Activation of intestinal Cl- secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator.
Lubiprostone alleviates constipation by stimulating intestinal fluid secretion, purportedly through activation of ClC-2-type Cl(-) channels. Intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductance regulator (CFTR) Cl(-) channel activity. Because ClC-2 recruitment might be beneficial to CF patients, we investigated lubiprostone's mode of action. Cl(-) transport was measured in an Ussing chamber, in 3 model systems: (1) T84 colonocytes, (2) intestinal epithelium of wild-type and CF mice, and (3) intestinal epithelium of CF patients and controls. In T84 monolayers, lubiprostone induced a robust secretory response. Selective permeabilization of the basolateral plasma membrane revealed that lubiprostone activated an apical Cl(-) conductance. The lubiprostone response was attenuated by H89, an inhibitor of the cAMP-dependent protein kinase, and lubiprostone precluded responsiveness to the cAMP agonist forskolin. CFTR blockage by CFTRinh172, but not ClC-2 blockage by CdCl(2), inhibited the lubiprostone response. Lubiprostone induced a CdCl(2)-insensitive secretory response in mouse intestine, but failed to induce intestinal Cl(-) secretion in Cftr-null mice. Correspondingly, lubiprostone induced a secretory response in human intestinal epithelium, but not in tissue of CF patients. The EP(4)-type prostanoid receptor antagonist L-161,982 blocked the lubiprostone response in all 3 models studied. In T84 cells, lubiprostone induced a rise in cAMP levels that was sensitive to EP(4)-receptor blockage. Lubiprostone enhances intestinal Cl(-) and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. Therefore, it is of limited use for treatment of CF-related intestinal disease.


Forces and shapes as determinants of micro-swimming: effect on synchronisation and the utilisation of drag.
In this analytical study we demonstrate the richness of behaviour exhibited by bead-spring micro-swimmers, both in terms of known yet not fully explained effects such as synchronisation, and hitherto undiscovered phenomena such as the existence of two transport regimes where the swimmer shape has fundamentally different effects on the velocity. For this purpose we employ a micro-swimmer model composed of three arbitrarily-shaped rigid beads connected linearly by two springs. By analysing this swimmer in terms of the forces on the different beads, we determine the optimal kinematic parameters for sinusoidal driving, and also explain the pusher/puller nature of the swimmer. Moreover, we show that the phase difference between the swimmer's arms automatically attains values which maximise the swimming speed for a large region of the parameter space. Apart from this, we determine precisely the optimal bead shapes that maximise the velocity when the beads are constrained to be ellipsoids of a constant volume or surface area. On doing so, we discover the surprising existence of the aforementioned transport regimes in micro-swimming, where the motion is dominated by either a reduction of the drag force opposing the beads, or by the hydrodynamic interaction amongst them. Under some conditions, these regimes lead to counter-intuitive effects such as the most streamlined shapes forming locally the slowest swimmers.


Bacillus thuringiensis as a Biofertilizer and Biostimulator: a Mini-Review of the Little-Known Plant Growth-Promoting Properties of Bt.
Bacillus thuringiensis (Bt) is a gram-positive spore-forming soil microorganism. Because the insecticidal activities of Bt are well known, it has been used as a tool for insect pest control worldwide. The beneficial features of Bt are not limited to its role as an insecticide; it is also used to control phytopathogenic fungi via chitinolytic activity. Bt-related studies are mostly focused on its biocontrol properties. However, studies focusing on the biostimulation and biofertilizer features of Bt, including its interactions with plants, are limited. Bt is a successful endophyte in many plants and can directly promote their development or indirectly induce plant growth by suppressing diseases. Although there are various commercial biopesticide Bt-based products, there are no commercial Bt-based plant growth-promoting rhizobacteria products on the biofertilizer market. As novel Bt strain exploration increases, there will likely be new Bt-based products with powerful biofertilizer activities in the future. The objective of this paper is to review, discuss, and evaluate the exceptional features of Bt as a plant growth promoter.


Two-wavelength holographic interferometry for transparent media using a diffraction grating.
A new technique of two-wavelength nondiffuse holographic interferometry is demonstrated that is capable of producing interferograms of transparent media with high or low sensitivity. Incorporating an arrangement similar to Bryngdahl's longitudinally reversed shearing interferometer, the technique works by superposing the reconstructed true and/or conjugate images of two transmission image holograms of the test medium recorded at different wavelengths. Extensions of the technique allow one to record interferograms sensitive only to the optical dispersion of the test medium and to generate light beams with phase distributions equal to the sum or difference of the phases of the original object beams.


Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells.
BHLHE40 and BHLHE41 (BHLHE40/41) are basic helix-loop-helix type transcription factors that play key roles in multiple cell behaviors. BHLHE40/41 were recently shown to be involved in an epithelial-to-mesenchymal transition (EMT). However, the precise mechanism of EMT control by BHLHE40/41 remains unclear. In the present study, we demonstrated that BHLHE40/41 expression was controlled in a pathological stage-dependent manner in human endometrial cancer (HEC). Our in vitro assays showed that BHLHE40/41 suppressed tumor cell invasion. BHLHE40/41 also suppressed the transcription of the EMT effectors SNAI1, SNAI2, and TWIST1. We identified the critical promoter regions of TWIST1 for its basal transcriptional activity. We elucidated that the transcription factor SP1 was involved in the basal transcriptional activity of TWIST1 and that BHLHE40/41 competed with SP1 for DNA binding to regulate gene transcription. This study is the first to report the detailed functions of BHLHE40 and BHLHE41 in the suppression of EMT effectors in vitro. Our results suggest that BHLHE40/41 suppress tumor cell invasion by inhibiting EMT in tumor cells. We propose that BHLHE40/41 are promising markers to predict the aggressiveness of each HEC case and that molecular targeting strategies involving BHLHE40/41 and SP1 may effectively regulate HEC progression.


