The sensitivity of joint kinematics and kinetics to marker placement during a change of direction task.
The conventional gait model (CGM) refers to several closely related biomechanical models used in the objective analysis of human motion. Their use has become popular in the analysis of change of direction tasks to inform best practice in the prevention and rehabilitation of anterior cruciate ligament injury. As externally-placed markers define segment axes origins and orientations, kinematic and kinetic outputs from the CGM are sensitive to marker placement. The aim of this investigation was to quantify the sensitivity of lower extremity kinematics and knee moments to systematic differences in marker placement across the stance phase of a change of direction task. Systematic anterior/posterior displacements were applied to the lateral thigh, femoral epicondyle and tibia markers in software. One-dimensional statistical parametric mapping was used to determine the effect of marker placement across the entire stance phase of a 90° change of direction task. Marker placement error within previously reported inter-tester variability ranges caused significant differences in knee abduction moment, hip rotation angle, knee rotation angle, ankle abduction and rotation angle across various periods of stance. Discrete measures of these variables have been associated with increased frontal plane knee loading during change of direction, considered a key mechanism of anterior cruciate ligament injury. Systematic differences in marker placement may lead to incorrect group statistical inferences in such discrete measures.


IQGAP1 interacts with components of the slit diaphragm complex in podocytes and is involved in podocyte migration and permeability in vitro.
IQGAP1 is a scaffold protein that interacts with proteins of the cytoskeleton and the intercellular adhesion complex. In podocytes, IQGAP1 is associated with nephrin in the glomerular slit diaphragm (SD) complex, but its role remains ill-defined. In this work, we investigated the interaction of IQGAP1 with the cytoskeleton and SD proteins in podocytes in culture, and its role in podocyte migration and permeability. Expression, localization, and interactions between IQGAP1 and SD or cytoskeletal proteins were determined in cultured human podocytes by Western blot (WB), immunocytolocalization (IC), immunoprecipitation (IP), and In situ Proximity Ligation assay (IsPL). Involvement of IQGAP1 in migration and permeability was also assessed. IQGAP1 expression in normal kidney biopsies was studied by immunohistochemistry. IQGAP1 expression by podocytes increased during their in vitro differentiation. IC, IP, and IsPL experiments showed colocalizations and/or interactions between IQGAP1 and SD proteins (nephrin, MAGI-1, CD2AP, NCK 1/2, podocin), podocalyxin, and cytoskeletal proteins (α-actinin-4). IQGAP1 silencing decreased podocyte migration and increased the permeability of a podocyte layer. Immunohistochemistry on normal human kidney confirmed IQGAP1 expression in podocytes and distal tubular epithelial cells and also showed an expression in glomerular parietal epithelial cells. In summary, our results suggest that IQGAP1, through its interaction with components of SD and cytoskeletal proteins, is involved in podocyte barrier properties.


Comparison of the EQ-5D and the SF-6D utility measures in 813 patients with early arthritis: results from the ESPOIR cohort.
The revolution of early aggressive therapy in early arthritis (EA) has fueled the search for better approaches to establish cost-effectiveness. Our objective was to compare the EuroQol EQ-5D health outcome measure and the SF-6D and to investigate their relationship to clinical variables in a large prospective cohort of patients with EA. The EQ-5D and SF-6D utility measures were longitudinally assessed in 813 patients with EA. Agreement and aspects of validity (construct validity, discrimination) were assessed. At baseline, mean values for EQ-5D were 0.52 ± 0.31 (range -0.59 to 1.0) and for SF-6D were 0.58 ± 0.11 (range 0.30 to 0.92), with a bimodal distribution for the EQ-5D. Agreement was low for patients with severe disability or active disease: the utility was systematically lower with EQ-5D. The intraclass correlation coefficient was 0.42 at baseline and increased to 0.53 at 6 months and 0.57 at 1 and 2 years. Correlations between the 2 utility scores and the Health Assessment Questionnaire were good, and remained similar and stable over 2 years (r = -0.70). Correlations with the Disease Activity Score for 28 joints and the physical component of the MOS 36-item Short-form Health Survey (SF-36) were moderate to good and stable. In contrast, correlation with the mental component of the SF-36 was better with the SF-6D, and the correlation with pain, weak at baseline, improved at 6 months and remained stable thereafter. The SF-6D was better able to discriminate patients with high disease activity. There was systematic disagreement between EQ-5D and SF-6D in EA, especially in patients with worse clinical outcomes. Using the 2 instruments could be appropriate to conduct sensitivity analyses of cost-utility ratios because the instruments measure utility with closely similar measured properties, but at different levels.


Assessing the perception of the childbirth experience in Italian women: a contribution to the adaptation of the Childbirth Perception Questionnaire.
childbirth is a crucial experience in women's life as it has a substantial psychological, emotional and physical impact. A childbirth positive experience is important to the woman, infant's health and well-being, and mother-infant relationship. Furthermore, it is useful for the care providers to guarantee the best preparation, health service and support to childbearing women. The Childbirth Perception Questionnaire (CPQ) is a 27-item instrument designed to assess women's perception of their childbirth experience. to provide a first attempt to adapt the Childbirth Perception Questionnaire (CPQ) using a sample of Italian women. The psychometric properties of the scale and the quality of women's childbirth experience perception were assessed. Furthermore, the potential relation between the childbirth perception and the pain perception was explored. two separate studies were conducted. In Study 1, the factor structure and the reliability of the Italian translation of CPQ were assessed. Also a quantitative analysis of respondents' mean ratings was conducted. In Study 2 the relation between the CPQ and the Italian Pain Questionnaire (IPQ) was examined. an inpatient gynaecologic-obstetric unit in a university medical centre in Italy. 195 women in Study 1 and 92 women in Study 2 completed the questionnaires. in Study 1 the translated form of CPQ was administered in the 24-48 hours post partum. In Study 2, the participants completed the Italian version of the CPQ and the Italian Pain Questionnaire (IPQ) in the same postpartum time frame. Socio-demographic details and information about women's obstetric history were collected in both Study 1 and Study 2. an exploratory factor analysis revealed a 24-item scale with a three-factor structure. The Italian version of the questionnaire was labelled Childbirth Experience Perception Scale (CEPS) and composed of three subscales: Labour and Delivery Perception, Control Perception and Change Perception. The questionnaire presented satisfactory internal consistency's indexes both in Study 1 (α coefficients range: .66-.83) and in Study 2 (α coefficients range: .70-.86). The analysis of women's mean scores on CEPS revealed a significant effect of age, social economic status, amniocentesis test, type of childbirth, childbirth preference, and disagreement between actual and preferred childbirth (p<.05). A significant correlation between the CEPS and IPQ scales was found (p<.05). the current research evidenced that the Italian first adaptation of the CPQ, the Childbirth Experience Perception Scale, may be a valid and reliable measure of childbirth experience perception for use in different women's health clinical outcome and studies.


What factors influence time-use of occupational therapists in the workplace? A systematic review.
Health-care expenditure is rapidly increasing in Australia with increasing pressure on health-care services to review processes, improve efficiency and ensure equity in service delivery. The nursing profession have improved efficiency and patient care by investigating time-use to describe current practice and support development of workforce planning models. There is, however, a lack of information to understand factors that impact on occupational therapists time-use in the clinical setting impacting the development of workforce planning models which adapt occupational therapy service delivery to match resources with demand. The objective of this review was to systematically identify known factors which impact on occupational therapists time-use in the clinical setting. A systematic review of Medline, PsycINFO and CINAHL databases and grey literature was completed in September 2016. Two authors independently screened studies for inclusion and quality was evaluated using the Downs and Black scale. Variables impacting on occupational therapists time-use were categorised and thematically analysed to synthesise key themes. Twenty studies met the inclusion criteria and were included in the review. Three key categories of factors influencing time-use were identified. These were: patient-related factors (e.g. level of function, therapy required, type, complexity of injury), therapist-related factors (e.g. experience, clinical vs non-clinical responsibility), and organisational-related factors (e.g. workplace characteristics, availability of staff, presence of students). Occupational therapist time-use in clinical settings is complex and difficult to quantify in research. How occupational therapists spend their time is impacted by a number of patient, clinician and service related factors reflecting the breadth of occupational therapy practice and client-centred nature of the profession.


Gene profiling reveals increased expression of uteroglobin and other anti-inflammatory genes in glucocorticoid-treated nasal polyps.
Treatment with local glucocorticoids (GCs) decreases symptoms and the size of nasal polyps. This might depend on the downregulation of proinflammatory genes, as well as the upregulation of anti-inflammatory genes. We sought to identify GC-regulated anti-inflammatory genes in nasal polyps. Affymetrix DNA microarrays were used to analyze the expression of 22,283 genes in 4 nasal polyps before and after local treatment with fluticasone (400 microg/d). Expression of uteroglobin and mammaglobin B was analyzed with real-time PCR in 6 nasal polyps and in nasal biopsy specimens from 6 healthy control subjects. Two hundred three genes had changed in expression in treated polyps, and 139 had known functions: 54 genes were downregulated, and 85 were upregulated. Genes associated with inflammation constituted the largest single functional group. These genes affected key steps in inflammation (eg, immunoglobulin production; antigen processing and presentation; and the chemoattraction and activation of granulocytes, T cells, and B cells). Several proinflammatory genes were downregulated. In contrast, some anti-inflammatory genes were upregulated. The gene that increased most in terms of expression was uteroglobin. This was confirmed with real-time PCR. By contrast, expression of uteroglobin was lower in untreated polyps than in healthy nasal mucosa. Immunohistochemical investigation showed staining of uteroglobin in the epithelium and in seromucous glands in control subjects and in nasal polyps. Upregulation of anti-inflammatory genes, such as uteroglobin, might contribute to the effects of local treatment with GCs in nasal polyps.


