, judgement and skills. Preparing graduates to be prescribers is one of the greatest challenges of modern undergraduate medical education and there is some evidence to suggest that training could be improved. The aims of this article are (i) to review some of the challenges of delivering effective prescribing education, (ii) to provide a clear statement of the learning outcomes in clinical pharmacology and prescribing that should be expected of all medical graduates and (iii) to describe a curriculum that might enable students to achieve these outcomes. We build on the previous curriculum recommendations of the British Pharmacological Society and take into account those of other key bodies, notably the General Medical Council. We have also reviewed relevant evidence from the literature and set our work in the context of recent trends in medical education. We divide our recommended learning objectives into four sections: principles of clinical pharmacology, essential drugs, essential therapeutic problems and prescribing skills. Although these will not necessarily be accepted universally we believe that they will help those who design and map undergraduate curricula to explore potential gaps and identify improvements.


The course and interrelationship of maternal and paternal perinatal depression.
The aims of the study were to describe course of depression in both mothers and fathers from the third trimester of pregnancy through 6 months postpartum and to examine the relationship between maternal and paternal depression. Hypotheses were as follows: (a) Depressive symptoms would be correlated between parents and (b) earlier depressive symptoms in one parent would predict later increases in depression in the other. Eighty cohabitating primiparous couples were recruited from prenatal OBGYN visits and community agencies and enrolled during pregnancy, between 28-week gestation and delivery. Participants completed measures of depression on four occasions: baseline and 1, 3, and 6 months postpartum. Ninety-eight percent of the enrolled couples (78; 156 individuals) completed the study. For both mothers and fathers, symptom severity ratings and classification as a probable case were stable across time, with prenatal depression persisting through 6 months in 75 % of mothers and 86 % of fathers. Prenatal depression in fathers predicted worsening depressive symptom severity in mothers across the first six postpartum months but not vice versa. In both expecting/new mothers and fathers, depression demonstrates a stable pattern of occurrence and symptom severity between 28-month gestation and 6 months postpartum. Although prenatal maternal depression is not predictive of symptom change in fathers, mothers with prenatally depressed partners showed significant worsening in overall symptom severity during the first six postpartum months.


Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study.
All spinocerebellar ataxias (SCAs) are rare diseases. SCA1, 2, 3 and 6 are the four most common SCAs, all caused by expanded polyglutamine-coding CAG repeats. Their pathomechanisms are becoming increasingly clear and well-designed clinical trials will be needed. To characterize the clinical manifestations of spinocerebellar ataxia (SCA) 1, 2, 3 and 6 and their natural histories in the United States (US), we conducted a prospective multicenter study utilized a protocol identical to the European consortium study, using the Scale for the Assessment and Rating of Ataxia (SARA) score as the primary outcome, with follow-ups every 6 months up to 2 years. We enrolled 345 patients (60 SCA1, 75 SCA2, 138 SCA3 and 72 SCA6) at 12 US centers. SCA6 patients had a significantly later onset, and SCA2 patients showed greater upper-body ataxia than patients with the remaining SCAs. The annual increase of SARA score was greater in SCA1 patients (mean ± SE: 1.61 ± 0.41) than in SCA2 (0.71 ± 0.31), SCA3 (0.65 ± 0.24) and SCA6 (0.87 ± 0.28) patients (p = 0.049). The functional stage also worsened faster in SCA1 than in SCA2, 3 and 6 (p = 0.002). The proportions of different SCA patients in US differ from those in the European consortium study, but as in the European patients, SCA1 progress faster than those with SCA2, 3 and 6. Later onset in SCA6 and greater upper body ataxia in SCA2 were noted. We conclude that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies.


Multidimensional differentiation in foraging resource use during breeding of two sympatric top predators.
Ecologically-similar species were found to develop specific strategies to partition their resources, leading to niche differentiation and divergence, in order to avoid interspecific competition. Our study determines multi-dimensional differentiation of two sympatric top-predators, long-legged buzzards (LLB) and short-toed eagles (STE), which recently became sympatric during their breeding season in the Judean Foothills, Israel. By combining information from comprehensive diet and movement analyses we found four dimensions of differentiation: (1) Geographic foraging area: LLB tended to forage relatively close to their nests (2.35 ± 0.62 km), while STE forage far from their nest (13.03 ± 2.20 km); (2) Foraging-habitat type: LLBs forage at low natural vegetation, avoiding cultivated fields, whereas STEs forage in cultivated fields, avoiding low natural vegetation; (3) Diurnal dynamics of foraging: LLBs are uniformly active during daytime, whereas STEs activity peaks in the early afternoon; and (4) Food-niche: while both species largely rely on reptiles (47.8% and 76.3% for LLB and STE, respectively), LLB had a more diverse diet and consumed significantly higher percentages of lizards, while STE consumed significantly higher percentages of snakes. Our results suggest that this multidimensional differentiation allows the spatial coexistence of these two dense populations in the study area.


An inverse approach to determine solute and solvent permeability parameters in artificial tissues.
This study presents a generic numerical model to simulate the coupled solute and solvent transport in tissue sections during addition and removal of chemical additives or cryoprotective agents (CPA; dimethylsulfoxide or DMSO). Osmotic responses of various tissue cells within the artificial tissue are predicted by the numerical model with three model parameters: Permeability of the tissue cell membrane to water (Lp), permeability of the tissue cell membrane to the solute or CPA (omega), and the diffusion coefficient of the solute or CPA in the extracellular space (D). By fitting the model results with published experimental data on solute/water concentrations at various locations within an artificial tissue, we were able to determine the permeability parameters of artificial tissue cells in the presence of 1.538 M DMSO. Lp and omega were determined at three different locations within the artificial tissue assuming a constant value of solute diffusivity (D = 1.0 x 10(-9) m2/s). The best fit values of Lp ranged from 0.59 x 10(-14) to 4.22 x 10(-14) m3/N-s while omega ranged from 0 to 6.6 x 10(-13) mol/N-s. Based on these values of Lp and omega, the solute reflection coefficient, sigma = 1 - omegav(-)CPA/Lp, ranged from 0.9923 to 1.0. The relative values of omega and sigma suggest that the artificial tissue cells are relatively impermeable to DMSO (or omega approximately 0 and sigma approximately 1.0). This observation was used to modify our model to predict the values of Lp and D assuming omega = 0 and sigma = 1.0. The best fit values of Lp ranged from 640 x 10(-14) to 2.1 x 10(-14) m3/N-s while D ranged from 0.63 x 10(-9) to 1.52 x 10(-9) m2/s. The permeability parameters obtained in the present study represent the first such effort for artificial tissues.


Advantages of percutaneous hollow needle technique for iliac bone harvest in alveolar cleft grafting.
To evaluate the percutaneous hollow needle technique for bone harvest to determine if morbidity from the bone donor site can be reduced significantly. A retrospective chart review was performed evaluating all patients undergoing alveolar bone grafting at our institution from January 1992 through December 1996. Patients who underwent additional major procedures were excluded. Group I consisted of 12 patients in whom the percutaneous technique was utilized. The patients had an average age of 11.1 years (range: 8 to 15 years). Six were male and six were female. One had a bilateral cleft. Group II consisted of 15 patients in whom the conventional open technique for iliac crest bone harvest was used. They had an average age of 13.1 years (range: 7 to 31 years). Six were male and nine were female. Two had bilateral clefts. Minimum follow-up was 6 months. We evaluated intraoperative blood loss, total postoperative analgesia requirement, and length of hospital stay based on a retrospective hospital chart review. A significant difference was found between the two groups regarding intraoperative blood loss (group I: 83.3 cm3, group II: 208 cm3; p = .0015), postoperative total analgesia requirement (group I: 0.04 mg/kg, range: 0 to 0.17 mg/kg; group II: 0.34 mg/kg, range: 0.03 to 0.74 mg/kg; p = .0002), and length of hospital stay (group I: 1.0 days, group II: 2.13 days; p = .0001). There was no significant change in these results when bilateral clefts were excluded. Iliac bone graft harvest using the percutaneous hollow needle technique results in less blood loss, decreased postoperative pain, and shorter hospital stays compared with the open technique.


L(infinity) constrained high-fidelity image compression via adaptive context modeling.
In this paper, we study high-fidelity image compression with a given tight L(infinity) bound. We propose some practical adaptive context modeling techniques to correct prediction biases caused by quantizing prediction residues, a problem common to the existing DPCM-type predictive near-lossless image coders. By incorporating the proposed techniques into the near-lossless version of CALIC that is considered by many as the state-of-the-art algorithm, we were able to increase its PSNR by 1 dB or more and/or reduce its bit rate by 10% or more, more encouragingly, at bit rates around 1.25 bpp or higher, our method obtained competitive PSNR results against the best L(2)-based wavelet coders, while obtaining much smaller L(infinity) bound.