Seeing orange: prawns tap into a pre-existing sensory bias of the Trinidadian guppy.
Sensory bias, a predisposition towards certain signals, has been implicated in the origin of mate preferences in some species. A risk associated with these biases is that they can be co-opted by predators as sensory lures. Here we propose that the orange spots on the brown pincers of a diurnal, predatory species of prawn function as lures for Trinidadian guppies, which have a sensory bias for orange. We exposed female guppies to (i) a life-like model of this Trinidadian prawn with orange, green or no spots on the pincers or (ii) a live, novel (non-Trinidadian) crustacean (crayfish), also with spotted pincers. First, we provide evidence that guppies sympatric with the prawn recognized our model as a potential predator. Next, we found that guppies spent more time in the dangerous head region of the model prawn with orange-spotted pincers compared with unspotted pincers. Finally, we show that allopatric, but not sympatric, guppies spent more time in the vicinity of the head of a live crayfish when orange spots were added to its pincers than when brown spots were added. Our results suggest that the orange spots on prawn pincers can act as a sensory lure.


Pain Assessment Strategies in Home Care and Nursing Homes in Mid-Norway: A Cross-sectional Survey.
The prevalence of pain ranges from 27.8% to 86.5% in nursing homes and 42% to 50% in home care. Pain assessment is the first step toward effective pain management. The aim of this study was to explore the use of pain assessment strategies (verbal, numeric, and observation rating scales and standardized questions) in home care and nursing homes. The study was a descriptive cross-sectional survey. Health care providers who were responsible for the patients' medications replied to a questionnaire. In-home care and nursing homes in 11 randomly selected municipalities in Mid-Norway were included. Three hundred ninety-two individuals were included in this study (70% response rate): 271 (69%) from nursing homes and 121 (31%) from home care. The respondents working in home care had a higher educational level than those in working in nursing homes. Pain assessment instruments were not used frequently in nursing homes and home care. Verbal and numeric rating scales were used significantly more frequently in home care than in nursing homes. Registered nurses (RNs) in nursing homes used standardized questions significantly more often than did RNs in home care. RNs and social educators in home care self-reported less competence in treating the patients' total pain experience than did those in nursing homes. Workplace (working in home care) and regular training in the use of pain assessment tools explained more than 20% of the variation in the use of pain assessment tools. Regular training in the use of pain assessment tools is needed for health care workers in home care and nursing homes.


Measure of HIV/STD risk-reduction: strategies for enhancing the utility of behavioral and biological outcome measures for African American couples.
Numerous studies have discussed the value of including biological outcome measures as a complement to behavioral outcome measures to assess the efficacy of HIV risk-reduction interventions. This article highlights strategies used to minimize the limitations of including both self-reported sexual behaviors and biologically confirmed sexually transmitted diseases as primary outcome measures in an HIV/sexually transmitted disease (STD) prevention program for African American serodiscordant couples (Eban). Couples receiving an HIV intervention condition (Eban) were compared with couples receiving a time-equivalent General Health Promotion condition on behavioral and biological outcomes. Both behavioral and biological data were collected at baseline, immediately postintervention, and at 6 and 12 months postintervention. Literature reviews, consulting other researchers who conducted couples studies, our investigative team's experience in previous HIV interventions, and formative work were used to develop procedures to minimize potential limitations associated with the inclusion of behavioral and biological outcome measures for Eban. Given the strengths of including behavioral and biological outcome measures, the Eban study chose to have both measures serve as primary outcomes. The primary behavioral outcome for the trial is the proportion of protected vaginal and anal intercourse episodes that occurred within the index couple in 90 days before each follow-up assessment and over the 12-month postintervention follow-up period. The primary biological outcome is the proportion of participants (male or female study partners) with an incident STD (Chlamydia, gonorrhea, or trichomoniasis) over the 12-month postintervention follow-up period. Employing procedures to minimize limitations of using self-reported sexual behaviors and STDs as complementary primary outcomes enhances their utility as measures of the efficacy of HIV/STD prevention interventions.


Multilevel analysis of the chronic care model and 5A services for treating tobacco use in urban primary care clinics.
To examine the chronic care model (CCM) as a framework for improving provider delivery of 5A tobacco cessation services. Cross-sectional surveys were used to obtain data from 497 health care providers in 60 primary care clinics serving low-income patients in New York City. A hierarchical generalized linear modeling approach to ordinal regression was used to estimate the probability of full 5A service delivery, adjusting for provider covariates and clustering effects. We examined associations between provider delivery of 5A services, clinic implementation of CCM elements tailored for treating tobacco use, and the degree of CCM integration in clinics. Providers practicing in clinics with enhanced delivery system design, clinical information systems, and self-management support for cessation were 2.04-5.62 times more likely to perform all 5A services ( p<.05). CCM integration in clinics was also positively associated with 5As delivery. Compared with none, implementation of one to six CCM elements corresponded with a 3.69-30.9 increased odds of providers delivering the full spectrum of 5As ( p<.01). Findings suggest that the CCM facilitates provider adherence to the Public Health Service 5A clinical guideline. Achieving the full benefits of systems change may require synergistic adoption of all model components.


Quantification of the changes in the openness of the major temporal arcade in retinal fundus images of preterm infants with plus disease.
We tested the hypothesis that the openness of the major temporal arcade (MTA) changes in the presence of plus disease, by quantification via parabolic modeling of the MTA, as well as measurement of an arcade angle for comparative analysis. Such analysis could assist in the detection and treatment of progressive retinopathy of prematurity. Digital image processing techniques were applied for the detection and modeling of the MTA via a graphical user interface (GUI) to quantify the openness of the MTA. An arcade angle measure, based on a previously proposed method, also was obtained via the GUI for comparative analysis. The statistical significance of the differences between the plus and no-plus cases for each parameter was analyzed using the P value. The area (Az) under the receiver operating characteristic curve was used to assess the diagnostic performance of each feature. The temporal arcade angle measure and the openness parameter of the parabolic model were used to perform discrimination of plus versus no-plus cases. Using a set of 19 cases with plus and 91 with no plus disease, Az=0.70 was obtained using the results of dual-parabolic modeling in screening for plus disease. The arcade angle measure provided comparable results with Az=0.73. Using our proposed image analysis techniques and software, this study demonstrates, for the first time to our knowledge, that the openness of the MTA decreases in the presence of plus disease.