Lessons from lonely flies: Molecular and neuronal mechanisms underlying social isolation.
Animals respond to changes in the environment which affect their internal state by adapting their behaviors. Social isolation is a form of passive environmental stressor that alters behaviors across animal kingdom, including humans, rodents, and fruit flies. Social isolation is known to increase violence, disrupt sleep and increase depression leading to poor mental and physical health. Recent evidences from several model organisms suggest that social isolation leads to remodeling of the transcriptional and epigenetic landscape which alters behavioral outcomes. In this review, we explore how manipulating social experience of fruit fly Drosophila melanogaster can shed light on molecular and neuronal mechanisms underlying isolation driven behaviors. We discuss the recent advances made using the powerful genetic toolkit and behavioral assays in Drosophila to uncover role of neuromodulators, sensory modalities, pheromones, neuronal circuits and molecular mechanisms in mediating social isolation. The insights gained from these studies could be crucial for developing effective therapeutic interventions in future.


Arthroscopic Hip Surgery in the Elite Athlete: Comparison of Female and Male Competitive Athletes.
Few studies have published the results of hip arthroscopic surgery in elite athletes and none studying a significant number of elite female athletes. (1) To compare sex-based differences in the ability to return to prior competitive sports activity after arthroscopic hip surgery. (2) To compare sex-based differences in the type of sports activity, diagnosis, and treatment in athletes requiring hip arthroscopic surgery. Cohort study; Level of evidence, 3. Data on all elite athletes who underwent primary hip arthroscopic surgery between 2007 and 2014 were included. Athletes with a Hip Sports Activity Scale (HSAS) score of over 6 were identified. The preoperative evaluation included a medical history, history of sports activity, and hip-specific outcome scores (Modified Harris Hip Score [MHHS] and International Hip Outcome Tool-33 [iHOT-33]). Surgical findings and time to return to competitive sports were documented. Of 547 hips in 484 consecutive patients, 98 elite athletes (49 female) with a mean follow-up of 18.9 ± 12.8 months were identified. Eighty patients desired to return to their original competitive activity: 38 were female (42 hips; mean age, 21.5 ± 3.9 years), and 42 were male (54 hips; mean age, 20.5 ± 1.9 years). Moreover, 84.2% of female athletes and 83.3% of male athletes were able to return to the same level of competition at a mean of 8.3 ± 3.0 and 8.8 ± 2.9 months, respectively. Significant improvements between preoperative and postoperative outcome scores were seen in both groups (all P < .0001). Female athletes had more pincer femoroacetabular impingement (FAI) ( P = .0004) and instability ( P < .0001). Conversely, male athletes were diagnosed more commonly with combined FAI ( P < .0001), demonstrated greater acetabular cartilage damage ( P = .0004), and required microfracture more often ( P = .0014). Female athletes competed more frequently in flexibility (4/38, 11%; P = .047) and endurance (9/38, 24%) sports, while male athletes participated in cutting (14/42, 33%), contact (6/42, 14%), and asymmetric (13/42, 31%) sports more often. Patients who returned to their baseline level of competition had a shorter duration of symptoms preoperatively ( P = .001). Microfracture status did not affect the ability to return to sports. Female and male elite athletes were able to return to competitive sports activity at the same or higher level after hip arthroscopic surgery at a similar rate, although their performance in sports was not measured. Distinct differences in the diagnosis, treatment, and type of sports activity between sexes were seen. The duration of symptoms negatively correlated with outcomes. Microfracture did not affect the return to sports.


[The action of fenasal on the cestode Diphyllobothrium latum].
The present study used an experimental invasion model to examine the invasion and behaviour of D.latum cestoda and its tissue structural disorders after in vivo phenasal administration. Phenasal caused an increased development of the granular endoplasmic reticulum in the cells of the tegument and yolk glands, their local spread, and a formation of vacuoles in the tegumental cells and an appearance of myelins which were rather great in size. There were no changes in tegumental microtrichia.


Enhanced functions of osteoblasts on nanophase ceramics.
Select functions of osteoblasts (bone-forming cells) on nanophase (materials with grain sizes less than 100 nm) alumina, titania, and hydroxyapatite (HA) were investigated using in vitro cellular models. Compared to conventional ceramics, surface occupancy of osteoblast colonies was significantly less on all nanophase ceramics tested in the present study after 4 and 6 days of culture. Osteoblast proliferation was significantly greater on nanophase alumina, titania, and HA than on conventional formulations of the same ceramic after 3 and 5 days. More importantly, compared to conventional ceramics, synthesis of alkaline phosphatase and deposition of calcium-containing mineral was significantly greater by osteoblasts cultured on nanophase than on conventional ceramics after 21 and 28 days. The results of the present study provided the first evidence of enhanced long-term (on the order of days to weeks) functions of osteoblasts cultured on nanophase ceramics; in this manner, nanophase ceramics clearly represent a unique and promising class of orthopaedic/dental implant formulations with improved osseointegrative properties.


Experiences of hospital care reported by bereaved relatives of patients after a stroke: a retrospective survey using the VOICES questionnaire.
This paper is a report of a study conducted to explore the determinants of satisfaction with health and social care services in the last 3 months and 3 days of life as reported by bereaved relatives of those who died from a stroke in an institutional setting. There is limited research about how best to meet the needs of those who die from stroke. A thorough understanding of the determinants of satisfaction with end of life care is crucial for effective service provision to increase awareness of the needs of dying patients. During a six-month period in 2003, a population-based survey of bereaved relatives of patients after stroke was conducted using a stroke-specific version of the Views of Informal Carers Evaluation of Services postal questionnaire (183 informants, response rate 37%). The sub-sample included those informants who reported that the deceased person had died in an institutional setting (91%, n = 165). The analysis was divided into two phases: univariate (Pearson chi-square test) and multivariate phase (logistic regression). Logistic regressions showed that discussing any worries about the treatment of the deceased person and feeling that the doctors and nurses knew enough about their condition were predictors of satisfaction with doctors and nurses in the last 3 months of life. Meeting the personal care needs of the deceased person, being involved in decisions and feeling that the deceased person died in the right place were predictors of satisfaction with care in the last 3 days of life. End of life care needs to address the individual needs of patients who die from stroke and those close to them. This study shows that individualised end of life care increases satisfaction and, although the data reported in this paper reflect care in 2003, there is no more recent evidence that contradicts this important overall finding.


[The option for nursing: a retrospective study in Sergipe].
A quantitative and qualitative retrospective study was carried out about career choice, motivation and identification in the Nurse profession among graduate professionals and graduate students at UFS (Federal University of Sergipe) who called in from 1992/1 through 1997/1, identifying facilities or difficulties they have found along this process. It consists of documental research in the official lists of the Institution, and of semi-structured interviews with, at least, 20% of the population. Results showed that only 31.5% students had graduated over this period, the other ones ranging from 5 to 7 years studying in the program. We found that 76.92% of them would prefer alternative programs, and difficulties were found either in knowledge or identification with the profession prior its start, which came from stereotypes and cultural taboos.


Lower Limb Motion Estimation Using Ultrasound Imaging: A Framework for Assistive Device Control.
Powered assistive devices need improved control intuitiveness to enhance their clinical adoption. Therefore, the intent of individuals should be identified and the device movement should adhere to it. Skeletal muscles contract synergistically to produce defined lower limb movements, so unique contraction patterns in lower extremity musculature may provide a means of device joint control. Ultrasound (US) imaging enables direct measurement of the local deformation of muscle segments. Hence, the objective of this study was to assess the feasibility of using US to estimate human lower limb movements. A novel algorithm was developed to calculate US features of the rectus femoris muscle during a non-weight-bearing knee flexion/extension experiment by nine able-bodied subjects. Five US features of the skeletal muscle tissue were studied, namely thickness, angle between aponeuroses, pennation angle, fascicle length, and echogenicity. A multiscale ridge filter was utilized to extract the structures in the image and a random sample consensus (RANSAC) model was used to segment muscle aponeuroses and fascicles. A localization scheme further guided RANSAC to enable tracking in a US image sequence. Gaussian process regression models were trained using segmented features to estimate both knee joint angle and angular velocity. The proposed segmentation-estimation approach could estimate knee joint angle and angular velocity with an average root mean square error value of 7.45° and 0.262 rad/s, respectively. The average processing rate was 3-6 frames/s that is promising toward real-time implementation. Experimental results demonstrate the feasibility of using US to estimate human lower extremity motion. The ability of the algorithm to work in real time may enable the use of US as a neural interface for lower limb applications. Intuitive intent recognition of human lower extremity movements using wearable US imaging may enable volitional assistive device control and enhance locomotor outcomes for those with mobility impairments.


The effects of declining transfusion rates on elective total hip arthroplasty.
The incidence of red blood cell transfusion is reviewed in a series of 130 elective total hip arthroplasties performed over a four-year period. A significant downward trend was noted in the hemoglobin level at which patients were transfused (p less than 0.01). Conversely, no significant differences were noted in the rate of rehabilitation, the length of hospitalization, or the incidence of complications. In addition, patients who predonated autologous blood were transfused at a higher rate than those who did not (p less than 0.001), but they received less homologous blood than patients who had not predonated.


Acceptance and commitment therapy and the new generation of cognitive behavioral treatments.
Acceptance and Commitment Therapy (ACT) is one of several recently-developed acceptance-based cognitive behavioral treatments which broaden the scope of CBT. The theory underlying ACT suggests that verbal representations generated by the human mind inevitably increase the psychological presence of pain and often lead to psychological inflexibility or the dominance of language products over other sources of information. Furthermore, the adequacy of problem-solving strategies that are used to achieve desired goals and decrease suffering is substantially decreased when applied to private experience. Therefore, humans have a greatly expanded capacity to experience aversive stimulation, but simultaneously are not well-equipped to deal effectively with such unwanted experiences. Acknowledging the inevitability of psychological pain, ACT aims at replacing experiential avoidance and similar harmful processes with more adaptive strategies, with the general goal of pursuing broad life objectives. This is achieved by encouraging mindful acceptance of unwanted experiences and by fostering committed action which is consistent with one's chosen values.