Postural control of mouth breathing school aged children regarding gender.
Postural control of mouth breathing school aged children. To compare the posture and body balance of school aged children groups, with and without oral breathing considering the variable gender. The study was developed at a municipal school in the city of Santa Maria (Brazil) and received prior approval of the ethics committee of the University of Santa Maria. The study group (with oral breathing) and the control group (without oral breathing) were selected based on an anamnesis, age (between 8 and 12 years), assessment of the stomatognathic system and auditory evaluation. The final sample was composed by 51 children in the study group (20 female and 31 male) and 58 in the control group (34 female and 24 male). Both groups were submitted to a dynamic posturography (sensory organization test--SOT) and to a postural assessment in right and left lateral view. Regarding the female gender, a statistically significant difference was observed for the angle that evaluates head horizontal alignment; for the SOT III value and for all SOT mean values. As for the male gender, a significant numerical difference was observed for the knee angle, for the ankle angle, for the SOT III value, for the SOT IV value and for all SOT mean values. School aged children with oral breathing present postural alterations; females present head positing alterations and males present alterations in the position of the inferior limbs. The body balance of school aged children with oral breathing, of both genders, demonstrated to be altered when compared to children without oral breathing, especially in the presence of sensorial conflict.


A field study of bar-sponsored drink specials and their associations with patron intoxication.
The study examined associations between bar-sponsored drink specials and alcohol intoxication at the patron level. Data were collected in a college bar district located in a large campus community in the southeastern United States. Random and self-selected samples of patrons were interviewed after exiting college bars at night on four different nights (N=383). Anonymous interview and questionnaire data were collected as well as breath alcohol concentration (BrAC) readings. Significant gender differences existed in patron drinking practices. Women were more likely to take advantage of drink specials, whereas men reported greater alcohol expenditures, consumed more drinks, and drank for longer periods of time. Gender differences in BrAC were very small and not meaningful. Patrons who did not take advantage of drink specials reported consuming more drinks before bar entry than patrons who did participate in these promotions. Participation in "all-you-can-drink" promotions was significantly associated with higher BrAC readings after adjusting for covariates and random effects attributable to drinking establishment. Other drink specials did not have significant associations with alcohol intoxication. The all-you-can-drink special may be the specific discounting practice with the greatest potential for boosting patron intoxication and thus may need to be a stronger focus of alcohol-control policies aimed at improving the beverage service of drinking establishments.


Hospital and nursing home use from 2002 to 2008 among U.S. older adults with cognitive impairment, not dementia in 2002.
Little is known about health care use in the cognitive impairment, not dementia (CIND) subpopulation. Using a cohort of 7130 persons aged 71 years or over from the Health and Retirement Survey, we compared mean and total health care use from 2002 to 2008 for those with no cognitive impairment, CIND, or dementia in 2002. Cognitive status was determined using a validated method based on self or proxy interview measures. Health care use was also based on self or proxy reports. On the basis of the Health and Retirement Survey, the CIND subpopulation in 2002 was 5.3 million or 23% of the total population 71 years of age or over. Mean hospital nights was similar and mean nursing home nights was less in persons with CIND compared with persons with dementia. The CIND subpopulation, however, had more total hospital and nursing home nights--71,000 total hospital nights and 223,000 total nursing home nights versus 32,000 hospital nights and 138,000 nursing home nights in the dementia subpopulation. A relatively large population and high health care use result in a large health care impact of the CIND subpopulation.


Impact of indoleamine 2,3-dioxygenase on the antioxidant system in the placentas of severely pre-eclamptic patients.
Indoleamine 2,3-dioxygenase (IDO) is the rate limiting enzyme of the kynurenine pathway that degrades L-tryptophan, but a wider range of functions have now been proposed for this enzyme, including antioxidant activity. Our previous study revealed that reduced IDO expression in the placenta induces defective feto-maternal immuno-tolerance leading to the onset of pre-eclampsia. In our present study, we assessed the effects of low placental IDO activity as an antioxidant. The placental levels of 8-hydroxy-2'-deoxy-guanosine (8-OHdG), a maker for oxidative damage to DNA, were significantly higher in pre-eclamptic than normotensive pregnancies (P<0.05). Immunohistochemical signals of 8-OHdG were detected mainly in syncytiotrophoblasts and vascular endothelial cells, and co-localized with those for IDO. Furthermore, a significant inverse correlation was found between the IDO activity and 8-OhdG levels. These results show that oxidative stress is associated with decreased IDO activity in the pre-eclamptic placenta and suggest an impact of low IDO activity other than immune modulation in promoting the onset of this disorder.


Utilizing audit and feedback to improve hospitalists' performance in tobacco dependence counseling.
Hospitalized smokers benefit from smoking cessation counseling and nicotine replacement therapy (NRT). However, inpatient providers who care for hospitalized patients carry out these preventive measures inconsistently. We designed a peer-led audit and feedback intervention to improve (a) the frequency of smoking cessation counseling and (b) the appropriateness of the prescribing of NRT by hospitalist practitioners in our hospital. Documentation of tobacco cessation counseling in progress notes and discharge summaries and the ordering and dosing of NRT were assessed for 30 hospitalists before and after an intervention. This intervention included specific feedback on their counseling and prescribing practices as well as education and was delivered as part of a one-on-one academic detailing session. Five hundred and forty five and 1,119 patient-days were considered for this analysis in the pre- and postperiods, respectively. Documentation of tobacco dependence counseling in progress notes increased from 36% to 44% (p = .002) and from 7.5% to 46.8% in discharge summaries (p < .0001) following the intervention. The appropriateness of NRT dosing increased from 26% (before) to 64% (after) the intervention (p < .0001). A peer-led audit and feedback intervention for hospitalists significantly increases the frequency of smoking cessation counseling and the adequacy of NRT prescribing for hospitalized smokers.


Proteomic profiling of inflammatory signaling molecules in the tears of patients on chronic glaucoma medication.
To identify the tear proteins associated with the long-term use of glaucoma medication by using proteomic analysis and to compare these proteins to those previously reported in primary dry eye disease. Eighteen patients treated with topical antiglaucoma medications and 10 normal age-matched subjects with no prior topical treatment were recruited for the study. Tears were collected by using Schirmer's strip and analyzed by iTRAQ (isobaric tag for relative and absolute quantitation) for tear proteins by mass spectrometry. Conjunctival samples were collected and RNA expression determined by PCR. Of the 124 identified tear proteins (99% confidence, ProtScore ≥ 2.0), we found that the tear levels of S100-A8, S100-A9, mammaglobin B, and 14-3-3 ζ/δ were significantly increased in the medicated group compared with levels in the nonmedicated group (P < 0.05). For S100-A9, mammaglobin B, and 14-3-3 ζ/δ, use of topical medication for less than 1 year did not reach statistical significance compared with that in the nonmedicated group. Eyes on topical medication for less than 1 year showed a decrease in proline-rich 4 protein tear level (P = 0.0049) compared to nonmedicated group. The tear proteins detected in the medicated group differed from those in the primary dry eye group. Treatment with topical antiglaucoma medications for longer than 1 year may start to induce ocular surface inflammation. The inflammatory tear protein profile present in chronically medicated glaucomatous eyes appears to be different from that found in primary dry eye. Identification of tear proteins specific to medicated glaucomatous eyes will help to specifically develop targeted screening modalities and therapeutic agents different from current conventional dry eye management.


Photoconductive coaxial nanotubes of molecularly connected electron donor and acceptor layers.
Controlled self-assembly of a trinitrofluorenone-appended gemini-shaped amphiphilic hexabenzocoronene selectively formed nanotubes or microfibers with different photochemical properties. In these nanotubes, which are 16 nanometers in diameter and several micrometers long, a molecular layer of electron-accepting trinitrofluorenone laminates an electron-donating graphitic layer of pi-stacked hexabenzocoronene. The coaxial nanotubular structure allows photochemical generation of spatially separated charge carriers and a quick photoconductive response with a large on/off ratio greater than 10(4). In sharp contrast, the microfibers consist of a charge-transfer complex between the hexabenzocoronene and trinitrofluorenone parts and exhibit almost no photocurrent generation.