The accuracy of first trimester ultrasound in the diagnosis of hydatidiform mole.
Previous studies have examined ultrasound findings in histopathologically confirmed cases of hydatidiform mole. The aim of this study was to assess the first-trimester ultrasonographic findings in all women suspected of having hydatidiform mole on ultrasound and those subsequently diagnosed with hydatidiform mole after histological examination of removed products of conception after surgical evacuation of the uterus. The aim was to obtain a true sensitivity and positive predictive value for ultrasound in the diagnosis of hydatidiform mole. A retrospective analysis was performed of all cases of sonographically suspected hydatidiform mole and histologically proven hydatidiform mole presenting to the Early Pregnancy Unit of an inner city hospital over a 4-year period. The sensitivity and positive predictive value (PPV) of ultrasound in the detection of histologically proven hydatidiform mole was calculated. The study group consisted of 90 women; 56 were suspected of having hydatidiform mole on ultrasound, and of these 27 (48%) had hydatidiform mole confirmed after histopathological examination of the products of conception, while no changes suggestive of hydatidiform mole were present in the other 29 cases. Overall, 61 women had hydatidiform mole confirmed on histology-41 (67%) partial hydatidiform moles (PHM) and 20 (33%) complete hydatidiform moles (CHM). The ultrasound findings in the 34 cases not suspected of hydatidiform mole were an empty sac in 8/34 (24%) women and a delayed miscarriage in the other 26/34 (76%). The overall sensitivity and positive predictive value for the ultrasound diagnosis of hydatidiform mole was 44% and 48%, respectively. For PHMs the respective values were 20% and 22% and for CHMs they were 95% and 40%. Ultrasonography is more reliable for diagnosing CHMs than for PHMs. Overall, the sensitivity of ultrasound for accurately predicting hydatidiform mole is 44%, and one in two women with an abnormal scan will have the disease confirmed on histology.


Distance matters: barriers to antenatal care and safe childbirth in a migrant population on the Thailand-Myanmar border from 2007 to 2015, a pregnancy cohort study.
Antenatal care and skilled childbirth services are important interventions to improve maternal health and lower the risk of poor pregnancy outcomes and mortality. A growing body of literature has shown that geographic distance to clinics can be a disincentive towards seeking care during pregnancy. On the Thailand-Myanmar border antenatal clinics serving migrant populations have found high rates of loss to follow-up of 17.4%, but decades of civil conflict have made the underlying factors difficult to investigate. Here we perform a comprehensive study examining the geographic, demographic, and health-related factors contributing to loss to follow-up. Using patient records we conducted a spatial and epidemiological analysis looking for predictors of loss to follow-up and pregnancy outcomes between 2007 and 2015. We used multivariable negative binomial regressions to assess for associations between distance travelled to the clinic and birth outcomes (loss to follow-up, pregnancy complications, and time of first presentation for antenatal care.) RESULTS: We found distance travelled to clinic strongly predicts loss to follow-up, miscarriage, malaria infections in pregnancy, and presentation for antenatal care after the first trimester. People lost to follow-up travelled 50% farther than people who had a normal singleton childbirth (a ratio of distances (DR) 1.5; 95% confidence interval (CI): 1.4 - 1.5). People with pregnancies complicated by miscarriage travelled 20% farther than those who did not have miscarriages (DR: 1.2; CI 1.1-1.3), and those with Plasmodium falciparum malaria in pregnancy travelled 60% farther than those without P. falciparum (DR: 1.6; CI: 1.6 - 1.8). People who delayed antenatal care until the third trimester travelled 50% farther compared to people who attended in the first trimester (DR: 1.5; CI: 1.4 - 1.5). This analysis provides the first evidence of the complex impact of geography on access to antenatal services and pregnancy outcomes in the rural, remote, and politically complex Thailand-Myanmar border region. These findings can be used to help guide evidence-based interventions to increase uptake of maternal healthcare both in the Thailand-Myanmar region and in other rural, remote, and politically complicated environments.


Learning nonlinear image manifolds by global alignment of local linear models.
Appearance-based methods, based on statistical models of the pixel values in an image (region) rather than geometrical object models, are increasingly popular in computer vision. In many applications, the number of degrees of freedom (DOF) in the image generating process is much lower than the number of pixels in the image. If there is a smooth function that maps the DOF to the pixel values, then the images are confined to a low-dimensional manifold embedded in the image space. We propose a method based on probabilistic mixtures of factor analyzers to (1) model the density of images sampled from such manifolds and (2) recover global parameterizations of the manifold. A globally nonlinear probabilistic two-way mapping between coordinates on the manifold and images is obtained by combining several, locally valid, linear mappings. We propose a parameter estimation scheme that improves upon an existing scheme and experimentally compare the presented approach to self-organizing maps, generative topographic mapping, and mixtures of factor analyzers. In addition, we show that the approach also applies to finding mappings between different embeddings of the same manifold.


Lysine methylation regulates the pRb tumour suppressor protein.
The pRb tumour suppressor protein has a central role in coordinating early cell cycle progression. An important level of control imposed on pRb occurs through post-translational modification, for example, phosphorylation. We describe here a new level of regulation on pRb, mediated through the targeted methylation of lysine residues, by the methyltransferase Set7/9. Set7/9 methylates the C-terminal region of pRb, both in vitro and in cells, and methylated pRb interacts with heterochromatin protein HP1. pRb methylation is required for pRb-dependent cell cycle arrest and transcriptional repression, as well as pRb-dependent differentiation. Our results indicate that methylation can influence the properties of pRb, and raise the interesting possibility that methylation modulates pRb tumour suppressor activity.