[Errors in performing artificial ventilation of the lungs in the wounded and casualties].
Under investigation in the clinics of the Military-Medical Academy there was a group of the wounded and casualties whose lungs were artificially ventilated. The systemic hemodynamics, indices of gas exchange and the acid-base condition were controlled. The invasive and non-invasive methods were used. The most typical errors during performing lung ventilation were revealed and the causes of them were analyzed.


Influence of the substitution of 3-vinyl by 3-formyl group on the photodynamic properties of chlorin P6: molecular, cellular and in vivo studies.
Molecular in vitro and in vivo properties of 3-devinyl-3-formylchlorin p6 (FCp6) were examined in order to characterize this derivative as a new prospective photosensitizer. The long-wavelength absorption maximum of FCp6 was 690-696 nm (depending on environment). FCp6 was found to bind readily to membranous structures and form complexes with some proteins. The dye was associated with the plasmalemma and distributed rather diffusely along the cytoplasm with ca a three-fold higher accumulation within mitochondria in A549 human adenocarcinoma cells. The spectral analysis revealed that the major part of FCp6 was bound to membranes within cells. The membrane-bound FCp6 was shown to generate singlet oxygen efficiently. The average cytoplasmic concentration of FCp6 in A549 cells achieved ca 80% of its extracellular concentration in complete medium. The dye was characterized by a very fast efflux (16-fold decrease in 2 h). The ex vivo analysis of FCp6 fluorescence in mice revealed that the maximal dye content in blood, tissues, organs and tumor was achieved in less than 1 h after injection, followed by a considerable (ca six-fold) decrease during the next 23 h and a long-term persistence at low level. A preferential accumulation of FCp6 in subcutaneously implanted Ehrlich carcinoma along with its higher retention level comparing to the surrounding skin and muscles were observed in mice treated with different dye doses. In vitro cytotoxic assays with A549 and Raji B-cell lymphoma cells as well as in vivo analyses using Ehrlich carcinoma in mice revealed the very low toxicity of FCp6 without light irradiation and the significant photodynamic activity of this compound.


A Computational Analysis of Alternative Splicing across Mammalian Tissues Reveals Circadian and Ultradian Rhythms in Splicing Events.
Mounting evidence points to a role of the circadian clock in the temporal regulation of post-transcriptional processes in mammals, including alternative splicing (AS). In this study, we carried out a computational analysis of circadian and ultradian rhythms on the transcriptome level to characterise the landscape of rhythmic AS events in published datasets covering 76 tissues from mouse and olive baboon. Splicing-related genes with 24-h rhythmic expression patterns showed a bimodal distribution of peak phases across tissues and species, indicating that they might be controlled by the circadian clock. On the output level, we identified putative oscillating AS events in murine microarray data and pairs of differentially rhythmic splice isoforms of the same gene in baboon RNA-seq data that peaked at opposing times of the day and included oncogenes and tumour suppressors. We further explored these findings using a new circadian RNA-seq dataset of human colorectal cancer cell lines. Rhythmic isoform expression patterns differed between the primary tumour and the metastatic cell line and were associated with cancer-related biological processes, indicating a functional role of rhythmic AS that might be implicated in tumour progression. Our data shows that rhythmic AS events are widespread across mammalian tissues and might contribute to a temporal diversification of the proteome.


Differences in incidence of reported asthma related to age in men and women. A retrospective analysis of the data of the European Respiratory Health Survey.
Sex differences in asthma prevalence and morbidity, assessed with different methods in different populations, have raised several hypotheses about the different susceptibility to asthma in men and women. However, information on the incidence of asthma by age and sex is limited. The aim of this study was to estimate the age- and sex-specific incidence of asthma from birth to 44 yr of age in men and women across several countries, and to evaluate the main factors influencing asthma incidence in young adults. The data of the European Community Respiratory Health Survey, an international, cross-sectional, population-based survey, which were collected in 16 countries from 1991 to 1993 according to a common protocol, and which pertained to 18,659 subjects, were analyzed retrospectively, using the reported age of the first attack as the onset of asthma. During childhood, girls had a significantly lower risk of developing asthma than did boys (relative risk [RR]: 0.74 and 0.56 in the 0- to 5-yr and 5- to 10-yr age classes, respectively). Around puberty, the risk was almost equal in the two sexes (RR = 0.84; 95% confidence interval [CI]: 0.65 to 1.10 in the 10 to 15-yr age class). After puberty, the risk in women was always significantly higher than that in men (RR: 1.38 to 5.91). This pattern was consistent in all of the 16 countries studied, and was not influenced by recall or cohort effects. When the effects of airway caliber and smoking were studied with a case-control design, the results showed that women's greater susceptibility to asthma in early adulthood was at least partly, explained by their smaller airway caliber (the OR decreased from 2. 04 [95% CI: 1.32 to 3.15] to 1.47 [95% CI: 0.89 to 2.44] after controlling for height-adjusted FEV(1)); while smoking did not increase the risk. This analysis strongly confirms that the incidence of asthma shows a sex reversal during puberty, and suggests that airway caliber, in addition to hormonal factors, could play an important role in explaining the different patterns of asthma incidence in men and women.


Effects of Bacterial Contamination on Dental Implants During Surgery: A Systematic Review.
Contamination during surgery negatively influences the prognosis of orthopaedic implants; however, it has not been proven whether contamination influences the success of dental implant treatment. The aim of the systematic review was to investigate if there exists evidence in the literature whether contamination of dental implants during surgery affects osseointegration and clinical success. Four data bases were used for the literature search. Primary studies and reviews regarding both clinical and preclinical research were eligible. Rating of the summarized quality of the evidence was performed. Five preclinical studies were included. Because of the estimated high risk of bias in all included studies and extensive differences in study design between the included studies, meta-analysis was not performed and no reliable aggregated data could be extracted. It is suggested that the scientific evidence with regard to the current topic is insufficient. Further controlled studies are warranted.


Current Advances in Checkpoint Inhibitors: Lessons from Non-Central Nervous System Cancers and Potential for Glioblastoma.
The adaptive immune system depends on the sequence of antigen presentation, activation, and then inhibition to mount a proportionate response to a threat. Tumors evade the immune response partly by suppressing T-cell activity using immune checkpoints. The use of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) antibodies counteract this suppression, thereby enhancing the antitumor activity of the immune system. This approach has proven efficacy in melanoma, renal cancer, and lung cancer. There is growing evidence that the central nervous system is accessible to the immune system in the diseased state. Moreover, glioblastomas (GBMs) attract CTLA-4-expressing T-cells and express PD-L1, which inhibit activation and continuation of a cytotoxic T-cell response, respectively. This may contribute to the evasion of the host immune response by GBM. Trials are in progress to determine if checkpoint inhibitors will be of benefit in GBM. Radiotherapy could also be helpful in promoting inflammation, enhancing the immunogenicity of tumors, disrupting the blood-brain barrier and creating greater antigen release. The combination of radiotherapy and checkpoint inhibitors has been promising in preclinical trials but is yet to show efficacy in humans. In this review, we summarize the mechanism and current evidence for checkpoint inhibitors in gliomas and other solid tumors, examine the rationale of combining radiotherapy with checkpoint inhibitors, and discuss the potential benefits and pitfalls of this approach.


Antimicrobial resistance determinants in Acinetobacter baumannii isolates taken from military treatment facilities.
Multidrug-resistant (MDR) Acinetobacter baumannii infections are of particular concern within medical treatment facilities, yet the gene assemblages that give rise to this phenotype remain poorly characterized. In this study, we tested 97 clinical A. baumannii isolates collected from military treatment facilities (MTFs) from 2003 to 2009 by using a molecular epidemiological approach that enabled for the simultaneous screening of 236 antimicrobial resistance genes. Overall, 80% of the isolates were found to be MDR, each strain harbored between one and 17 resistant determinants, and a total of 52 unique resistance determinants or gene families were detected which are known to confer resistance to β-lactam (e.g., blaGES-11, blaTEM, blaOXA-58), aminoglycoside (e.g., aphA1, aacC1, armA), macrolide (msrA, msrB), tetracycline [e.g., tet(A), tet(B), tet(39)], phenicol (e.g., cmlA4, catA1, cat4), quaternary amine (qacE, qacEΔ1), streptothricin (sat2), sulfonamide (sul1, sul2), and diaminopyrimidine (dfrA1, dfrA7, dfrA19) antimicrobial compounds. Importantly, 91% of the isolates harbored blaOXA-51-like carbapenemase genes (including six new variants), 40% harbored the blaOXA-23 carbapenemase gene, and 89% contained a variety of aminoglycoside resistance determinants with up to six unique determinants identified per strain. Many of the resistance determinants were found in potentially mobile gene cassettes; 45% and 7% of the isolates contained class 1 and class 2 integrons, respectively. Combined, the results demonstrate a facile approach that supports a more complete understanding of the genetic underpinnings of antimicrobial resistance to better assess the load, transmission, and evolution of MDR in MTF-associated A. baumannii.


Controlling the velocity of a femtosecond laser pulse using refractive lenses.
The combination of temporal chirp with a simple chromatic aberration known as longitudinal chromatism leads to extensive control over the velocity of laser intensity in the focal region of an ultrashort laser beam. We present the first implementation of this effect on a femtosecond laser. We demonstrate that by using a specially designed and characterized lens doublet to induce longitudinal chromatism, this velocity control can be implemented independent of the parameters of the focusing optic, thus allowing for great flexibility in experimental applications. Finally, we explain and demonstrate how this spatiotemporal phenomenon evolves when imaging the ultrashort pulse focus with a magnification different from unity.