Efficacy of family-based weight control program for preschool children in primary care.
To test the efficacy of an innovative family-based intervention for overweight preschool-aged children and overweight parents conducted in the primary care setting. Children with BMI ≥ 85th percentile and an overweight parent were randomized to intervention or information control (IC). Trained staff delivered dietary and physical/sedentary activities education to parents over 6 months (10 group meetings and 8 calls). Parents in the intervention received also behavioral modification. An intention-to-treat analysis was performed by using mixed analysis of variance models to test changes in child percent over BMI (%OBMI) and z-BMI and to explore potential moderators of group differences in treatment response. Ninety-six of 105 randomized families started the program: 46 children (31 girls/15 boys) in the intervention and 50 (33 girls/17 boys) in the IC, with 33 and 39 mothers and 13 and 11 fathers in intervention and IC, respectively. Baseline characteristics did not differ between groups. Children in the intervention group had greater %OBMI and z-BMI decreases at 3 and 6 months compared with those assigned to IC (P < .0021). A greater BMI reduction over time was also observed in parents in the intervention compared with parents assigned to IC (P < .0001). Child %OBMI and parent BMI changes were correlated (r = .31; P = .003). Children with greater baseline %OBMI were more likely to have a greater %OBMI decrease over time (P = .02). Concurrently targeting preschool-aged overweight youth and their overweight parents for behavioral weight control in a primary care setting reduced child %OBMI and parent BMI, with parent and child weight changes correlating.


Physical activity patterns in a diverse population of women.
Demographic and psychosocial correlates of activity in domains other than recreational activity have not been well characterized and may be particularly relevant for health promotion efforts aimed at women. Cross-sectional relationships between recreational, occupational, and household/caregiving physical activity and demographic and psychosocial factors were assessed with a mail survey in a random sample of 2,636 ethnically diverse women members of a large health maintenance organization, ages 20-65. Activity was assessed with a modified Baecke questionnaire that uses categorical responses regarding frequency of domain-specific activities to create four semicontinuous activity indices (sports/exercise, active living, occupational, household/caregiving). Multivariable logistic regression analysis showed that the likelihood of being in the highest quartile of the sports/exercise and active-living indices, compared with the other three quartiles, was decreased among older, nonwhite, less well educated, heavier women who had young children at home, lacked motivation to exercise, and perceived external obstacles to exercise behavior. The odds ratios (ORs) ranged from 0.38, 95% confidence interval (CI) 0.33-0.45, associated with low motivation, to 0.95, 95% CI 0.93-0.98, associated with increasing body mass index. Social support and confidence in one's ability to continue to exercise, even when faced with other pressures and demands (termed self-efficacy), were associated with increased likelihood of high levels of sports/exercise and active living (OR = 2.34, 95% CI 1. 83-2.98 and OR = 3.96, 95% CI 2.92-5.38, respectively). In contrast, the highest quartile of household/caregiving activity was positively associated with increasing age (OR = 1.28, 95% CI 1.16-1.42), Hispanic ethnicity (OR = 1.58, 95% CI 0.55-1.01), being married (OR = 1.70, 95% CI 1.33-2.18), having young children at home (OR = 6.99, 95% CI 4.33-11), and greater time constraints as a barrier to exercise (OR = 1.55, 95% CI 1.38-1.74) and was negatively associated with employment (OR = 0.38, 95% CI 0.30-0.47). Increased likelihood of the highest quartile of occupational activity was associated with high school education or less (OR = 2.26, 95% CI 1.74-2.94) and current smoking (OR = 1.66, 95% CI 1.23-2.23), while self-efficacy regarding exercise was associated with decreased likelihood (OR = 0. 77, 95% CI 0.61-0.96). These findings suggest that demographic and psychosocial correlates of physical activity vary by domain and that initiatives to promote physical activity in the population need to take these differences into account.


Ready both to your and to my hands: mapping the action space of others.
To date, mutual interaction between action and perception has been investigated mainly by focusing on single individuals. However, we perceive affording objects and acts upon them in a surrounding world inhabited by other perceiving and acting bodies. Thus, the issue arises as to whether our action-oriented object perception might be modulated by the presence of another potential actor. To tackle this issue we used the spatial alignment effect paradigm and systematically examined this effect when a visually presented handled object was located close either to the perceiver or to another individual (a virtual avatar). We found that the spatial alignment effect occurred whenever the object was presented within the reaching space of a potential actor, regardless of whether it was the participant's own or the other's reaching space. These findings show that objects may afford a suitable motor act when they are ready not only to our own hand but also, and most importantly, to the other's hand. Our proposal is that this effect is likely to be due to a mapping of our own and the other's reaching space and we posit that such mapping could play a critical role in joining our own and the other's action.


Abiotic and biotic resistance to grass invasion in serpentine annual plant communities.
Biological invasions severely impact native plant communities, causing dramatic shifts in species composition and the restriction of native species to spatially isolated refuges. Competition from resident species and the interaction between resource limitation and competition have been overlooked as mechanisms of community resistance in refugia habitats. We examined the importance of these factors in determining the resistance of California serpentine plant communities to invasion by three common European grasses, Avena barbata, Bromus diandrus, and Hordeum murinum. We added seeds of each of these grasses to plots subjected to six levels of resource addition (N, P, Ca, H2O, all resources together, and a no-addition control) and two levels of competition (with resident community present or removed). Resource limitation and competition had strong effects on the biomass and reproduction of the three invaders. The addition of all resources together combined with the removal of the resident community yielded individual plants that were fourfold to 20-fold larger and sixfold to 20-fold more fecund than plants from control plots. Competitor removal alone yielded invaders that were twofold to sevenfold larger and twofold to ninefold more fecund. N addition alone or in combination with other resources led to a twofold to ninefold increase in the biomass and fecundity of the invaders. No other resource alone significantly affected native or invader performance, suggesting that N was the key limiting resource during our experiment. We found a significant interaction between abiotic and biotic resistance for Bromus, which experienced increased competitive suppression in fertilized plots. The threefold increase in resident biomass with N addition was likely responsible for this result. Our results confirm that serpentine plant communities are severely N limited, which, in combination with competition from resident species, promotes the resistance of these systems to invasions. Our work suggests that better understanding the relative sensitivities of invaders and residents to the physical environment is critical to predicting how abiotic and biotic factors interact to determine community resistance.


Psychiatric disorders after traumatic brain injury.
Substantial psychological and neurobehavioural evidence is available to support the hypothesis that traumatic brain injury (TBI) is a risk factor for subsequent psychiatric disorders. However, studies utilizing established psychiatric diagnostic schemes to study these outcomes after TBI are scarce, and no studies have included an assessment of personality disorders in addition to the major psychiatric disorders. This study utilizes structured psychiatric interviews to measure the prevalence of DSM-III(R) disorders in a sample of 18 subjects derived from a TBI rehabilitation programme. Results revealed high rates for major depression, bipolar affective disorder, generalized anxiety disorder, borderline and avoidant personality disorders. Co-morbidity was also high. A preliminary study of postulated predictive factors revealed possible roles for sex and for initial severity of injury. The study supports the association between TBI and psychiatric disorder, and suggests the need for monitoring, for prevention, and for treatment of psychiatric disorders after TBI.


Dendritic cells are the principal cells in mouse spleen bearing immunogenic fragments of foreign proteins.
We monitored the APC function of cells taken from the spleen and peritoneal cavity of mice that had been given protein antigens via the intravenous or intraperitoneal routes. Using the mAb 33D1 and N418 to negatively and positively select dendritic cells, we obtained evidence that dendritic cells are the main cell type in spleen that carries the protein in a form that is immunogenic for antigen-specific T cells. In vivo pulsed macrophages were not immunogenic and did not appear capable of transferring peptide fragments to dendritic cells.


Understanding factors that influence the integration of acute malnutrition interventions into the national health system in Niger.
Since 2007 to address a high burden, integration of acute malnutrition has been promoted in Niger. This paper studies factors that influenced the integration process of acute malnutrition into the Niger national health system.We used qualitative methods of observation, key informant interviews and focus group discussions at national level, two districts and nine communities selected through convenience sampling, as well as document review. A framework approach constructed around the problem, intervention, adoption system, health system characteristics and broad context guided the analysis. Data were recorded on paper, transcribed in a descriptive record, coded by themes deduced by building on the framework and triangulated for comprehensiveness.Key facilitating factors identified were knowledge and recognition of the problem helped by accurate information; effectiveness of decentralized continuity of care; compatibility with goals, support and involvement of health actors; and leadership for aligning policies and partnerships and mobilizing resources within a favourable political context driven by multisectoral development goals. Key hindering factors identified were not fully understanding severity, causes and consequences of the problem; limited utilization and trust in health interventions; high workload, and health worker turnover and attrition; and high dependence on financial and technical support based on short-term emergency funding within a context of high demographic pressure.The study uncovered influencing factors of integrating acute malnutrition into the national health system and their complex dynamics and relationships. It elicited the need for goal-oriented strategies and alignment of health actors to achieve sustainability, and systems thinking to understand pathways that foster integration. We recommend that context-specific learning of integrating acute malnutrition may expand to include causal modelling and scenario testing to inform strategy designs. The method may also be applied to monitor progress of integrating nutrition by the multisectoral nutrition plan to guide change.