Microfluidic cell culture chip with multiplexed medium delivery and efficient cell/scaffold loading mechanisms for high-throughput perfusion 3-dimensional cell culture-based assays.
This study reports a microfluidic cell culture chip consisting of 48 microbioreactors for high-throughput perfusion 3-dimensional (3-D) cell culture-based assays. Its advantages include the capability for multiplexed and backflow-free medium delivery, and both efficient and high-throughput micro-scale, 3-D cell culture construct loading. In this work, the microfluidic cell culture chip is fabricated using two major processes, specifically, a computer-numerical-controlled (CNC) mold machining process and a polydimethylsiloxane (PDMS) replication process. The chip is composed of micropumps, microbioreactors, connecting microchannels and a cell/agarose scaffold loading mechanism. The performance of the new pneumatic micropumps and the cell/agarose scaffold loading mechanism has been experimentally evaluated. The experimental results show that this proposed multiplexed medium-pumping design is able to provide a uniform pumping rate ranging from 1.5 to 298.3 μl hr(-1) without any fluid backflow and the resultant medium contamination. In addition, the simple cell/agarose loading method has been proven to be able to load the 3-D cell culture construct uniformly and efficiently in all 48 microbioreactors investigated. Furthermore, a micro-scale, perfusion, 3-D cell culture-based assay has been successfully demonstrated using this proposed cell culture chip. The experimental results are also compared to a similar evaluation using a conventional static 3-D cell culture with a larger scale culture. It is concluded that the choice of a cell culture format can influence assay results. As a whole, because of the inherent advantages of a miniaturized perfusion 3-D cell culture assay, the cell culture chip not only can provide a stable, well-defined and more biologically-meaningful culture environment, but it also features a low consumption of research resources. Moreover, due to the integrated medium pumping mechanism and the simple cell/agarose loading method, this chip is economical and time efficient. All of these traits are particularly useful for high-precision and high-throughput 3-D cell culture-based assays.


Historical influence on the practice of chiropractic radiology: Part I - a survey of Diplomates of the American Chiropractic College of Radiology.
It is known that not all chiropractors follow mainstream guidelines on the use of diagnostic ionising radiation. Various reasons have been discussed in the literature, including using radiography to screen for congenital anomalies, to perform postural analysis, to search for contraindications to spinal manipulation, and to document chiropractic subluxations, i.e., tiny anatomical displacements of vertebrae thought to affect nerves and health. The visualisation of subluxations was the reason chiropractic first adopted the x-ray in 1910. There has never been a study of the influence of this historical paradigm of radiography on the practices of chiropractic radiologists (DACBRs or Diplomates of the American Chiropractic College of Radiology). A survey was administered with a modified Dillman method using SurveyMonkey and supplemented by hard copies distributed at a professional conference. The target population was all active DACBRs. There were 34 items, which consisted of multiple choice and open-ended interrogatives on all three areas in which chiropractic radiologists work: education, clinical practice, and radiology practice. The response rate was 38% (73 of 190 DACBRs). Respondents reported that the historical paradigm of radiography was found in all areas of practice, but not as a major aspect. The majority of respondents did not condone that historical paradigm, but many tolerated it, particularly from referring chiropractors. Radiographic subluxation analysis was reportedly perpetuated by private clinical practitioners as well as technique instructors and supervising clinicians in the teaching institutions. Within the chiropractic profession, there is a continuing belief in radiographically visible subluxations as a cause of suboptimal health. This situation is sustained in part due to the reticence of other chiropractors to report these practices to licensing and registration boards. Investigation into other structures supporting a vitalistic belief system over science in chiropractic is recommended. In addition, it may be useful to explore remunerative systems that move beyond the inherently conflicted fee-for-service model.


A comparative study of tea-tree oil versus benzoylperoxide in the treatment of acne.
Tea-tree oil (an essential oil of the Australian native tree Melaleuca alternifolia) has long been regarded as a useful topical antiseptic agent in Australia and has been shown to have a variety of antimicrobial activities; however, only anecdotal evidence exists for its efficacy in the treatment of various skin conditions. We have performed a single-blind, randomised clinical trial on 124 patients to evaluate the efficacy and skin tolerance of 5% tea-tree oil gel in the treatment of mild to moderate acne when compared with 5% benzoyl peroxide lotion. The results of this study showed that both 5% tea-tree oil and 5% benzoyl peroxide had a significant effect in ameliorating the patients' acne by reducing the number of inflamed and non-inflamed lesions (open and closed comedones), although the onset of action in the case of tea-tree oil was slower. Encouragingly, fewer side effects were experienced by patients treated with tea-tree oil.


Novel regulatory cascades controlling expression of nitrogen-fixation genes in Geobacter sulfurreducens.
Geobacter species often play an important role in bioremediation of environments contaminated with metals or organics and show promise for harvesting electricity from waste organic matter in microbial fuel cells. The ability of Geobacter species to fix atmospheric nitrogen is an important metabolic feature for these applications. We identified novel regulatory cascades controlling nitrogen-fixation gene expression in Geobacter sulfurreducens. Unlike the regulatory mechanisms known in other nitrogen-fixing microorganisms, nitrogen-fixation gene regulation in G. sulfurreducens is controlled by two two-component His-Asp phosphorelay systems. One of these systems appears to be the master regulatory system that activates transcription of the majority of nitrogen-fixation genes and represses a gene encoding glutamate dehydrogenase during nitrogen fixation. The other system whose expression is directly activated by the master regulatory system appears to control by antitermination the expression of a subset of the nitrogen-fixation genes whose transcription is activated by the master regulatory system and whose promoter contains transcription termination signals. This study provides a new paradigm for nitrogen-fixation gene regulation.