Bacterial drug resistance in meat animals: a review.
Prolonged oral or parenteral administration of antibiotics has led to the development of resistant strains of microorganisms. Bacteria acquire drug resistance by mutation, conjugation and transduction. Oral antibiotics by a process of selection pressure facilitate the proliferation of resistant population of bacteria. Drug resistant bacteria are capable of transferring their resistance to drugs to other bacteria by the process of transferable drug resistance (TDR). This can lead to multiple resistance to a vast number of therapeutically useful antibiotics which will, therefore, become ineffective for treatment. TDR can occur between pathogenic organism, between organism of different species, such as E. coli, Salmonella and Shigella; and also between pathogenic and non-pathogenic organisms. Faecal contamination of meat during slaughter may result in the transfer of antibiotic resistant E. coli to the meat. In the human gut this E. coli could transfer resistance to other gut flora, namely E. coli or Salmonella. Antibiotic-resistant coliforms have been isolated from carcases, fresh and cooked meat, raw meat handlers and livestock handlers. Handling of raw market meat by buyers in Nigeria could also lead to contamination of meat with resistant microorganisms. Veterinary drugs are sold and used without much control in Nigeria. This practice may have created a population of resistant bacteria in the meat animals. The presence of antibiotic residues in meat, milk and their products pose potential health hazards for man. Allergic skin conditions, nausea, vomiting, anaphylactic shock and even death have resulted from the ingestion of residues. Cooking and freezing have minimal effect on residues. Resistance to antibiotics have been detected in food poisoning bacteria, namely Salmonella typhimurium, Staphylococcus aureus and Clostridium perfringens. Some epidemiological link has been established between S. typhimurium of calves and food poisoning in man. Judicious use of antibiotics, public education on the health risks of the promiscuous use of drugs in livestock production; and hygienic slaughter at the slaughter houses, will help to reduce bacterial drug resistance in man and animals.


Impact of previous disease-modifying treatment on effectiveness and safety outcomes, among patients with multiple sclerosis treated with alemtuzumab.
Alemtuzumab is effective in patients with active multiple sclerosis but has a complex safety profile, including the development of secondary autoimmunity. Most of patients enrolled in randomised clinical trials with alemtuzumab were either treatment naïve or pretreated with injectable substances. Other previous disease-modifying treatments (DMTs) were not used in the study cohorts, and therefore, associated risks might yet remain unidentified. We retrospectively evaluated a prospective dual-centre alemtuzumab cohort of 170 patients. We examined the baseline characteristics as well as safety and effectiveness outcomes, including the time to first relapse, the time to 3 months confirmed disability worsening and the time to secondary autoimmunity. The regression analysis showed that, among all previously used DMTs, the pretreatment with fingolimod (n=33 HRs for the time to first relapse (HR 5.420, 95% CI 2.520 to 11.660; p<0.001)) and for the time to worsening of disability (HR 7.676, 95% CI 2.870 to 20.534; p<0.001). Additionally, patients pretreated with fingolimod were more likely to experience spinal relapses (55% vs 10% among previously naïve patients; p<0.001) and had an increased risk of secondary autoimmunity (HR 5.875, 95% CI 2.126 to 16.27; p<0.001). In the real-world setting, we demonstrated suboptimal disease control and increased risk of secondary autoimmunity following alemtuzumab, among patients previously treated with fingolimod. These data can provide guidance for improving MS therapeutic management.


Effects of dairy system, herd within dairy system, and individual cow characteristics on the volatile organic compound profile of ripened model cheeses.
The objective of this work was to study the effect of dairy system, herd within dairy system, and characteristics of individual cows (parity, days in milk, and daily milk yield) on the volatile organic compound profile of model cheeses produced under controlled conditions from the milk of individual cows of the Brown Swiss breed. One hundred fifty model cheeses were selected from 1,272 produced for a wider study of the phenotypic and genetic variability of Brown Swiss cows. In our study, we selected 30 herds representing 5 different dairy systems. The cows sampled presented different milk yields (12.3-43.2kg/d), stages of lactation (10-412 d in milk), and parity (1-7). In total, 55 volatile compounds were detected by solid-phase microextraction and gas chromatography-mass spectrometry, including 14 alcohols, 13 esters, 11 free fatty acids, 8 ketones, 4 aldehydes, 3 lactones, 1 terpene, and 1 pyrazine. The most important sources of variation in the volatile organic profiles of model cheeses were dairy system (18 compounds) and days in milk (10 compounds), followed by parity (3 compounds) and milk yield (5 compounds). The model cheeses produced from the milk of tied cows reared on traditional farms had lower quantities of 3-methyl-butan-1-ol, 6-pentyloxan-2-one, 2-phenylethanol, and dihydrofuran-2(3H)-one compared with those reared in freestalls on modern farms. Of these, milk from farms using total mixed rations had higher contents of alcohols (hexan-1-ol, octan-1-ol) and esters (ethyl butanoate, ethyl pentanoate, ethyl hexanoate, and ethyl octanoate) and lower contents of acetic acid compared with those using separate feeds. Moreover, dairy systems that added silage to the total mixed ration produced cheeses with lower levels of volatile organic compounds, in particular alcohols (butan-1-ol, pentan-1-ol, heptan-1-ol), compared with those that did not. The amounts of butan-2-ol, butanoic acid, ethyl-2-methylpropanoate, ethyl-3-methylbutanoate, and 6-propyloxan-2-one increased linearly during lactation, whereas octan-1-ol, 3-methyl-3-buten-1-ol, 2-butoxyethanol, 6-pentyloxan-2-one, and 2,6-dimethylpyrazine showed a more complex pattern during lactation. The effect of the number of lactations (parity) was significant for octan-1-ol, butanoic acid, and heptanoic acid. Finally, concentrations of octan-1-ol, 2-phenylethanol, pentanoic acid, and heptanoic acid increased with increasing daily milk yield, whereas dihydrofuran-2(3H)-one decreased. In conclusion, the volatile organic compound profile of model cheeses from the milk of individual cows was affected by dairy farming system and stage of lactation and, to lesser extent, by parity and daily milk yield.


The hybrid cytomegalovirus enhancer/chicken beta-actin promoter along with woodchuck hepatitis virus posttranscriptional regulatory element enhances the protective efficacy of DNA vaccines.
DNA vaccines represent a novel and powerful alternative to conventional vaccine approaches. They are extremely stable and can be produced en masse at low cost; more importantly, DNA vaccines against emerging pathogens or bioterrorism threats can be quickly constructed based solely upon the pathogen's genetic code. The main drawback of DNA vaccines is that they often induce lower immune responses than traditional vaccines, particularly in nonrodent species. Thus, improving the efficacy of DNA vaccines is a critical issue in vaccine development. In this study we have enhanced the efficacy of DNA vaccines by adopting strategies that increase gene expression. We generated influenza-hemagglutinin (HA)-encoding DNA vaccines that contain the hybrid CMV enhancer/chicken beta-actin (CAG) promoter and/or the mRNA-stabilizing post-transcriptional regulatory element from the woodchuck hepatitis virus (WPRE). Mice were immunized with these DNA vaccines, and the influenza-HA-specific cellular and humoral immune responses were compared with a conventional, HA-encoding DNA vaccine whose gene expression was driven by the CMV immediate-early promoter (pCMV-HA). CAG promoter-driven DNA vaccines elicited significantly higher humoral and cellular immune responses compared with the pCMV-HA vaccine. DNA vaccines consisting of both CAG and WPRE elements (pCAG-HA-WPRE) induced the highest level of protective immunity, such that immunization with 10-fold lower DNA doses prevented death in 100% of the mice upon lethal viral challenge, whereas all mice immunized with the conventional pCMV-HA vaccine succumbed to influenza infection.


High incidence and severity of injection site reactions in the first cycle compared with subsequent cycles of subcutaneous bortezomib.
Subcutaneous (sc) administration of bortezomib (Bor) has become more common than intravenous (iv) administration in the treatment of multiple myeloma (MM), because scBor results in a lower incidence and severity of peripheral neuropathy and shows efficacy equivalent to ivBor. Bor is an irritant cytotoxic agent when it extravasates from the vasculature. Therefore, it is recommended that sc injections of Bor should be delivered on a rotating basis across eight sites on the abdomen and thighs. Previously, we reported that sc injections of Bor in the abdomen caused fewer grade 2 injection site reactions (ISRs) than those in the thigh. In the present study, we recruited more patients and expanded the scale of our analysis into ISRs following treatment with 300 scBor injections in 20 patients. ISRs of ≥grade 2 were documented in 12 of 109 (11.0 %) thigh injections, but only in three of 191 (1.6 %) abdominal injections (p < 0.001). Interestingly, ISRs of ≥grade 2 occurred more frequently in the first cycle than in the second and subsequent cycles (16.3 vs. 0.91 %, p < 0.001). These results clearly indicate that closer attention should be paid to ISR management, particularly with regard to the first cycle of scBor administration in the thigh. To our knowledge, this is the first report showing that ≥grade 2 ISRs are more common in the first cycle compared with subsequent cycles of scBor in the treatment of MM.


FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.
Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis). Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).