The role of MAPKs in adipocyte differentiation and obesity.
The ERK, p38 and JNK mitogen activated protein kinases (MAPKs) are intracellular signalling pathways that play a pivotal role in many essential cellular processes such as proliferation and differentiation. MAPKs are activated by a large variety of stimuli and one of their major functions is to connect cell surface receptors to transcription factors in the nucleus, which consequently triggers long-term cellular responses. This review focuses on their in vitro and in vivo roles in adipocyte differentiation and obesity. Hyperplasia of adipose tissue is a critical event for the development of obesity. Several studies have analysed the role of MAPKs in vitro in adipocyte differentiation of preadipocyte established cell lines. In the case of ERK, although the first data appeared contradictory, a consensus scenario arises: ERK would be necessary to initiate the preadipocyte into the differentiation process and, thereafter, this signal transduction pathway needs to be shut-off to proceed with adipocyte maturation. The limitation of these cellular models is that only terminal adipocyte differentiation can be analysed, eluding the early proliferative steps of adipogenesis. New insights are now emerging by investigations conducted either in vitro with the use of embryonic stem (ES) cells or in vivo with mice where these genes are invalidated. These studies not only confirm and/or precise the various functions of MAPKs in adipogenesis but, importantly, reveal unsuspected roles, for example JNK in obesity or ERK in adipogenesis of ES cells, and, for a given pathway, assign specific functions to each isoform. It appears now that a fine tuning of the MAPKs regulates both normal and pathological adipogenesis. The precise understanding of the cascade of these molecular events and the way to regulate them will be certainly crucial in order to efficiently fight obesity.


The effect of a pre- and post-operative orthogeriatric service on cognitive function in patients with hip fracture. The protocol of the Oslo Orthogeriatrics Trial.
Hip fractures mainly affect older people. It is associated with high morbidity and mortality, and in particular a high frequency of delirium. Incident delirium following hip fracture is associated with an increased risk of dementia in the following months, but it is still not firmly established whether this is an association or a causal relationship. Orthogeriatric units vary with respect to content and timing of the intervention. One main effect of orthogeriatric care may be the prevention of delirium, especially if preoperative and postoperative care are provided. Thus, the aim of Oslo Orthogeriatric Trial, is to assess whether combined preoperative and postoperative orthogeriatric care can reduce the incidence of delirium and improve cognition following hip fracture. Inclusion and randomisation will take place in the Emergency Department, as soon as possible after admission. All patients with proximal femur fractures are eligible, irrespective of age, pre-fracture function and accommodation, except if the fracture is caused by a high energy trauma or the patient is terminally ill. The intervention is pre-and post-operative orthogeriatric care delivered on a dedicated acute geriatric ward. The primary outcome measure is a composite endpoint combining the Clinical Dementia Rating Scale (CDR) and the 10 word memory task at four months after surgery. Secondary outcomes comprise incident delirium, length of stay, cognition, mobility, place of residence, activities of daily living and mortality, measured at 4 and 12 months after surgery. We have included 332 patients in the period 17th September 2009 to 5th January 2012. Our choice of outcome measures and our emphasis of orthogeriatric care in the preoperative as well as the postoperative phase will enable us to provide new knowledge on the impact of orthogeriatric care on cognition. ClinicalTrials.gov NCT01009268.


Gigabit free-space multi-level signal transmission with a mid-infrared quantum cascade laser operating at room temperature.
Gigabit free-space transmissions are experimentally demonstrated with a quantum cascaded laser (QCL) emitting at mid-wavelength infrared of 4.65 μm, and a commercial infrared photovoltaic detector. The QCL operating at room temperature is directly modulated using on-off keying and, for the first time, to the best of our knowledge, four- and eight-level pulse amplitude modulations (PAM-4, PAM-8). By applying pre- and post-digital equalizations, we achieve up to 3 Gbit/s line data rate in all three modulation configurations with a bit error rate performance of below the 7% overhead hard decision forward error correction limit of 3.8×10-3. The proposed transmission link also shows a stable operational performance in the lab environment.


A simplified prognostic system for resected pancreatic neuroendocrine neoplasms.
A number of prognostically relevant clinicopathological variables have been proposed for pancreatic neuroendocrine neoplasms. However, a standardized prognostication system has yet to be established for patients undergoing potentially curative tumour resection. We examined a prospectively maintained, single-institution database to identify patients who underwent potentially curative resection of non-metastatic primary pancreatic neuroendocrine neoplasms. Patient, operative and pathological characteristics were analysed to identify variables associated with disease-specific and disease-free survival. Between 1991 and 2007, 43 patients met inclusion criteria. After a median follow-up of 68 months, 5-year disease-specific survival was 94% and 5-year disease-free survival was 72%. Tumours sized > or = 5 cm and vascular invasion were associated with worse disease-specific survival. Tumours sized > or = 5 cm, nodal metastases, positive resection margins and perineural invasion were associated with worse disease-free survival. A scoring system consisting of tumour size > or = 5 cm, histological grade, nodal metastases and resection margin positivity (SGNM) permitted stratification of disease-specific (P= 0.006) and disease-free (P= 0.0004) survival. This proposed scoring system demonstrated excellent discrimination of individual disease-specific and disease-free survival outcomes as reflected by concordance indices of 0.814 and 0.794, respectively. A simple scoring system utilizing tumour size, histological grade, nodal metastases and resection margin status can be used to stratify outcomes in patients undergoing resection of primary pancreatic neuroendocrine neoplasms.


Multispectral intensity diffraction tomography: single material objects with variable densities.
A reconstruction theory for multispectral intensity diffraction tomography (I-DT) is established and investigated for use with single material objects whose dispersion characteristics are known a priori. Instead of varying the object-to-detector distance, as prescribed by the original I-DT method and other classic in-line holographic reconstruction methods, the temporal frequency of the illuminating plane wave represents the degree of freedom of the imaging system that is varied to acquire two independent intensity measurements at each tomographic view angle. Unlike previous multispectral I-DT methods, the proposed method does not require a nondispersive assumption. A computer-simulation study is presented to demonstrate and corroborate the method.


Usefulness of right ventricular basal free wall strain by two-dimensional speckle tracking echocardiography in patients with chronic thromboembolic pulmonary hypertension.
Recently two-dimensional (2D) speckle tracking echocardiography (STE) derived from right ventricular (RV) free wall has been shown to be a very useful tool for the estimation of RV performance. The purpose of this study was to examine whether RV basal free wall strain can detect increased mean pulmonary arterial pressure (mPAP) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We investigated a total of 126 patients with CTEPH (mean age, 56 ± 12 years). They underwent echocardiography and right heart catheter examination. 2D STE-derived longitudinal strain was measured by placing 2 regions of interests (ROIs) on the RV basal free wall in RV-focused apical 4-chamber view. Peak strain (RV-PS) was acquired between the 2 ROIs. Conventional echocardiographic RV parameters (RV fractional area change, RV myocardial performance index, tricuspid annular plane systolic excursion, tricuspid annular peak systolic velocity, and tricuspid regurgitant pressure gradient) were evaluated as well. Right heart catheterization was performed on the day following of echocardiographic evaluation. Among RV echo parameters, RV-PS showed the best correlation with mPAP (r = 0.75, P < 0.0001). Receiver operating characteristic analysis revealed that a cut-off value of RV-PS -20.8% could detect mPAP ≧ 25 mmHg (sensitivity 78%, specificity 93%, area under the curve 0.90, P < 0.001). RV basal free wall strain was a useful tool for the non-invasive detection of increased mPAP in patients with CTEPH.