Divergent responses of chondrocytes and endothelial cells to shear stress: cross-talk among COX-2, the phase 2 response, and apoptosis.
Fluid shear exerts anti-inflammatory and anti-apoptotic effects on endothelial cells by inducing the coordinated expression of phase 2 detoxifying and antioxidant genes. In contrast, high shear is pro-apoptotic in chondrocytes and promotes matrix degradation and cartilage destruction. We have analyzed the mechanisms regulating shear-mediated chondrocyte apoptosis by cDNA microarray technology and bioinformatics. We demonstrate that shear-induced cyclooxygenase (COX)-2 suppresses phosphatidylinositol 3-kinase (PI3-K) activity, which represses antioxidant response element (ARE)/NF-E2 related factor 2 (Nrf2)-mediated transcriptional response in human chondrocytes. The resultant decrease in antioxidant capacity of sheared chondrocytes contributes to their apoptosis. Phase 2 inducers, and to a lesser extent COX-2-selective inhibitors, negate the shear-mediated suppression of ARE-driven phase 2 activity and apoptosis. The abrogation of shear-induced COX-2 expression by PI3-K activity and/or stimulation of the Nrf2/ARE pathway suggests the existence of PI3-K/Nrf2/ARE negative feedback loops that potentially interfere with c-Jun N-terminal kinase 2 activity upstream of COX-2. Reconstructing the signaling network regulating shear-induced chondrocyte apoptosis may provide insights to optimize conditions for culturing artificial cartilage in bioreactors and for developing therapeutic strategies for arthritic disorders.


Conformational changes in the photocycle of Anabaena sensory rhodopsin: absence of the Schiff base counterion protonation signal.
Anabaena sensory rhodopsin (ASR) is a novel microbial rhodopsin recently discovered in the freshwater cyanobacterium Anabaena sp. PCC7120. This protein most likely functions as a photosensory receptor as do the related haloarchaeal sensory rhodopsins. However, unlike the archaeal pigments, which are tightly bound to their cognate membrane-embedded transducers, ASR interacts with a soluble cytoplasmic protein analogous to transducers of animal vertebrate rhodopsins. In this study, infrared spectroscopy was used to examine the molecular mechanism of photoactivation in ASR. Light adaptation of the pigment leads to a phototransformation of an all-trans/15-anti to 13-cis/15-syn retinylidene-containing species very similar in chromophore structural changes to those caused by dark adaptation in bacteriorhodopsin. Following 532 nm laser-pulsed excitation, the protein exhibits predominantly an all-trans retinylidene photocycle containing a deprotonated Schiff base species similar to those of other microbial rhodopsins such as bacteriorhodopsin, sensory rhodopsin II, and Neurospora rhodopsin. However, no changes are observed in the Schiff base counterion Asp-75, which remains unprotonated throughout the photocycle. This result along with other evidence indicates that the Schiff base proton release mechanism differs significantly from that of other known microbial rhodopsins, possibly because of the absence of a second carboxylate group at the ASR photoactive site. Several conformational changes are detected during the ASR photocycle including in the transmembrane helices E and G as indicated by hydrogen-bonding alterations of their native cysteine residues. In addition, similarly to animal vertebrate rhodopsin, perturbations of the polar head groups of lipid molecules are detected.


A sexually dimorphic pattern of growth hormone secretion in the elderly.
In rodents, the sexually dimorphic pattern of pulsatile GH secretion is an important determinant of growth, liver enzyme function and insulin-like growth factor I (IGF-I) expression. Whether this difference is present in humans at different ages is unclear. We studied GH secretory patterns in the elderly by constructing 24-h serum GH profiles in 45 male and 38 female (age, 59.4-73.0 yr) volunteers and related patterns to IGF-I, IGF-binding protein-3 (IGFBP-3), and GH-binding protein levels; body mass index; and waist/hip ratio. Serum GH concentrations were measured in samples drawn at 20-min intervals and analyzed using a sensitive chemiluminescent assay (Nichols Institute Diagnostics: sensitivity, 0.036 mU/L). The 24-h serum GH profiles were analyzed using a concentration distribution method to determine GH peak and trough levels, spectral analysis, and assessment of serial irregularity by approximate entropy (ApEn). There was a highly significant difference in mean 24-h serum GH concentrations in females compared to males (males, 0.88 mU/L; females, 1.31 mU/L; P = 0.009) as a result of significantly higher trough GH levels (males, 0.04 mU/L; females, 0.16 mU/L; P < 0.001). Peak values were not significantly different. Serum IGF-I levels were significantly higher in males (males, 162.4 ng/mL; females, 87.8 ng/ mL; P < 0.001). Peak GH values were related to serum IGF-I levels (males: r = 0.39; P = 0.009; females: r = 0.5; P = 0.002), whereas trough GH levels were not. IGFBP-3 levels were similar and related to GH peaks only in males (r = 0.32; P = 0.03). GH was secreted with a dominant periodicity of 200 min in males and 280 min in females (P < 0.025). The proportion of time taken up by regular oscillatory activity was less in females (females, 11.1%; males, 14.7%; P = 0.01). GH secretion assessed by ApEn was more disordered in females (males, 0.60; females, 0.81; P < 0.001), and increasing disorder was associated with lower IGF-I levels. Body mass index was negatively related to GH in both sexes. In males, trough values were the major determinant (r = -0.31; P = 0.04), whereas in females, the peak value was the major determinant (r = 0.35; P = 0.04). Trough GH levels were inversely related in both sexes to waist/hip ratio (males: r = -0.40; P = 0.006; females: r = -0.44; P = 0.006) and to increasing secretory disorder (ApEn; r = -0.46; P < 0.001). These data demonstrate a sexually dimorphic pattern of GH secretion in the elderly.