The low frequency power of heart rate variability is neither a measure of cardiac sympathetic tone nor of baroreflex sensitivity.
The lack of noninvasive approaches to measure cardiac sympathetic nerve activity (CSNA) has driven the development of indirect estimates such as the low-frequency (LF) power of heart rate variability (HRV). Recently, it has been suggested that LF HRV can be used to estimate the baroreflex modulation of heart period (HP) rather than cardiac sympathetic tone. To test this hypothesis, we measured CSNA, HP, blood pressure (BP), and baroreflex sensitivity (BRS) of HP, estimated with the modified Oxford technique, in conscious sheep with pacing-induced heart failure and in healthy control sheep. We found that CSNA was higher and systolic BP and HP were lower in sheep with heart failure than in control sheep. Cross-correlation analysis showed that in each group, the beat-to-beat changes in HP correlated with those in CSNA and in BP, but LF HRV did not correlate significantly with either CSNA or BRS. However, when control sheep and sheep with heart failure were considered together, CSNA correlated negatively with HP and BRS. There was also a negative correlation between CSNA and BRS in control sheep when considered alone. In conclusion, we demonstrate that in conscious sheep, LF HRV is neither a robust index of CSNA nor of BRS and is outperformed by HP and BRS in tracking CSNA. These results do not support the use of LF HRV as a noninvasive estimate of either CSNA or baroreflex function, but they highlight a link between CSNA and BRS.


Review article: acute inorganic mercury vapor inhalation poisoning.
Mercury contamination is a serious environmental problem worldwide. Two primary sources of contamination are dumping of large quantities of inorganic mercury and exposure in the mining industry. Although the actual fatal level of mercury vapor is not known, exposure to more than 1-2 mg/m3 of elemental mercury vapor (Hg0) for a few hours causes acute chemical bronchiolitis and pneumonitis. Two hours after exposure, lung injury appears as hyaline membrane formation, and finally, extensive pulmonary fibrosis occurs. Clinical findings correlate with the duration of exposure, the concentration of mercury, and the survival time after exposure. There is no correlation between pathological findings and the concentration of mercury in the tissues. Necrosis of proximal convoluted tubules may be attributed to the disruption of the enzyme systems of Hg2+-sulfhydryl compounds. Metallothionein protein (MT), induced by the accumulation of Hg2+ in the kidneys, may play an important role in detoxication after it forms a non-toxic Hg2+-MT compound. Despite the deposition of mercury in the brain, compared with organic mercury, inorganic mercury did not seem to damage the neurons. Drugs such as chelating agents and corticosteroids appear to effectively decrease the inflammation and delay pulmonary fibrosis.


Role of endoreduplication and apomeiosis during parthenogenetic reproduction in the model brown alga Ectocarpus.
• The filamentous brown alga Ectocarpus has a complex life cycle, involving alternation between independent and morphologically distinct sporophyte and gametophyte generations. In addition to this basic haploid-diploid life cycle, gametes can germinate parthenogenetically to produce parthenosporophytes. This article addresses the question of how parthenosporophytes, which are derived from a haploid progenitor cell, are able to produce meiospores in unilocular sporangia, a process that normally involves a reductive meiotic division. • We used flow cytometry, multiphoton imaging, culture studies and a bioinformatics survey of the recently sequenced Ectocarpus genome to describe its life cycle under laboratory conditions and the nuclear DNA changes which accompany key developmental transitions. • Endoreduplication occurs during the first cell cycle in about one-third of parthenosporophytes. The production of meiospores by these diploid parthenosporophytes involves a meiotic division similar to that observed in zygote-derived sporophytes. By contrast, meiospore production in parthenosporophytes that fail to endoreduplicate occurs via a nonreductive apomeiotic event. • Our results highlight Ectocarpus's reproductive and developmental plasticity and are consistent with previous work showing that its life cycle transitions are controlled by genetic mechanisms and are independent of ploidy.


Post-licensure safety evaluation of dihydroartemisinin piperaquine in the three major ecological zones across Ghana.
Uncommon and rare adverse events (AEs), with delayed onset may not be detected before new drugs are licensed and deployed. The present study examined the post licensure safety of dihydroartemisinin-piperaquine (DHP) as an additional treatment for malaria in Ghana. The relationship between the incidence of AEs, treatment completion rate, participant characteristics and concomitant medications are reported. A study conducted from September 2013 to June 2014 in Navrongo, Kintampo and Dodowa health research centres in Ghana is presented. Participants had confirmed malaria and no known allergy to study drug. Patients provided informed consent and had their symptoms and results of their clinical examinations documented. Treatment with Eurartesim® (20/160mg dihydroartemisinin and 40/320mg piperaquine by Sigma-Tau Incorporated) was given, according to the body weight of patients. First treatment doses were under observation but the second and third doses were taken at home except in a sub-study involving a nested cohort. Patients were contacted at Day 5 (± 2 days) either on telephone or by a home visit to document any AEs experienced. Patients were asked to report to the study team any other AEs that occurred within 28 days post-treatment. All patients in the nested cohort had electrocardiogram (ECG). A total of 4563 patients, 52.1% females and 48.2% <6 years completed the study. A total of 444 patients were enrolled into the nested cohort. About 33% had temperature ≥ 37.5°C at enrolment. Approximately 3.4% reported taking prior antimalarials, 19.4% other medications and 86% took at least one concomitant medication. Incidence of AEs was 7.6% including infections (4.6%), gastrointestinal disorders (1.0%) and local reactions at the site of venesection (0.5%). Others were respiratory disorders (0.4%) and nervous system disorders (0.3%). There were nine adverse events of special interest (AESI); itching/pruritus (7), dizziness (1), and skin lesions (1). Patients who took medications prior to enrolment had higher incidence of AEs compared with those without (9.3% vs. 6.1%; P<0.001). Statistically significant associations were found between the reported AEs and age of patients (P<0.001), their body mass index (BMI) (P< 0.001) and parasite densities (P< 0.001). Dihydroartemisinin-Piperaquine was well tolerated with no serious safety concerns identified. Obesity and prior enrolment medication were among significant factors associated with increased AEs reporting.


Validating the Use of Conductive Atomic Force Microscopy for Defect Quantification in 2D Materials.
Defects significantly affect the electronic, chemical, mechanical, and optical properties of two-dimensional (2D) materials. Thus, it is critical to develop a method for convenient and reliable defect quantification. Scanning transmission electron microscopy (STEM) and scanning tunneling microscopy (STM) possess the required atomic resolution but have practical disadvantages. Here, we benchmark conductive atomic force microscopy (CAFM) by a direct comparison with STM in the characterization of transition metal dichalcogenides (TMDs). The results conclusively demonstrate that CAFM and STM image identical defects, giving results that are equivalent both qualitatively (defect appearance) and quantitatively (defect density). Further, we confirm that CAFM can achieve single-atom resolution, similar to that of STM, on both bulk and monolayer samples. The validation of CAFM as a facile and accurate tool for defect quantification provides a routine and reliable measurement that can complement other standard characterization techniques.


The good, the bad and the ugly: surgical resection for non-colorectal, non-neuroendocrine liver metastases.
The aim of this retrospective study was to analyze outcomes after partial hepatectomy for non-colorectal non-neuroendocrine metastases (mNCRNNE) and to identify prognostic factors associated with survival. Patient demographics, tumor characteristics, treatment and outcome of 30 consecutive patients operated between January 1995 and June 2012 were analyzed. The Kaplan-Meier method was used to analyze survival and Cox regression models were applied to identify independent prognostic variables. NCRNNE primaries included stomach (n=13), breast (n=5), pancreas (n=3), choroid melanoma (n=2), unknown primary (n=1) and others (n=6). Thirty-day mortality. rate was 3.3% and morbidity rate was 23.3%. Following hepatectomy, median overall (OS) and disease- free survival (DFS) were 24 and 12 months, respectively. In univariate analysis, longer disease-free interval (p=0.04) was associated with better OS. Histology of the primary tumor (p=0.003) and the presence of extrahepatic disease (p=0.04) were associated with a lower DFS. Cox regression analysis identified histology as an independent prognostic factor for DFS (p=0.013). In selected patients, resection of mNCRNNE appears associated with prolonged survival and may be performed in a specialized environment with acceptable morbidity and mortality. Patients with a longer disease-free interval, specific primary location and histology and absence of extra-hepatic disease seem to benefit the most from this approach.


[Physiological and adaptive value of Na+,K+-ATPase isoenzymes].
A current state of the researches related to functional specificity of the Na+, K(+)-ATP-ase isozymes determined by their catalytic properties, individual sensitivity to regulation by hormones and other endogenic substances and to membrane structural disorders has been reviewed to clarify the physiological expediency of the Na+, K(+)-ATP-ase isoforms. The data on isozymes expression in brain in the ontogenesis, their individual sensitivity to ouabain and peculiarities of the membrane properties are considered. The adaptive significance of the Na+, K(+)-ATP-ase isozymes in expansion of tissue compensatory resources at some physiological and pathological states of organism is supposed.


The acceptability and feasibility of conducting a randomised controlled trial to test the effectiveness of a walking intervention for older people with persistent musculoskeletal pain in primary care: A mixed methods evaluation of the iPOPP pilot trial.
Persistent musculoskeletal (MSK) pain is associated with physical inactivity in older people. While walking is an acceptable form of physical activity, the effectiveness of walking interventions in this population has yet to be established. To assess the acceptability and feasibility of conducting a randomised controlled trial (RCT) to test the effectiveness of a healthcare assistant-led walking intervention for older people with persistent MSK pain (iPOPP) in primary care. A mixed method, three arm pilot RCT was conducted in four general practices and recruited patients aged ≥65 years with persistent MSK pain. Participants were randomised in a 1:1:1 ratio to: (i) usual care, (ii) usual care plus a pedometer intervention, or (iii) usual care plus the iPOPP walking intervention. Descriptive statistics were used in an exploratory analysis of the quantitative data. Qualitative data were analysed using thematic analysis. A triangulation protocol was used to integrate the analyses from the mixed methods. All pre-specified success criteria were achieved in terms of feasibility (recruitment, follow-up and iPOPP intervention adherence) and acceptability. Triangulation of the data identified the need, in the future, to make the iPOPP training (for intervention deliverers) more patient-centred to better support already active patients and the use of individualised goal setting and improve accelerometry data collection processes to increase the amount of valid data. This pilot trial suggests that the iPOPP intervention and a future full-scale RCT are both acceptable and feasible. The use of a triangulation protocol enabled more robust conclusions about acceptability and feasibility to be drawn.