Assessment of laboratory and daily energy expenditure estimates from consumer multi-sensor physical activity monitors.
Wearable physical activity monitors are growing in popularity and provide the opportunity for large numbers of the public to self-monitor physical activity behaviours. The latest generation of these devices feature multiple sensors, ostensibly similar or even superior to advanced research instruments. However, little is known about the accuracy of their energy expenditure estimates. Here, we assessed their performance against criterion measurements in both controlled laboratory conditions (simulated activities of daily living and structured exercise) and over a 24 hour period in free-living conditions. Thirty men (n = 15) and women (n = 15) wore three multi-sensor consumer monitors (Microsoft Band, Apple Watch and Fitbit Charge HR), an accelerometry-only device as a comparison (Jawbone UP24) and validated research-grade multi-sensor devices (BodyMedia Core and individually calibrated Actiheart™). During discrete laboratory activities when compared against indirect calorimetry, the Apple Watch performed similarly to criterion measures. The Fitbit Charge HR was less consistent at measurement of discrete activities, but produced similar free-living estimates to the Apple Watch. Both these devices underestimated free-living energy expenditure (-394 kcal/d and -405 kcal/d, respectively; P<0.01). The multi-sensor Microsoft Band and accelerometry-only Jawbone UP24 devices underestimated most laboratory activities and substantially underestimated free-living expenditure (-1128 kcal/d and -998 kcal/d, respectively; P<0.01). None of the consumer devices were deemed equivalent to the reference method for daily energy expenditure. For all devices, there was a tendency for negative bias with greater daily energy expenditure. No consumer monitors performed as well as the research-grade devices although in some (but not all) cases, estimates were close to criterion measurements. Thus, whilst industry-led innovation has improved the accuracy of consumer monitors, these devices are not yet equivalent to the best research-grade devices or indeed equivalent to each other. We propose independent quality standards and/or accuracy ratings for consumer devices are required.


Influence of a dispersion of magnetic and nonmagnetic nanoparticles on the magnetic Fredericksz transition of the liquid crystal 5CB.
A long time ago, Brochard and de Gennes predicted the possibility of significantly decreasing the critical magnetic field of the Fredericksz transition (the magnetic Fredericksz threshold) in a mixture of nematic liquid crystals and ferromagnetic particles, the so-called ferronematics. This phenomenon is rarely measured to be large, due to soft homeotropic anchoring induced at the nanoparticle surface. Here we present an optical study of the magnetic Fredericksz transition combined with a light scattering study of the classical nematic liquid crystal: the pentylcyanobiphenyl (5CB), doped with 6 nm diameter magnetic and nonmagnetic nanoparticles. Surprisingly, for both nanoparticles, we observe at room temperature a net decrease of the threshold field of the Fredericksz transition at low nanoparticle concentrations, which appears associated with a coating of the nanoparticles by a brush of polydimethylsiloxane copolymer chains inducing planar anchoring of the director on the nanoparticle surface. Moreover, the magnetic Fredericksz threshold exhibits nonmonotonic behavior as a function of the nanoparticle concentration for both types of nanoparticles, first decreasing down to a value from 23% to 31% below that of pure 5CB, then increasing with a further increase of nanoparticle concentration. This is interpreted as an aggregation starting at around 0.02 weight fraction that consumes more isolated nanoparticles than those introduced when the concentration is increased above c=0.05 weight fraction (volume fraction 3.5×10^{-2}). This shows the larger effect of isolated nanoparticles on the threshold with respect to aggregates. From dynamic light scattering measurements we deduced that, if the decrease of the magnetic threshold when the nanoparticle concentration increases is similar for both kinds of nanoparticles, the origin of this decrease is different for magnetic and nonmagnetic nanoparticles. For nonmagnetic nanoparticles, the behavior may be associated with a decrease of the elastic constant due to weak planar anchoring. For magnetic nanoparticles there are non-negligible local magnetic interactions between liquid crystal molecules and magnetic nanoparticles, leading to an increase of the average order parameter. This magnetic interaction thus favors an easier liquid crystal director rotation in the presence of external magnetic field, able to reorient the magnetic moments of the nanoparticles along with the molecules.


Leuprolide acetate treatment of adrenocortical disease in ferrets.
To determine the effects of leuprolide acetate, a long-acting gonadotropin-releasing hormone analog, in ferrets with adrenocortical diseases. Case series. 20 ferrets with adrenocortical disease diagnosed on the basis of clinical signs and plasma sex hormone concentrations. Ferrets were treated with leuprolide (100 microg, IM, once), and plasma hormone concentrations were measured before and 3 to 6 weeks after treatment. Leuprolide treatment resulted in significant reductions in plasma estradiol, 17 alpha-hydroxyprogesterone, androstenedione, and dehydroepiandrosterone concentrations and eliminated or reduced clinical signs associated with adrenocortical disease. Decreases in vulvar swelling, pruritus, and undesirable sexual behaviors and aggression were evident 14 days after treatment; hair regrowth was evident by 4 weeks after treatment. The response to treatment was transitory, and clinical signs recurred in all ferrets. Mean +/- SEM time to recurrence was 3.7 +/- 0.4 months (range, 1.5 to 8 months). Results suggest that leuprolide can be safely used to temporarily eliminate clinical signs and reduce sex hormone concentrations in ferrets with adrenocortical diseases. However, the safety of long-term leuprolide use in ferrets has not been investigated, and the long-term effects of leuprolide in ferrets with nodular adrenal gland hyperplasia or adrenal gland tumors are unknown.


The challenges and opportunities of conducting a clinical trial in a low resource setting: the case of the Cameroon mobile phone SMS (CAMPS) trial, an investigator initiated trial.
Conducting clinical trials in developing countries often presents significant ethical, organisational, cultural and infrastructural challenges to researchers, pharmaceutical companies, sponsors and regulatory bodies. Globally, these regions are under-represented in research, yet this population stands to gain more from research in these settings as the burdens on health are greater than those in developed resourceful countries. However, developing countries also offer an attractive setting for clinical trials because they often have larger treatment naive populations with higher incidence rates of disease and more advanced stages. These factors can present a reduction in costs and time required to recruit patients. So, balance needs to be found where research can be encouraged and supported in order to bring maximum public health benefits to these communities. The difficulties with such trials arise from problems with obtaining valid informed consent, ethical compensation mechanisms for extremely poor populations, poor health infrastructure and considerable socio-economic and cultural divides. Ethical concerns with trials in developing countries have received attention, even though many other non-ethical issues may arise. Local investigator initiated trials also face a variety of difficulties that have not been adequately reported in literature. This paper uses the example of the Cameroon Mobile Phone SMS trial to describe in detail, the specific difficulties encountered in an investigator-initiated trial in a developing country. It highlights administrative, ethical, financial and staff related issues, proposes solutions and gives a list of additional documentation to ease the organisational process.


History of liver surgery.
Although battle surgeons had débrided small bits of liver protruding through wounds since ancient times, formal entry into the peritoneal cavity to staunch hemorrhage due to trauma or to remove tumors or drain cysts had to await the advent of general anesthesia and antisepsis. After a burst of pioneering activity from 1880 to 1910, little progress was made until after World War II. In the last 40 years, remarkable advances have been made in the techniques of liver resection, our understanding of liver diseases requiring operation, and our ability to support patients through major resections. Liver transplantation epitomizes the challenges that can now be accepted, and its success augurs well for an increase in liver operations in the future.


Comparing solid-body with point-light animations.
The movement of faces provides useful information for a variety of tasks and is now an active area of research. We compare here two ways of presenting face motion in experiments: as solid-body animations and as point-light displays. In the first experiment solid-body and point-light animations, based on the same motion-captured marker data, produced similar levels of performance on a sex-judgment task. The trend was for an advantage for the point-light displays, probably in part because of residual spatial cues available in such stimuli. In the second experiment we compared spatially normalised point-light displays of marker data with solid-body animations and pseudorandom point-light animations. Performance with solid-body animations and normalised point-light displays was similar and above chance, while performance with the pseudorandom point-light stimuli was not above chance. We conclude that both relatively few well-placed points and solid-body animations provide useful information about facial motion, but that a greater number of randomly placed points does not support above-chance performance. Solid-body animations have the methodological advantages of reducing the importance of marker placement and are more effective in isolating motion information, even if they are subsequently rendered as point-light displays.


On the chromatic aberration of microlenses.
The optical properties of plano-convex refractive microlenses with low Fresnel Number (typically FN < 10) are investigated. It turns out that diffraction effects at the lens aperture limit the range of the effective focal length. The upper limit of the focal length is determined by the diffraction pattern of a pinhole with equal diameter. In addition achromatic microlenses can be realized because refraction and diffraction have opposing effects on the focal length. Gaussian beam propagation method has been used for simulation. The presented results are of relevance for applications, where microlenses with small apertures and long focal lengths are used, for example, Shack Hartmann wavefront sensors or confocal microscopes.