Risk factors associated with musculoskeletal disorders of the neck and shoulder in the personnel of Kerman University of Medical Sciences.
Musculoskeletal disorders (MSDs) of the neck and shoulder are the most common and most influential factors causing disorder in the performance and absenteeism of work in administrative personnel. To identify risk factors which affect musculoskeletal disorders of neck and shoulder areas in headquarters staff of Kerman University of Medical Sciences. The present cross-sectional study was conducted in 2015 on 282 headquarters personnel of Kerman University of Medical Sciences (Kerman, Iran). The desired headquarters staff were selected from seven Deputy Vice-Chancellors of Kerman University of Medical Sciences, including Deputy of Health; Deputy of Treatment; Deputy of Education; Deputy of Students and Cultural Affairs; Deputy of Food and Drugs; Deputy of Management Development and Resource Planning; Deputy of Research and Technology, and data were gathered by using a standard Nordic musculoskeletal questionnaire NMQ (Nordic) and were analyzed by using SPSS version 16. The impact of various factors on the most common complications (neck and shoulder pains) was analyzed separately through logistic regression analysis and detailed Odds Ratio (OR) was calculated for each individual. The occurrence of neck and shoulder pains in headquarters staff were 42.14% and 40.71%, respectively. In the prevalence of neck pain variables such as marital status (single than married p=0.01, OR=0.24), work experience (p=0.03, OR=1.07 ), education (bachelor's degree and lower than master's degree and higher p=0.003, OR=2.69), right / left-handedness (left than right p=0.03, OR=0.33), weight (p=0.04, OR=1.04), place of work (p<0.05); as well as in the prevalence of shoulder pain variables such as marital status (single than married p=0.04, OR=0.48), work experience (p=0.01, OR=1.20), education (bachelor and lower than master and higher p=0.04, OR=1.97), right / left handedness (left than right p=0.01, OR=0.42), age (p=0.02, OR=1.05), and gender (male than female p=0.03, OR=0.65) affected. The results of this study showed that the prevalence of neck and shoulder pains is influenced by various risk factors and some of which were identified and an amount of their influence in this study was found. Therefore, it is suggested by considering the risk factors and planning control programs, a major step is taken in reducing the musculoskeletal disorders of office staff.


1.01 kW superfluorescent source in all-fiberized MOPA configuration.
We present a high power all-fiberized master oscillator power amplifier (MOPA) structured superfluorescent source based on dual-cladding ytterbium-doped fiber. The seed source is a 0.814 W homemade amplified spontaneous emission (ASE) source. Two-stage high power fiber amplifier is utilized to boost the seed power to 1.01 kW with a beam quality of M(x)(2) = 1.688 and M(y)(2) = 1.728. The central wavelength of the output light is 1074.4 nm, and the full width at half maximum (FWHM) linewidth is about 8.1 nm. No self pulsing or relaxation oscillation effect is observed and the power fluctuation is less than 2% in 100 seconds continuous operating. In additional, spectral evolution effects of central-wavelength-drifting and linewidth-narrowing of broadband amplification in high power superfluorescent source system are investigated. To the best of our knowledge, this is the first demonstration of an all-fiberized superfluorescent source with output power exceeding kilowatt.


Noma (cancrum oris): case report in a 4-year-old HIV-positive South African child.
Cancrum oris (noma) is a gangrenous infection that develops in the mouth and spreads rapidly to other parts of the face. The disease occurs mostly in conditions of poverty, poor hygiene and malnutrition. In sub-Saharan Africa the frequency in several countries is estimated to be 1-7 cases per 1,000 population, and as many as 12 cases per 1,000 in the most affected communities. About 90% of these children die without receiving any care, yet the disease can, and should, be prevented. With increasing numbers of children who are malnourished and who have compromised immune systems (compounded by the HIV pandemic) the prevalence of conditions such as noma is likely to increase. Among the earliest features of noma are excessive salivation, marked fetor oris, facial oedema and a greyish-black discolouration of the skin in the affected area. This devastating gangrenous lesion may involve the cheek, the chin, the infra-orbital margin, palate, nose, antrum and virtually any part of the face. This report describes a 4-year-old HIV-positive African girl, who was abandoned, discharged from the Plastics Unit and now lives in a child care sanctuary. Little is known about her history prior to her arrival at the home a few weeks previously. The clinical examination revealed a delay in growth and physical development equivalent to that of a 2-year-old child. The left cheek had a perforating ulcer in a healing phase. The perforation, about 1 cm in diameter, was surrounded by oedematous tissues showing a mild to moderate erythema. The peripheral oedema extended to the lower palpebral, the upper labial, left labial commissural, mandibular and pre-parotid regions. Submental, submandibular and cervical lymph nodes were mildly painful upon palpation. The child was not pyretic. The intra-oral examination revealed the features of acute necrotising gingivitis (ANG). ANG was generalised and showed classic interdental crater-like ulcers covered with whitish debris. Halitosis was pronounced. Examination of the second quadrant revealed a large ulcer extending from the distal aspect of the deciduous canine to the distal aspect of the second deciduous molar. The adjacent palatal mucosa was severely oedematous. The alveolar bone supporting the first and the second molars was completely exposed to the fundus of the vestibulum. It was not possible to obtain intraoral photographs or radiographs. Chlorhexidine gluconate (0.2% solution) and metronidazole tablets, 200 mg twice daily for 15 days were prescribed. The child was seen every alternate day for 10 days and her condition improved rapidly. Halitosis had subsided. She was then referred to the Johannesburg Hospital for further treatment under general anaesthesia. The proposed treatment plan was as follows: removal of dental accretions and polishing of all teeth, extraction of the left maxillary teeth supported by non-vital bone, resection of the necrotic bone in the left maxilla and reconstructive surgery in the left cheek.