Dyke award. Harmonic modulation of proton MR precessional phase by pulsatile motion: origin of spinal CSF flow phenomena.
The effects of pulsatile motion on MR imaging of spinal CSF were quantitatively evaluated with a spine phantom that simulated spinal CSF pulsation. Two fundamental interdependent pulsation flow phenomena were observed: variable reductions in signal intensity of pulsatile CSF (signal loss) and spatial mismapping of this signal beyond the confines of the subarachnoid space (phase-shift images). Phase-shift images were observed as multiple regions of signal intensity conforming morphologically to the subarachnoid space but displaced symmetrically from it along the phase-encoding axis, either added to or subtracted from stationary signal intensity. Both CSF pulsation flow phenomena occurred secondary to harmonic modulation of proton precessional phase (temporal phase shift) by the unique pulsatile motion of spinal CSF when the repetition time was not an integral multiple of the pulsation period. Each flow phenomenon was analyzed with the spine phantom independently to control individual imaging and physiologic parameters including imaging plane, repetition time, echo time, slice thickness, number of echoes, number of excitations, CSF pulsation amplitude, and CSF pulsation period. In the axial plane, signal loss was present on both first- and second-echo images and was more pronounced with larger pulsation amplitudes and smaller slice thicknesses. A quantitative relationship between these two parameters allowed the prediction of CSF pulsation amplitude when the slice thickness was known and the CSF signal intensity was measured. In the sagittal plane, signal loss was present on first-echo images, was more pronounced with larger pulsation amplitudes, and underwent incomplete even-echo rephasing on second-echo images. Phase-shift images were influenced by the relationship between repetition time and CSF pulsation period. They were partly eliminated on sagittal but not on axial second-echo images because of incomplete even-echo rephasing. Both signal loss and phase-shift images were completely eliminated with CSF gating or pseudogating, indicating the rationale for gating during clinical spinal MR. The clinical significance of these findings is that awareness of the existence of spinal CSF pulsation flow phenomena avoids diagnostic confusion, whereas understanding their etiology provides a rational approach, such as CSF gating, to eliminate them.


Contribution of the Twin-Arginine Translocation System to the Intracellular Survival of Salmonella Typhimurium in Dictyostelium discoideum.
The twin-arginine translocation (Tat) system is a specialized secretion pathway required for bacteria to export fully folded proteins through the cytoplasmic membrane. This system is crucial during Salmonella infection of animal hosts. In this study, we show that Salmonella enterica serovar Typhimurium (S. Typhimurium) requires the Tat system to survive and proliferate intracellularly in the social amoeba Dictyostelium discoideum. To achieve this, we developed a new infection assay to assess intracellular bacterial loads in amoeba by direct enumeration of colony forming units (CFU) at different times of infection. Using this assay we observed that a ΔtatABC mutant was internalized in higher numbers than the wild type, and was defective for intracellular survival in the amoeba at all times post infection evaluated. In addition, we assessed the effect of the ΔtatABC mutant in the social development of D. discoideum. In contrast to the wild-type strain, we observed that the mutant was unable to delay the social development of the amoeba at 2 days of co-incubation. This phenotype correlated with defects in intracellular proliferation presented by the ΔtatABC mutant in D. discoideum after 24 h of infection. All phenotypes described for the mutant were reverted by the presence of a plasmid carrying tatABC genes, indicating that abrogation of Tat system attenuates S. Typhimurium in this model organism. Overall, our results indicate that the Tat system is crucial for S. Typhimurium to survive and proliferate intracellularly in D. discoideum and for virulence in this host. To the best of our knowledge, this is the first report on the relevance of the Tat system in the interaction of any bacterial pathogen with the social amoeba D. discoideum.


Cortical lesions in children with multiple sclerosis.
Double inversion recovery (DIR) sequences have improved the detection of cortical lesions (CLs) in adult patients with multiple sclerosis (MS). We evaluated the presence and frequency of CLs in pediatric patients with relapsing-remitting MS (RRMS) in comparison to adult patients with MS with the same clinical phenotype. Using a 3.0-T scanner, brain DIR, dual-echo, and 3-dimensional T1-weighted scans were acquired from 24 pediatric patients with RRMS, 15 adult patients with RRMS, and 10 pediatric healthy controls. CLs and white matter (WM) lesions were identified, and their volumes measured. Brain gray matter and WM volumes were also calculated. Between-group comparisons were performed using χ(2), Mann-Whitney, and analysis of variance tests. Poisson regressions for count data were used to model the number of lesions of the 2 groups of patients. Compared to adults, pediatric patients had shorter disease duration and lower disability. WM lesion number and volume did not differ between pediatric and adult patients with MS. CLs were detected in 2 (8%) pediatric and 10 (66%) adult patients. Median CL volume was lower in pediatric than adult patients with RRMS (p = 0.0003). Regression analysis showed that pediatric patients had a lower number of CLs than adults (p = 0.0003), after adjusting for age, gender, Expanded Disability Status Scale score, and disease duration. CLs are rare in pediatric patients with MS. Since pediatric patients with MS have a clinical onset closer to the biological onset of the disease than adult patients with MS, our findings indicate that CL formation is likely not to be an initial event in this disease.


Role of TGF-β in pancreatic ductal adenocarcinoma progression and PD-L1 expression.
The transforming growth factor-beta (TGF-β) pathway plays a paradoxical, context-dependent role in pancreatic ductal adenocarcinoma (PDAC): a tumor-suppressive role in non-metastatic PDAC and a tumor-promotive role in metastatic PDAC. We hypothesize that non-SMAD-TGF-β signaling induces PDAC progression. We investigated the expression of non-SMAD-TGF-β signaling proteins (pMAPK14, PD-L1, pAkt and c-Myc) in patient-derived tissues, cell lines and an immunocompetent mouse model. Experimental models were complemented by comparing the signaling proteins in PDAC specimens from patients with various survival intervals. We manipulated models with TGF-β, gemcitabine (DNA synthesis inhibitor), galunisertib (TGF-β receptor inhibitor) and MK-2206 (Akt inhibitor) to investigate their effects on NF-κB, β-catenin, c-Myc and PD-L1 expression. PD-L1 expression was also investigated in cancer cells and tumor associated macrophages (TAMs) in a mouse model. We found that tumors from patients with aggressive PDAC had higher levels of the non-SMAD-TGF-β signaling proteins pMAPK14, PD-L1, pAkt and c-Myc. In PDAC cells with high baseline β-catenin expression, TGF-β increased β-catenin expression while gemcitabine increased PD-L1 expression. Gemcitabine plus galunisertib decreased c-Myc and NF-κB expression, but induced PD-L1 expression in some cancer models. In mice, gemcitabine plus galunisertib treatment decreased metastases (p = 0.018), whereas galunisertib increased PD-L1 expression (p < 0.0001). In the mice, liver metastases contained more TAMs compared to the primary pancreatic tumors (p = 0.001), and TGF-β increased TAM PD-L1 expression (p < 0.05). In PDAC, the non-SMAD-TGF-β signaling pathway leads to more aggressive phenotypes, TAM-induced immunosuppression and PD-L1 expression. The divergent effects of TGF-β ligand versus receptor inhibition in tumor cells versus TAMs may explain the TGF-β paradox. Further evaluation of each mechanism is expected to lead to the development of targeted therapies.


Biosurfactant-enhanced solubilization of NAPL mixtures.
Remediation of nonaqueous phase liquids (NAPLs) by conventional pump-and-treat methods (i.e., water flushing) is generally considered to be ineffective due to low water solubilities of NAPLs and to mass-transfer constraints. Chemical flushing techniques, such as surfactant flushing, can greatly improve NAPL remediation primarily by increasing the apparent solubility of NAPL contaminants. NAPLs at hazardous waste sites are often complex mixtures. However, the equilibrium and nonequilibrium mass-transfer characteristics between NAPL mixtures and aqueous surfactant solutions are not well understood. This research investigates the equilibrium solubilization behavior of two- and three-component NAPL mixtures (containing akylbenzenes) in biosurfactant solutions. NAPL solubilization is found to be ideal in water (i.e., obeys Raoult's Law), while solubilization in biosurfactant solutions was observed to be nonideal. Specifically, the relatively hydrophobic compounds in the mixture experienced solubility enhancements that were greater than those predicted by ideal enhanced solubilization theory, while the solubility enhancements for the relatively hydrophilic compounds were less than predicted. The degree of nonideality is shown to be a nonlinear function of the NAPL-phase mole fraction. Empirical relationships based on the NAPL-phase mole fraction and/or micelle-aqueous partition coefficients measured in single-component NAPL systems are developed to estimate values for the multicomponent partition coefficients. Empirical relationships that incorporate both the NAPL-phase mole fraction and single-component partition coefficients yield much improved estimates for the multicomponent partition coefficient.