A pre-neoplastic epigenetic field defect in HCV-infected liver at transcription factor binding sites and polycomb targets.
The predisposition of patients with Hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) involves components of viral infection, inflammation and time. The development of multifocal, genetically distinct tumours is suggestive of a field defect affecting the entire liver. The molecular susceptibility mediating such a field defect is not understood. One potential mediator of long-term cellular reprogramming is heritable (epigenetic) regulation of transcription, exemplified by DNA methylation. We studied epigenetic and transcriptional changes in HCV-infected livers in comparison with control, uninfected livers and HCC, allowing us to identify pre-neoplastic epigenetic and transcriptional events. We find the HCV-infected liver to have a pattern of acquisition of DNA methylation targeted to candidate enhancers active in liver cells, enriched for the binding sites of the FOXA1, FOXA2 and HNF4A transcription factors. These enhancers can be subdivided into those proximal to genes implicated in liver cancer or to genes involved in stem cell development, the latter distinguished by increased CG dinucleotide density and polycomb-mediated repression, manifested by the additional acquisition of histone H3 lysine 27 trimethylation (H3K27me3). Transcriptional studies on our samples showed that the increased DNA methylation at enhancers was associated with decreased local gene expression, results validated in independent samples from The Cancer Genome Atlas. Pharmacological depletion of H3K27me3 using the EZH2 inhibitor GSK343 in HepG2 cells suppressed cell growth and also revealed that local acquired DNA methylation was not dependent upon the presence of polycomb-mediated repression. The results support a model of HCV infection influencing the binding of transcription factors to cognate sites in the genome, with consequent local acquisition of DNA methylation, and the added repressive influence of polycomb at a subset of CG-dense cis-regulatory sequences. These epigenetic events occur before neoplastic transformation, resulting in what may be a pharmacologically reversible epigenetic field defect in HCV-infected liver.


Soilborne Oospores of Phytophthora infestans in Central Mexico Survive Winter Fallow and Infect Potato Plants in the Field.
Survival and infectivity of oospores in soils naturally infested with P. infestans oospores were studied in central Mexico. Sporangia were selectively eliminated from soil samples to determine infectivity attributable to the presence of oospores. Selective elimination of sporangia was achieved by two cycles of wetting and drying the soil. Oospore concentration, viability, and infectivity varied among soils collected during the winter fallow in different locations of central Mexico. In some soils, oospores were infective regardless of the time at which they were collected during the winter fallow. However, oospore viability and infectivity decreased following 2 years of intercropping. The number of stem lesions and initial disease severity were significantly higher in soils with moderate (20 to 39 oospores g-1 soil) oospore infestation compared with soils with low (0 to 19 oospores g-1 soil) infestation. Our study confirms that oospores can survive winter fallow and serve as a source of primary inoculum in the central highlands of Mexico. Oospore survival appeared lower in the Toluca Valley soil, which may be an indication of soil suppressiveness.


Tandem electrospinning for heterogeneous nanofiber patterns.
Smart nanofibrillar constructs can be a promising technological solution for many emerging and established fields, facilitating the potential impact of nano-scale strategies to address relevant technological challenges. As a fabrication technique, electrospinning (ESP) is relatively well-known, accessible, economic, and fast, though until now has shown limitation over control and design of the fibrillar constructs which can be produced. Here, we introduce 'Tandem Electrospinning' (T-ESP), a novel technique able to create increasingly complex patterns of fibrous polymeric constructs on a micro and nano-scale. Modifying a standard ESP configuration results in a focusing electric field that is able to spatially define the deposition pattern of multiple polymer jets simultaneously. Additional spatially defined heterogeneity is achieved by tuning polymer solution properties to obtain a gradient of fiber alignment. Heterogeneous fibrous meshes are created with either random, aligned, or a divergent fiber patterns. This approach holds potential for many fields, with application examples shown for tissue engineering and separation technologies. The technique outlined here provides a rapid, versatile, and accessible method for polymeric nanofabrication of patterned heterogeneous fibrous constructs. Polymer properties are also shown to dictate fiber alignment, providing further insight into the mechanisms involved in the electrospinning fabrication process.


Going to sleep in the supine position is a modifiable risk factor for late pregnancy stillbirth; Findings from the New Zealand multicentre stillbirth case-control study.
Our objective was to test the primary hypothesis that maternal non-left, in particular supine going-to-sleep position, would be a risk factor for late stillbirth (≥28 weeks of gestation). A multicentre case-control study was conducted in seven New Zealand health regions, between February 2012 and December 2015. Cases (n = 164) were women with singleton pregnancies and late stillbirth, without congenital abnormality. Controls (n = 569) were women with on-going singleton pregnancies, randomly selected and frequency matched for health region and gestation. The primary outcome was adjusted odds of late stillbirth associated with self-reported going-to-sleep position, on the last night. The last night was the night before the late stillbirth was thought to have occurred or the night before interview for controls. Going-to-sleep position on the last night was categorised as: supine, left-side, right-side, propped or restless. Multivariable logistic regression adjusted for known confounders. Supine going-to-sleep position on the last night was associated with increased late stillbirth risk (adjusted odds ratios (aOR) 3.67, 95% confidence interval (CI) 1.74 to 7.78) with a population attributable risk of 9.4%. Other independent risk factors for late stillbirth (aOR, 95% CI) were: BMI (1.04, 1.01 to 1.08) per unit, maternal age ≥40 (2.88, 1.31 to 6.32), birthweight <10th customised centile (2.76, 1.59 to 4.80), and <6 hours sleep on the last night (1.81, 1.14 to 2.88). The risk associated with supine-going-to-sleep position was greater for term (aOR 10.26, 3.00 to 35.04) than preterm stillbirths (aOR 3.12, 0.97 to 10.05). Supine going-to-sleep position is associated with a 3.7 fold increase in overall late stillbirth risk, independent of other common risk factors. A public health campaign encouraging women not to go-to-sleep supine in the third trimester has potential to reduce late stillbirth by approximately 9%.


Multi-Solvent Microdroplet Evaporation: Modeling and Measurement of Spray-Drying Kinetics with Inhalable Pharmaceutics.
Evaporation and particle formation from multi-solvent microdroplets containing solid excipients pertaining to spray-drying of therapeutic agents intended for lung delivery were studied. Various water and ethanol co-solvent systems containing a variety of actives and excipients (beclomethasone, budesonide, leucine, and trehalose) were considered. Numerical methods were used to predict the droplet evaporation rates and internal solute transfers, and their results verified and compared with results from two separate experimental setups. In particular, an electrodynamic balance was used to measure the evaporation rates of multicomponent droplets and a monodisperse droplet chain setup collected dried microparticles for further analytical investigations and ultramicroscopy. The numerical results are used to explain the different particle morphologies dried from solutions at different co-solvent compositions. The obtained numerical data clearly show that the two parameters controlling the general morphology of a dried particle, namely the Péclet number and the degree of saturation, can change with time in a multi-solvent droplet. This fact complicates product development for such systems. However, this additional complexity vanishes at what we define as the iso-compositional point, which occurs when the solvent ratios and other composition-dependent properties of the droplet remain constant during evaporation, similar to the azeotrope of such systems during distillation. Numerical and experimental analysis of multi-solvent systems indicate that spray-drying near the iso-compositional ratio simplifies the design and process development of such systems.


Expression of human papillomavirus type 16 L1 protein in Escherichia coli: denaturation, renaturation, and self-assembly of virus-like particles in vitro.
Major capsid protein L1 of HPV16 was produced in a fused form in Escherichia coli using an inducible expression system. The protein formed insoluble aggregations (inclusion bodies) and the yield was more than 10% of total cell proteins. The inclusion bodies were isolated and solubilised with 8 M urea and the L1 proteins were purified by chromatographic separation. Following removal of the urea by gradual dialysis, the denatured L1 proteins spontaneously renatured and subsequently assembled into polymorphologic aggregations in vitro. Electron microscopy showed that the assembled material included structures resembling native empty capsids as well as incompletely formed capsids. After separation from the pool of polymorphologic structures by sucrose gradient sedimentation, the correctly formed virus-like particles (VLE. coliPs) were recognised by a HPV16 type-specific, conformational-dependent monoclonal antibody in an ELISA. This system offers not only a model for investigation of the intrinsic interactions that occur during L1 assembly, but also a potential route for convenient manufacture of highly purified VLP vaccines.


Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).
Angiosarcoma is a rare aggressive endothelial cell cancer with high mortality. Isolated reports suggest immune checkpoint inhibition efficacy in angiosarcoma, but no prospective studies have been published. We report results for angiosarcoma treated with ipilimumab and nivolumab as a cohort of an ongoing rare cancer study. This is a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) for metastatic or unresectable angiosarcoma. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free (PFS) and overall survival, and toxicity. A two-stage design was used. Overall, there were 16 evaluable patients. Median age was 68 years (range, 25-81); median number of prior lines of therapy, 2. Nine patients had cutaneous and seven non-cutaneous primary tumors. ORR was 25% (4/16). Sixty per cent of patients (3/5) with primary cutaneous scalp or face tumors attained a confirmed response. Six-month PFS was 38%. Altogether, 75% of patients experienced an adverse event (AE) (at least possibly related to drug) (25% grade 3-4 AE); 68.8%, an immune-related AE (irAE) (2 (12.5%), grade 3 or 4 irAEs (alanine aminotransferase/aspartate aminotransferase increase and diarrhea)). There were no grade 5 toxicities. One of seven patients in whom tumor mutation burden (TMB) was assessed showed a high TMB (24 mutations/mb); that patient achieved a partial response (PR). Two of three patients with PDL1 immunohistochemistry assessed had high PDL1 expression; one achieved a PR. The combination of ipilimumab and nivolumab demonstrated an ORR of 25% in angiosarcoma, with three of five patients with cutaneous tumors of the scalp or face responding. Ipilimumab and nivolumab warrant further investigation in angiosarcoma. NCT02834013.


The Vermont-Oxford Trials Network: very low birth weight outcomes for 1990. Investigators of the Vermont-Oxford Trials Network Database Project.
This report describes the Vermont-Oxford Trials Network, a voluntary collaborative research network, and summarizes the outcomes and medical interventions for very low birth weight infants at participating centers in 1990. The Vermont-Oxford Trials Network included 36 centers in 1990 (11% university hospitals, 44% university affiliates, 44% nonaffiliated) with a total of 2961 infants weighing 501 to 1500 g (median 73 infants, range 5 to 172). Eighty percent of the infants were inborn and 65% were white. The overall network frequencies for selected interventions and outcomes were as follows: prenatal care, 90%; a complete course of antenatal corticosteroids, 12%; cesarean section, 56%; surfactant therapy, 49%; postnatal steroids for chronic lung disease, 16%; high-frequency ventilation, 4%; patent ductus arteriosus, 31%; necrotizing enterocolitis, 6%; bacterial sepsis, 16%; and intraventricular hemorrhage, 26%. By 28 days, 15% of the infants had died and 8% had been transferred, whereas by discharge 18% had died and 18% had been transferred. There were marked variations among the centers in the frequencies of different medical interventions and in the frequencies of various clinical outcomes. The Vermont-Oxford Trials Network is a unique collaborative research group composed of a broad range of neonatal intensive care units. During 1990 there were considerable differences among the centers in the interventions used and patient outcomes observed. The investigators plan to devote the resources of the Network to a research program of randomized trials and outcome studies so that effective interventions can be identified and the quality of neonatal intensive care can be continuously improved.


Pathogenesis, Diagnosis, and Treatment of Cervical Vertigo.
Cervical vertigo is characterized by vertigo from the cervical spine. However, whether cervical vertigo is an independent entity still remains controversial. In this narrative review, we outline the basic science and clinical evidence for cervical vertigo according to the current literature. So far, there are 4 different hypotheses explaining the vertigo of a cervical origin, including proprioceptive cervical vertigo, Barré-Lieou syndrome, rotational vertebral artery vertigo, and migraine-associated cervicogenic vertigo. Proprioceptive cervical vertigo and rotational vertebral artery vertigo have survived with time. Barré-Lieou syndrome once was discredited, but it has been resurrected recently by increased scientific evidence. Diagnosis depends mostly on patients' subjective feelings, lacking positive signs, specific laboratory examinations and clinical trials, and often relies on limited clinical experiences of clinicians. Neurological, vestibular, and psychosomatic disorders must first be excluded before the dizziness and unsteadiness in cervical pain syndromes can be attributed to a cervical origin. Treatment for cervical vertigo is challenging. Manual therapy is recommended for treatment of proprioceptive cervical vertigo. Anterior cervical surgery and percutaneous laser disc decompression are effective for the cervical spondylosis patients accompanied with Barré-Liéou syndrome. As to rotational vertebral artery vertigo, a rare entity, when the exact area of the arterial compression is identified through appropriate tests such as magnetic resonance angiography (MRA), computed tomography angiography (CTA) or digital subtraction angiography (DSA) decompressive surgery should be the chosen treatment.


Effect of growth hormone treatment on sleep EEGs in growth hormone-deficient children.
Total sleep time, sleep stages 1-4, REM, REM latency, and sleep efficiency were analyzed in seven children with growth hormone deficiency (GHD) before and after growth hormone (GH) therapy. Before GH therapy, GHD children spent 19.5% of their total sleep time in REM sleep, 9.7% in stage 1, 41.0% in stage 2, 10.0% in stage 3, and 19.7% in stage 4. GHD children had more stage 1 and 3 sleep and less REM as compared with age-matched normal children reported by Williams et al. After GH therapy was initiated, six of the seven patients had decreases in the duration of stage 3 sleep, with an average decrease of 21.8 min. The difference between stage 3 sleep before and during GH treatment was significant, with a p value of less than 0.025. When the results were expressed as the percentage of the total sleep period, the difference was also significant, (10.0 +/- 2.0 to 7.5 +/- 3.1%, mean +/- SD; p less than 0.05). No other sleep parameters were significantly affected by GH therapy. The changes observed in stage 3 sleep, non-REM sleep, and the lack of any other changes in sleep before and after GH therapy have not been described before in GH-deficient children. They differ from studies in normal humans and animals which showed that REM sleep increased with administration of growth hormone. These differences suggest that GH deficiency is associated with a specific sleep EEG anomaly that is corrected in part by GH therapy.


[Participation in health behaviour change programmes: results of the German Health Interview and Examination Survey for Adults (DEGS1)].
Health behaviour change programmes to promote healthy behaviours are aimed at, among other things, counteracting the emergence of widespread non-communicable diseases. Which population groups use these programmes? This analysis is based on data from DEGS1, which was conducted from 2008-2011. People aged 18-79 years were asked about their participation in programmes in the last 12 months in the fields of nutrition, physical activity and relaxation (n = 7,807). The analysis was stratified by sex, age, socioeconomic status (SES), and type of statutory health insurance fund. A total of 16.6 % of respondents participate in at least one programme for behaviour change, with women using these programmes significantly more frequently, indeed twice as often, as men (22.1 % versus 11 %). The older population participates more often than younger age groups. Women and men with low SES use the programmes significantly less frequently than those with middle or high SES. Women who are insured by the AOK health insurance group have a significantly lower rate of participation than women insured by any other statutory health insurance fund. Overall participation has almost doubled since the "German National Health Interview and Examination Survey 1998" (9.1 %). Further efforts are necessary to reach population groups with low participation rates. An English full-text version of this article is available at SpringerLink as supplemental.


Evidence implying DNA polymerase beta function in excision repair.
Comparison was made of the ability of calf thymus DNA polymerases alpha and beta to replicate the following templates: native E. coli CR-34 DNA (T-DNA), calf thymus DNA activated by DNase I (act.DNA), BU-DNA (from E. coli CR-34 cells cultured on BUdR-containing medium) with damages resulting from incomplete excision repair, as well as thermally denatured act.DNA and BU-DNA (s.s.act.DNA and s.s.BU-DNA). 3H-TTP incorporation during extensive replication of act.DNA was similar for both enzymes, being, as expected, 40 times higher than for T-DNA. Likewise, the differences in the yield of the s.s.act.DNA or s.s.BU-DNA replication between both enzymes were negligible. In contrast, damaged native DNA was 6 - 30 times more extensively replicated by DNA polymerase beta than alpha. We propose that this is due to the greater ability of DNA polymerase beta compared with alpha to replicate single-stranded gaps, the presence of which is more likely in damaged BU-DNA than in T-DNA and act.DNA.


The structure of carbamoyl phosphate synthetase determined to 2.1 A resolution.
Carbamoyl phosphate synthetase catalyzes the formation of carbamoyl phosphate from one molecule of bicarbonate, two molecules of Mg2+ATP and one molecule of glutamine or ammonia depending upon the particular form of the enzyme under investigation. As isolated from Escherichia coli, the enzyme is an alpha,beta-heterodimer consisting of a small subunit that hydrolyzes glutamine and a large subunit that catalyzes the two required phosphorylation events. Here the three-dimensional structure of carbamoyl phosphate synthetase from E. coli refined to 2.1 A resolution with an R factor of 17.9% is described. The small subunit is distinctly bilobal with a catalytic triad (Cys269, His353 and Glu355) situated between the two structural domains. As observed in those enzymes belonging to the alpha/beta-hydrolase family, the active-site nucleophile, Cys269, is perched at the top of a tight turn. The large subunit consists of four structural units: the carboxyphosphate synthetic component, the oligomerization domain, the carbamoyl phosphate synthetic component and the allosteric domain. Both the carboxyphosphate and carbamoyl phosphate synthetic components bind Mn2+ADP. In the carboxyphosphate synthetic component, the two observed Mn2+ ions are both octahedrally coordinated by oxygen-containing ligands and are bridged by the carboxylate side chain of Glu299. Glu215 plays a key allosteric role by coordinating to the physiologically important potassium ion and hydrogen bonding to the ribose hydroxyl groups of ADP. In the carbamoyl phosphate synthetic component, the single observed Mn2+ ion is also octahedrally coordinated by oxygen-containing ligands and Glu761 plays a similar role to that of Glu215. The carboxyphosphate and carbamoyl phosphate synthetic components, while topologically equivalent, are structurally different, as would be expected in light of their separate biochemical functions.