Role of Galectins in Allergic Disorders.
Allergen avoidance, pharmacotherapy; with antihistamines, anti-leukotrienes, corticosteroids and bronchodilators.as well as monoclonal antibodies; and allergen specific immunotherapy stand as confirmed approaches for the management of allergic disorders as asthma, allergic rhinitis/rhinoconjunctivitis, atopic dermatitis, food allergies and anaphylaxis. Galectins are members of animal lectin protein family, with binding specificity for β-galactoside sugars. These highly conserved proteins are known to be expressed in various effector cells of the immune system, exert immuno-regulatory activities, and enroll in tissue inflammation and regulation of immune homeostasis. This review aims to explain the galectin family and influence of galectins in the immune mechanisms of allergic disorders. Galectins have multiple roles in innate and adaptive immunity. Intense research in the field of immunology related with galectins have given rise to several patent applications. Those, increasing in vivo efficacy of galectins for therapeutic applications, utilizing galectins for immune stimulation and prolongation of immune responses, utilization of them as disease markers are pioneers. As immune cells can be targeted by galectins, cells containing these molecules can be used for immune intervention. Regulation of cytokine productions by immune cells as IL-1β and IL-10 as well as dendritic cell functions by galectins may be efficient in limitation of some immune-mediated disorders. Taken all together, better learning of galectin biology together with detailed revealing of galectin-immune system interactions have great potential for immune interventions targeting allergy-related disorders.


Elevated rates of testosterone-related disorders in women with autism spectrum conditions.
The androgen theory of autism proposes that autism spectrum conditions (ASC) are in part due to elevated fetal testosterone (FT) levels, which are positively correlated with a number of autistic traits and inversely correlated with social development and empathy. A medical questionnaire was completed by n=54 women with ASC, n=74 mothers of children with ASC, and n=183 mothers of typically developing children to test whether women with ASC have an increased rate of testosterone-related medical conditions, and to see whether mothers of children with ASC show similar abnormalities, as part of the 'broader autism phenotype'. Compared to controls, significantly more women with ASC reported (a) hirsutism, (b) bisexuality or asexuality, (c) irregular menstrual cycle, (d) dysmenorrhea, (e) polycystic ovary syndrome, (f) severe acne, (g) epilepsy, (h) tomboyism, and (i) family history of ovarian, uterine, and prostate cancers, tumors, or growths. Compared to controls, significantly more mothers of ASC children reported (a) severe acne, (b) breast and uterine cancers, tumors, or growths, and (c) family history of ovarian and uterine cancers, tumors, or growths. These results suggest current hormone abnormalities in women with ASC and their mothers. Direct investigations of serum testosterone levels and genetic susceptibility to high testosterone production or sensitivity in women with ASC would illuminate the origin of these conditions. The relationship between FT and current testosterone levels also needs to be clarified. The present results may be relevant to understanding the increased male risk to developing autism.


The Caenorhabditis elegans centrosomal protein SPD-2 is required for both pericentriolar material recruitment and centriole duplication.
The centrosome is composed of a centriole pair and pericentriolar material (PCM). By marking the site of PCM assembly, the centrioles define the number of centrosomes present in the cell. The PCM, in turn, is responsible for the microtubule (MT) nucleation activity of centrosomes. Therefore, in order to assemble a functional bipolar mitotic spindle, a cell needs to control both centriole duplication and PCM recruitment. To date, however, the molecular mechanisms that govern these two processes still remain poorly understood. Here we show that SPD-2 is a novel component of the C. elegans centrosome. SPD-2 localizes to the centriole throughout the cell cycle and accumulates on the PCM during mitosis. We show that SPD-2 requires SPD-5 for its accumulation on the PCM and that in the absence of SPD-2, centrosome assembly fails. We further show that centriole duplication is also defective in spd-2(RNAi) embryos, but not in spd-5(RNAi) embryos, where PCM recruitment is efficiently blocked. Taken together, our results suggest that SPD-2 may link PCM recruitment and centriole duplication in C. elegans. SPD-2 shares homology with a human centrosome protein, suggesting that this key component of the C. elegans centrosome is evolutionarily conserved.


Using voluntary motor commands to inhibit involuntary arm movements.
A hallmark of voluntary motor control is the ability to stop an ongoing movement. Is voluntary motor inhibition a general neural mechanism that can be focused on any movement, including involuntary movements, or is it mere termination of a positive voluntary motor command? The involuntary arm lift, or 'floating arm trick', is a distinctive long-lasting reflex of the deltoid muscle. We investigated how a voluntary motor network inhibits this form of involuntary motor control. Transcranial magnetic stimulation of the motor cortex during the floating arm trick produced a silent period in the reflexively contracting deltoid muscle, followed by a rebound of muscle activity. This pattern suggests a persistent generator of involuntary motor commands. Instructions to bring the arm down voluntarily reduced activity of deltoid muscle. When this voluntary effort was withdrawn, the involuntary arm lift resumed. Further, voluntary motor inhibition produced a strange illusion of physical resistance to bringing the arm down, as if ongoing involuntarily generated commands were located in a 'sensory blind-spot', inaccessible to conscious perception. Our results suggest that voluntary motor inhibition may be a specific neural function, distinct from absence of positive voluntary motor commands.