Single gene obesities in rodents: possible relevance to human obesity.
Obesity is a complex phenotype which "resolves" the influences of genes, development and environment. In any individual - and in the same individual at different times of life - the relative influence of these factors may vary. In this sense, obesity is a prototype of many of the diseases now confronting medical science. Among the most important concepts regarding such phenotypes is the idea that relevant genes mediate susceptibility to disease in a specific environmental context, not the inevitable occurrence of the phenotype regardless of the environment. Individuals with otherwise potent genetic predisposition to obesity will be lean in an environment of food deprivation/high demand for physical activity, and individuals not genetically predisposed to obesity may become so in an environment that includes tasty, calorically dense foods and/or few inducements to physical activity. Thus, in any effort to elucidate the genetic bases for susceptibility to obesity, the "environment" in which the obesity is occurring remains a critical factor regarding what sorts of genes will be identified. Because the genes that mediate susceptibility to obesity may affect energy intake, energy expenditure and/or the partitioning of calories between lean tissues and fat, the ability to define the gross metabolic basis for the obesity is very important in determining which genes are relevant to the phenotype. Because it is so difficult to experimentally define/control the environment of humans, and because the attainment of an obese state may actually rectify the metabolic differences predisposing to obesity, animal models of obesity have been looked at intensively for clues to the relevant genes in humans. Over the past 40 years, a series of autosomal dominant (Yellow) and recessive (obese, diabetes, tubby, fat, fatty) obesity mutations have been described in mice and rats. The molecular cloning of all of these genes has been accomplished within the past 4 years, providing an exciting array of new reagents for the molecular analysis of obesity. These genes encode molecules that appear to interact in physiologic systems that influence body fat stores. The genes and their apparent functions are summarized in the Table . The locations of these genes in the genomes of rodents and human are known, as are their genetic structure/sequence. Thus, their role(s) in human obesity can now be assessed directly.


Donepezil for dementia in Parkinson's disease: a randomised, double blind, placebo controlled, crossover study.
To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD). This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5-10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog). Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale.There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant. Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.


Community perspective of maternal mortality: experience from Konduga Local Government Area, Borno State, Nigeria.
High maternal mortality in Nigeria in particular and Sub-Saharan Africa in general has remained one of the key indicators of our poor health care services, infrastructural facilities and negative socio-cultural attitudes to healthy living. The objective is to identify barriers to prompt and effective treatment of obstetric complications leading to maternal mortality in order to develop appropriate strategies to address them at the community level. The study took place between 10th October and 10th December 2003. An in-depth interview guide developed by the network for the prevention of maternal mortality (NPMM), which contains mainly open ended questions, modified to suit our socio-cultural setting was used. There was a good understanding among the people of the area that women are dying during pregnancy, labour and puerperium. 28(93.3%) of the respondents recognized some obstetric complications. The main obstacles to accessing the hospital for emergency obstetric care were lack of money and transportation difficulties. Equipping the health facilities, employment of qualified staff, community supported emergency funds for obstetric emergency and the provision of reliable, effective and affordable transport are identified as necessary measures to prevent maternal mortality. The Local Government Areas and community leaders are to champion the cause for the provision of these facilities in their localities. There is a good understanding of obstetric complications in the community leading to maternal death. The main reasons for delay in seeking care are ignorance, poverty, lack of transportation and distance. Community enlightenment, health education, training of TBAs, poverty reduction and effective, affordable and reliable transportation are means of obviating delays in the decision and transportation leading to maternal mortality. Upgrading and re-equipping of health facilities to provide emergency obstetric care services are mandatory. Community participation in the safe motherhood drive can be ensured using the traditional rulers, religious leaders and the Local Government Authority.


Recent Advances in Probabilistic Dose-Response Assessment to Inform Risk-Based Decision Making.
Paradoxically, risk assessments for the majority of chemicals lack any quantitative characterization as to the likelihood, incidence, or severity of the risks involved. The relatively few cases where "risk" is truly quantified are based on either epidemiologic data or extrapolation of experimental animal cancer bioassay data. The paucity of chemicals and health endpoints for which such data are available severely limits the ability of decisionmakers to account for the impacts of chemical exposures on human health. The development by the World Health Organization International Programme on Chemical Safety (WHO/IPCS) in 2014 of a comprehensive framework for probabilistic dose-response assessment has opened the door to a myriad of potential advances to better support decision making. Building on the pioneering work of Evans, Hattis, and Slob from the 1990s, the WHO/IPCS framework provides both a firm conceptual foundation as well as practical implementation tools to simultaneously assess uncertainty, variability, and severity of effect as a function of exposure. Moreover, such approaches do not depend on the availability of epidemiologic data, nor are they limited to cancer endpoints. Recent work has demonstrated the broad feasibility of such approaches in order to estimate the functional relationship between exposure level and the incidence or severity of health effects. While challenges remain, such as better characterization of the relationship between endpoints observed in experimental animal or in vitro studies and human health effects, the WHO/IPCS framework provides a strong basis for expanding the breadth of risk management decision contexts supported by chemical risk assessment.


Endovascular Versus External Targeted Temperature Management for Patients With Out-of-Hospital Cardiac Arrest: A Randomized, Controlled Study.
Targeted temperature management is recommended after out-of-hospital cardiac arrest. Whether advanced internal cooling is superior to basic external cooling remains unknown. The aim of this multicenter, controlled trial was to evaluate the benefit of endovascular versus basic surface cooling. Inclusion criteria were the following: age of 18 to 79 years, out-of-hospital cardiac arrest related to a presumed cardiac cause, time to return of spontaneous circulation <60 minutes, delay between return of spontaneous circulation and inclusion <240 minutes, and unconscious patient after return of spontaneous circulation and before the start of cooling. Exclusion criteria were terminal disease, pregnancy, known coagulopathy, uncontrolled bleeding, temperature on admission <30°C, in-hospital cardiac arrest, immediate need for extracorporeal life support or hemodialysis. Patients were randomized between 2 cooling strategies: endovascular femoral devices (Icy catheter, Coolgard, Zoll, formerly Alsius; n=203) or basic external cooling using fans, a homemade tent, and ice packs (n=197). The primary end point, that is, favorable outcome evaluated by survival without major neurological damage (Cerebral Performance Categories 1-2) at day 28, was not significantly different between groups (odds ratio, 1.41; 95% confidence interval, 0.93-2.16; P=0.107). Improvement in favorable outcome at day 90 in favor of the endovascular group did not reach significance (odds ratio, 1.51; 95% confidence interval, 0.96-2.35; P=0.07). Time to target temperature (33°C) was significantly shorter and target hypothermia was more strictly maintained in the endovascular than in the surface group (P<0.001). Minor side effects directly related to the cooling method were observed more frequently in the endovascular group (P=0.009). Despite better hypothermia induction and maintenance, endovascular cooling was not significantly superior to basic external cooling in terms of favorable outcome. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00392639.


Factors Associated with Testing and Prompt Use of Recommended Antimalarials following Malaria Diagnosis: A Secondary Analysis of 2011-12 Tanzania HIV and Malaria Indicator Survey Data.
Malaria is still a public health problem in Sub-Saharan Africa. Malaria causes mortality mostly in children under-five years. Early detection and prompt treatment using recommended antimalarials is key to malaria control. However, in Tanzania, contrary to the national goals, a large proportion of children with fever taken to health facilities are not tested for malaria and those tested positive are not promptly treated using recommended antimalarials. The aim of this study was to determine factors associated with malaria testing and prompt use of recommended antimalarials among under-five children with fever in Tanzania. This was a secondary analysis of Tanzania HIV and Malaria Indicator Survey (THMIS) data 2011-12 obtained from a national cross sectional survey. The analysis involved children aged 6-59 months whose mothers reported they had fever two weeks preceding the survey. Factors associated with testing and uses of recommended antimalarials were obtained using logistic regression. Of the 1675 under-five children with fever, 951 (56.8%) were taken to the health facilities. Of the 951 children, only 394 (41.48%) febrile children were tested for malaria. Of those tested, 291 (78.91%) were diagnosed with malaria. Of those diagnosed with malaria, only 124 (42.68%) children used recommended antimalarials within 1st 24 hours of diagnosis. In multivariate analysis, children taken to health centers (OR 1.79; 95%CI: 1.07-3.00) and to the hospitals (OR 3.4; 95%CI: 1.75-6.77) had higher odds of being tested compared to those taken to dispensary and other lower level health facilities. Children were more likely to use recommended antimalarial promptly if they had a caretaker with secondary or higher education (OR: 4.07; 95%CI: 0.61-2.68) or living in the rural area (OR: 3.21; 95%CI: 1.09-9.44) compared to those with an uneducated caretaker or from an urban area. Training on malaria testing and treatment guidelines should be provided, and preventing stock outs of malaria testing kits and medications at dispensary level should be made available as it is the first point of health care for most Tanzanians. Reasons on why urban people are less likely to use recommended antimalarials need to be investigated and addressed for proper malaria management.


Predicting treatment Response based on Dual assessment of magnetic resonance Imaging kinetics and Circulating Tumor cells in patients with Head and Neck cancer (PREDICT-HN): matching 'liquid biopsy' and quantitative tumor modeling.
Magnetic resonance imaging (MRI) has improved capacity to visualize tumor and soft tissue involvement in head and neck cancers. Using advanced MRI, we can interrogate cell density using diffusion weighted imaging, a quantitative imaging that can be used during radiotherapy, when diffuse inflammatory reaction precludes PET imaging, and can assist with target delineation as well. Correlation of circulating tumor cells (CTCs) measurements with 3D quantitative tumor characterization could potentially allow selective, patient-specific response-adapted escalation or de-escalation of local therapy, and improve the therapeutic ratio, curing the greatest number of patients with the least toxicity. The proposed study is designed as a prospective observational study and will collect pretreatment CT, MRI and PET/CT images, weekly serial MR imaging during RT and post treatment CT, MRI and PET/CT images. In addition, blood sample will be collected for biomarker analysis at those time intervals. CTC assessments will be performed on the CellSave tube using the FDA-approved CellSearch® Circulating Tumor Cell Kit (Janssen Diagnostics), and plasma from the EDTA blood samples will be collected, labeled with a de-identifying number, and stored at - 80 °C for future analyses. The primary objective of the study is to evaluate the prognostic value and correlation of weekly tumor response kinetics (gross tumor volume and MR signal changes) and circulating tumor cells of mucosal head and neck cancers during radiation therapy using MRI in predicting treatment response and clinical outcomes. This study will provide landmark information as to the utility of CTCs ('liquid biopsy) and tumor-specific functional quantitative imaging changes during treatment to guide personalization of treatment for future patients. Combining the biological information from CTCs and the structural information from MRI may provide more information than either modality alone. In addition, this study could potentially allow us to determine the optimal time to obtain MR imaging and/ or CTCs during radiotherapy to assess tumor response and provide guidance for patient selection and stratification for future dose escalation or de-escalation strategies. Clinicaltrials.gov ( NCT03491176 ). Date of registration: 9th April 2018. (retrospectively registered). Date of enrolment of the first participant: 30th May 2017.