Re-interventions on the thoracic and thoracoabdominal aorta in patients with Marfan syndrome.
The advent of multi-gene panel genetic testing and the discovery of new syndromic and non-syndromic forms of connective tissue disorders have established thoracic aortic aneurysms as a genetically mediated disease. Surgical results in patients with Marfan syndrome (MFS) provide an important benchmark for this patient population. Prophylactic aortic root surgery prevents acute dissection and has contributed to the improved survival of MFS patients. In the majority of patients, re-interventions are driven by a history of dissection. Patients undergoing elective root repair have a low risk for re-interventions on the root itself. Experienced centers have results after valve-sparing procedures at 10 years comparable with those seen after a modified Bentall procedure. In patients where only the ascending aorta was replaced during the initial surgery, re-intervention rates are high as the root continues to dilate. The fate of the aortic arch in MFS patients presenting with dissection is strongly correlated with the extent of the initial surgery. Not replacing the entire ascending aorta and proximal aortic arch results in a high rate of re-interventions. Nevertheless, the additional burden of replacing the entire aortic arch during emergent proximal repair is not very well defined and makes comparisons with patients undergoing elective arch replacement difficult. Interestingly, replacing the entire aortic arch during initial surgery for acute dissection does not protect from re-interventions on downstream aortic segments. MFS patients suffering from type B dissection have a high risk for re-interventions ultimately leading up to replacement of the entire thoracoabdominal aorta even if the dissection was deemed uncomplicated by conventional criteria. While current guidelines do not recommend the implantation of stent grafts in MFS patients, implantation of a frozen-elephant-trunk to create a stable proximal landing zone for future endovascular or open procedures has emerged as a means to address aortic arch and descending aortic pathologies.


Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C.
Hepatitis C virus (HCV) protease inhibitors combined with pegylated alfa interferon-ribavirin have demonstrated improved efficacy compared with pegylated alfa interferon-ribavirin alone for the treatment of chronic hepatitis C. Asunaprevir (BMS-650032), a novel HCV NS3 protease inhibitor in clinical development, was evaluated for safety, antiviral activity, and resistance in four double-blind, placebo-controlled, sequential-panel, single- and multiple-ascending-dose (SAD and MAD) studies in healthy subjects or subjects with chronic HCV genotype 1 infection. In SAD studies, subjects (healthy or with chronic HCV infection) were randomized to receive asunaprevir in dose groups of 10 to 1,200 mg or a placebo. In MAD studies, healthy subjects were randomized to receive asunaprevir in dose groups of 10 to 600 mg twice daily or a placebo for 14 days; subjects with HCV infection received asunaprevir in dose groups of 200 to 600 mg twice daily, or a placebo, for 3 days. Across all four studies, headache and diarrhea were the most frequent adverse events in asunaprevir recipients. Asunaprevir at doses of 200 to 600 mg resulted in rapid HCV RNA decreases from the baseline; maximal mean changes in HCV RNA over time were 2.7 and 3.5 log(10) IU/ml in the SAD and MAD studies, respectively. No enrichment of signature asunaprevir-resistant viral variants was detected. In conclusion, the novel NS3 protease inhibitor asunaprevir, when administered at single or multiple doses of 200 to 600 mg twice daily, is generally well tolerated, achieving rapid and substantial decreases in HCV RNA levels in subjects chronically infected with genotype 1 HCV.


Reduced respiratory motion artefact in constant TR multi-slice MRI of the mouse.
Multi-slice scanning in the abdomen and thorax of small animals is compromised by the effects of respiration unless imaging and respiration are synchronised. To avoid the signal modulations that result from respiration motion and a variable TR, blocks of fully relaxed slices are typically acquired during inter-breath periods, at the cost of scan efficiency. This paper reports a conceptually simple yet effective prospective gating acquisition mode for multi-slice scanning in free breathing small animals at any fixed TR of choice with reduced sensitivity to respiratory motion. Multi-slice scan modes have been implemented in which each slice has its own specific projection or phase encode loop index counter. When a breath is registered RF pulses continue to be applied but data are not acquired, and the corresponding counters remain fixed so that the data are acquired one TR later, providing it coincides with an inter-breath period. The approach is refined to reacquire the slice data that are acquired immediately before each breath is detected. Only the data with reduced motion artefact are used in image reconstruction. The efficacy of the method is demonstrated in the RARE scan mode which is well known to be particularly useful for tumour visualization. Validation in mice with RARE demonstrates improved stability with respect to ungated scanning where signal averaging is often used to reduce artefacts. SNR enhancement maps demonstrate the improved efficiency of the proposed method that is equivalent to at least a 2.5 fold reduction in scan time with respect to ungated signal averaging. A steady-state magnetisation transfer contrast prepared gradient echo implementation is observed to highlight tumour structure. Supplementary simulations demonstrate that only small variations in respiration rate are required to enable efficient sampling with the proposed method. The proposed prospective gating acquisition scheme enables efficient multi-slice scanning in small animals at the optimum TR with reduced sensitivity to respiratory motion. The method is compatible with a wide range of complementary methods including non-Cartesian scan modes, partially parallel imaging, and compressed sensing. In particular, the proposed scheme reduces the need for continual close monitoring to effect operator intervention in response to respiratory rate changes, which is both difficult to maintain and precludes high throughput.


Multiple Sequence Alignments Enhance Boundary Definition of RNA Structures.
Self-contained structured domains of RNA sequences have often distinct molecular functions. Determining the boundaries of structured domains of a non-coding RNA (ncRNA) is needed for many ncRNA gene finder programs that predict RNA secondary structures in aligned genomes because these methods do not necessarily provide precise information about the boundaries or the location of the RNA structure inside the predicted ncRNA. Even without having a structure prediction, it is of interest to search for structured domains, such as for finding common RNA motifs in RNA-protein binding assays. The precise definition of the boundaries are essential for downstream analyses such as RNA structure modelling, e.g., through covariance models, and RNA structure clustering for the search of common motifs. Such efforts have so far been focused on single sequences, thus here we present a comparison for boundary definition between single sequence and multiple sequence alignments. We also present a novel approach, named RNAbound, for finding the boundaries that are based on probabilities of evolutionarily conserved base pairings. We tested the performance of two different methods on a limited number of Rfam families using the annotated structured RNA regions in the human genome and their multiple sequence alignments created from 14 species. The results show that multiple sequence alignments improve the boundary prediction for branched structures compared to single sequences independent of the chosen method. The actual performance of the two methods differs on single hairpin structures and branched structures. For the RNA families with branched structures, including transfer RNA (tRNA) and small nucleolar RNAs (snoRNAs), RNAbound improves the boundary predictions using multiple sequence alignments to median differences of -6 and -11.5 nucleotides (nts) for left and right boundary, respectively (window size of 200 nts).


CRISPR-Cas9: a new and promising player in gene therapy.
First introduced into mammalian organisms in 2013, the RNA-guided genome editing tool CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) offers several advantages over conventional ones, such as simple-to-design, easy-to-use and multiplexing (capable of editing multiple genes simultaneously). Consequently, it has become a cost-effective and convenient tool for various genome editing purposes including gene therapy studies. In cell lines or animal models, CRISPR-Cas9 can be applied for therapeutic purposes in several ways. It can correct the causal mutations in monogenic disorders and thus rescue the disease phenotypes, which currently represents the most translatable field in CRISPR-Cas9-mediated gene therapy. CRISPR-Cas9 can also engineer pathogen genome such as HIV for therapeutic purposes, or induce protective or therapeutic mutations in host tissues. Moreover, CRISPR-Cas9 has shown potentials in cancer gene therapy such as deactivating oncogenic virus and inducing oncosuppressor expressions. Herein, we review the research on CRISPR-mediated gene therapy, discuss its advantages, limitations and possible solutions, and propose directions for future research, with an emphasis on the opportunities and challenges of CRISPR-Cas9 in cancer gene therapy.