Effect of pterygium surgery on refractive spherocylinder power and corneal topography.
To evaluate the effect of pterygium surgery on refractive spherocylinder power and corneal topography. Twenty-four patients (27 eyes) undergoing pterygium surgery from January to December 2006 were retrospectively identified. Visual acuity, refractive spherocylinder power, and corneal topography were measured preoperatively and postoperatively. Improvement of visual acuity, decreases of refractive spherocylinder power, and significant differences of 3-mm topographic irregularity and 3-mm topographic astigmatism postoperatively were found. Differences of refractive spherocylinder power preoperatively and postoperatively correlated significantly with differences of 3-mm topographic irregularity (spherical, r = 0.828, P = .000; cylinder, r = -0.805, P= .000) and of 3-mm topographic astigmatism (spherical, r = 0.673, P= .000; cylinder, r = -0.811, P = .000) preoperatively and postoperatively. Pterygium surgery produces improvements in visual acuity, decreases of refractive spherocylinder power, topographic irregularity, and topographic astigmatism. Three-millimeter topographic irregularity and astigmatism have a close correlation with refractive spherocylinder power.


The role of bioactive compounds on the promotion of neurite outgrowth.
Neurite loss is one of the cardinal features of neuronal injury. Apart from neuroprotection, reorganization of the lost neuronal network in the injured brain is necessary for the restoration of normal physiological functions. Neuritogenic activity of endogenous molecules in the brain such as nerve growth factor is well documented and supported by scientific studies which show innumerable compounds having neurite outgrowth activity from natural sources. Since the damaged brain lacks the reconstructive capacity, more efforts in research are focused on the identification of compounds that promote the reformation of neuronal networks. An abundancy of natural resources along with the corresponding activity profiles have shown promising results in the field of neuroscience. Recently, importance has also been placed on understanding neurite formation by natural products in relation to neuronal injury. Arrays of natural herbal products having plentiful active constituents have been found to enhance neurite outgrowth. They act synergistically with neurotrophic factors to promote neuritogenesis in the diseased brain. Therefore use of natural products for neuroregeneration provides new insights in drug development for treating neuronal injury. In this study, various compounds from natural sources with potential neurite outgrowth activity are reviewed in experimental models.


Discontinuation symptoms associated with nefazodone.
We present a patient who developed discontinuation symptoms following abrupt cessation of nefazodone. Three days after the first appearance of the discontinuation symptoms (i.e. 5 days after cessation of the drug), all symptoms resolved spontaneously without a need for intervention. This case report emphasizes the importance of gradual discontinuation of serotonergic drugs to avoid any consequent unpleasant discontinuation symptoms.


Picosecond transient absorption spectroscopy in the blue spectral region of photosystem I.
Picosecond transient absorption difference spectroscopy in the blue wavelength region (380-500 nm) was used to study the early electron acceptors in photosystem I. Samples were photosystem I core particles with about 100 chlorophylls per reaction center isolated from the cyanobacterium Synechocystis sp. PCC 6803. After excitation at 590 nm at room temperature, decay-associated spectra (DAS) were determined from global analysis in the blue region, yielding two transient components and one nondecaying component. A 3 ps decay phase is interpreted as primarily due to antenna excited-state redistribution. A 28 ps decay phase is interpreted as due to overall excited-state decay by electron transfer. The nondecaying component is ascribed to the difference spectrum of P(700) and the quinone or A(1) electron acceptor (P(700)(+)A(1)(-) - P(700)A(1)). Decay curves on the millisecond time scale at different wavelengths were measured with an autoxidizable artificial electron acceptor, benzyl viologen, and the (P(700)(+) - P(700)) difference spectrum was constructed. The (A(1)(-) - A(1)) difference spectrum was obtained by taking the difference between the above two difference spectra. A parallel picosecond experiment under strongly reducing conditions was also done as a control experiment. These conditions stabilize the electron on an earlier acceptor, A(0). The nondecaying component of the DAS at low potential was assigned to (P(700)(+)A(0)(-) - P(700)A(0)) since the electron-transfer pathway from A(0) to A(1) was blocked. The [(P(700)(+)A(0)(-) - P(700)A(0)) - (P(700)(+) - P(700))] subtraction gives a spectrum, interpreted as the (A(0)(-) - A(0)) difference spectrum of a chlorophyll a molecule, consistent with previous studies. The (A(1)(-) - A(1)) spectrum resolved on the picosecond time scale shows significant differences with similar spectra measured on longer time scales. These differences may be due to electrochromic effects and spectral evolution.


Isomerism or heterotaxy: which term leads to better understanding?
Use of correct nomenclature is important in all aspects of medicine. Many of the controversies that have bedeviled paediatric cardiology have devolved from the inappropriate use of words to describe the lesions to be found when the heart is congenitally abnormal. A continuing area of disagreement is the situation currently described by many as representing "heterotaxy". When used literally, this word means any departure from the normal. Thus, all congenitally malformed hearts represent examples of heterotaxy. By convention, nonetheless, the term is used to describe the arrangement in which the bodily organs, including parts of the heart, are not in their usual or in their mirror-imaged patterns. The arrangements, therefore, represent the presence of the organs on the right and left sides of the body being mirror imaged, in other words isomeric; however, not all the organs are uniformly isomeric. In this review, we show that, when assessed on the basis of the morphology of the atrial appendages, specifically the extent of the pectinate muscles relative to the atrioventricular junctions, isomerism is an unequivocal finding within the heart. Only the atrial appendages, however, are truly isomeric. The potential problem of disharmony between the various systems of organs is resolved simply by accounting specifically for each of the systems. On these bases, we suggest that the isomeric arrangements can now readily be diagnosed in the clinical setting, and differentiated into their right and left isomeric variants. We propose that such distinctions will provide the key for establishing the genetic cues responsible for the formation of the isomeric as opposed to the lateralised arrangements.


Laparoscopic cholecystectomy for acute cholecystitis.
Acute cholecystitis was initially considered a contra-indication for laparoscopic cholecystectomy, but today the laparoscopic route is generally used even for severe acute cholecystitis. Several studies have shown that this is possible, although the conversion and complication rates are high, but there are no randomised controlled trials that evaluate the complications and costs of this technique compared with conventional open techniques. The timing of a laparoscopic cholecystectomy for acute cholecystitis is also a matter of debate as well as its use in elderly patients with this condition.


Reverse engineering biomolecular systems using -omic data: challenges, progress and opportunities.
Recent advances in high-throughput biotechnologies have led to the rapid growing research interest in reverse engineering of biomolecular systems (REBMS). 'Data-driven' approaches, i.e. data mining, can be used to extract patterns from large volumes of biochemical data at molecular-level resolution while 'design-driven' approaches, i.e. systems modeling, can be used to simulate emergent system properties. Consequently, both data- and design-driven approaches applied to -omic data may lead to novel insights in reverse engineering biological systems that could not be expected before using low-throughput platforms. However, there exist several challenges in this fast growing field of reverse engineering biomolecular systems: (i) to integrate heterogeneous biochemical data for data mining, (ii) to combine top-down and bottom-up approaches for systems modeling and (iii) to validate system models experimentally. In addition to reviewing progress made by the community and opportunities encountered in addressing these challenges, we explore the emerging field of synthetic biology, which is an exciting approach to validate and analyze theoretical system models directly through experimental synthesis, i.e. analysis-by-synthesis. The ultimate goal is to address the present and future challenges in reverse engineering biomolecular systems (REBMS) using integrated workflow of data mining, systems modeling and synthetic biology.


Necrosis-inducing peptide has the beneficial effect on killing tumor cells through neuropilin (NRP-1) targeting.
The therapeutic efficacy of most anti-cancer drugs depends on their apoptosis-inducing abilities. Previously, we showed that a peptide containing the mitochondrial targeting domain (MTD) found in Noxa, a BH-3 only protein of Bcl-2 family, induces necrosis. Here, a fusion peptide of neuropilin-1 (NRP-1) targeting peptide and MTD peptide, designated tumor homing motif 17:MTD (TU17:MTD), was found to induce necrosis in cancer cells in vitro and to cause the regression of tumors when intravenously injected into mice bearing subcutaneous CT26 colorectal carcinoma tumors. The necrosis within tumor tissues was evident upon administering TU17:MTD. TU17:MTD penetrated into tumor cells by targeting to Neuropilin-1, which could be blocked by anti-NRP-1 antibody. The efficacy of TU17:MTD on tumor regression was higher than that of TU17:D(KLAKLAK)2, a fusion peptide of NRP-1 targeting peptide and a pro-apoptotic peptide. The necrotic cell death within tumor tissues was evident at day 1 after administering TU17:MTD systemically. Transplanted subcutaneous substantially reduced in size within two weeks and 5 days, respectively, with no apparent side effects. Together, these results propose that the pro-necrotic peptide MTD may present an alternative approach for development of targeted anti-cancer agents.