Exploring 'generative mechanisms' of the antiretroviral adherence club intervention using the realist approach: a scoping review of research-based antiretroviral treatment adherence theories.
Poor retention in care and non-adherence to antiretroviral therapy (ART) continue to undermine the success of HIV treatment and care programmes across the world. There is a growing recognition that multifaceted interventions - application of two or more adherence-enhancing strategies - may be useful to improve ART adherence and retention in care among people living with HIV/AIDS. Empirical evidence shows that multifaceted interventions produce better results than interventions based on a singular perspective. Nevertheless, the bundle of mechanisms by which multifaceted interventions promote ART adherence are poorly understood. In this paper, we reviewed theories on ART adherence to identify candidate/potential mechanisms by which the adherence club intervention works. We searched five electronic databases (PubMed, EBSCOhost, CINAHL, PsycARTICLES and Google Scholar) using Medical Subject Headings (MeSH) terms. A manual search of citations from the reference list of the studies identified from the electronic databases was also done. Twenty-six articles that adopted a theory-guided inquiry of antiretroviral adherence behaviour were included for the review. Eleven cognitive and behavioural theories underpinning these studies were explored. We examined each theory for possible 'generative causality' using the realist evaluation heuristic (Context-Mechanism-Outcome) configuration, then, we selected candidate mechanisms thematically. We identified three major sets of theories: Information-Motivation-Behaviour, Social Action Theory and Health Behaviour Model, which explain ART adherence. Although they show potential in explaining adherence bebahiours, they fall short in explaining exactly why and how the various elements they outline combine to explain positive or negative outcomes. Candidate mechanisms indentified were motivation, self-efficacy, perceived social support, empowerment, perceived threat, perceived benefits and perceived barriers. Although these candidate mechanisms have been distilled from theories employed to explore adherence to ART in various studies, the theories by themselves do not provide an explanatory model of adherence based on the realist logic. The identified theories and candidate mechanisms offer possible generative mechanisms to explain how and why patients adhere (or not) to antiretroviral therapy. The study provides crucial insights to understanding how and why multifaceted adherence-enhancing interventions work (or not). These findings have implications for eliciting programme theories of group-based adherence interventions such as the adherence club intervention.


mPFC spindle cycles organize sparse thalamic activation and recently active CA1 cells during non-REM sleep.
Sleep oscillations in the neocortex and hippocampus are critical for the integration of new memories into stable generalized representations in neocortex. However, the role of the thalamus in this process is poorly understood. To determine the thalamic contribution to non-REM oscillations (sharp-wave ripples, SWRs; slow/delta; spindles), we recorded units and local field potentials (LFPs) simultaneously in the limbic thalamus, mPFC, and CA1 in rats. We report that the cycles of neocortical spindles provide a key temporal window that coordinates CA1 SWRs with sparse but consistent activation of thalamic units. Thalamic units were phase-locked to delta and spindles in mPFC, and fired at consistent lags with other thalamic units within spindles, while CA1 units that were active during spatial exploration were engaged in SWR-coupled spindles after behavior. The sparse thalamic firing could promote an incremental integration of recently acquired memory traces into neocortical schemas through the interleaved activation of thalamocortical cells.


Case-only Methods Identified Genetic Loci Predicting a Subgroup of Men with Reduced Risk of High-grade Prostate Cancer by Finasteride.
In the Prostate Cancer Prevention Trial (PCPT), genotypes that may modify the effect of finasteride on the risk of prostate cancer have not been identified. Germline genetic data from 1,157 prostate cancer cases in PCPT were analyzed by case-only methods. Genotypes included 357 SNPs from 83 candidate genes in androgen metabolism, inflammation, circadian rhythm, and other pathways. Univariate case-only analysis was conducted to evaluate whether individual SNPs modified the finasteride effect on the risk of high-grade and low-grade prostate cancer. Case-only classification trees and random forests, which are powerful machine learning methods with resampling-based controls for model complexity, were employed to identify a predictive signature for genotype-specific treatment effects. Accounting for multiple testing, a single SNP in SRD5A1 gene (rs472402) significantly modified the finasteride effect on high-grade prostate cancer (Gleason score > 6) in PCPT (family-wise error rate < 0.05). Men carrying GG genotype at this locus had a 55% reduction of the risk in developing high-grade cancer when assigned to finasteride (RR = 0.45; 95% confidence interval, 0.27-0.75). Additional effect-modifying SNPs with moderate statistical significance were identified by case-only trees and random forests. A prediction model built by the case-only random forest method with 28 selected SNPs classified 37% of PCPT men to have reduced risk of high-grade prostate cancer when taking finasteride, while the others have increased risk. In conclusion, case-only methods identified SNPs that modified the effect of finasteride on the risk of high-grade prostate cancer and predicted a subgroup of men who had reduced cancer risk by finasteride.


The Impact of Microsatellite Instability Status and Sidedness of the Primary Tumor on the Effect of Cetuximab-Containing Chemotherapy in Patients with Metastatic Colorectal Cancer.
Background: Colorectal cancer (CRC) has been reconsidered as a heterogeneous disease. Among advances of genomic analysis in CRC, the sidedness of tumors (left-sided colon vs. right-sided colon) and microsatellite instability (MSI)-high (H) tumors have been highlighted. Methods: We analyzed 153 CRC patients who were available for evaluation of MSI status and had been treated with cetuximab-containing chemotherapy between April 2008 and January 2013. KRAS mutational status was available in all 153 patients, but BRAF mutational status was only available in 72 patients (47.1%). We evaluated the impact of microsatellite instability status and location of the primary colon tumor on the effect of cetuximab-containing chemotherapy in patients with metastatic colorectal cancer. Results: MSI-H was detected in 3.9% of analyzed patients. Characteristics of patients, with the exception of BRAF mutational status, were generally similar between those with right and left-sided tumors. Right-sided tumors were significantly associated with a BRAF mutation (p=0.023). In addition, patient characteristics with an MSS tumor were not different from those with an MSI-H tumor. For all 153 patients, the most commonly used regimen that included cetuximab was irinotecan alone, irrespective of treatment line. There was no significant difference in treatment efficacy in either RR or disease control rate (DCR) between the MSI-H and MSS groups. There was also no difference in RR and DCR according to the location of the primary tumor (left side vs. right side). No significant difference in PFS was observed between the MSI-H and MSS groups (4.80 months vs. 5.80 months; p=0.238) or the left-side and right-side groups (6.10 months vs. 4.20 months; p=0.278). In a subgroup-analysis of 140 patients with wild-type KRAS, there was no difference in PFS following cetuximab-containing therapy based on MSI status or the location of the primary tumor. Conclusions: MSI status and the location of the primary tumor were not novel biomarkers for response to cetuximab-containing therapy in metastatic CRC. Further prospective validation of the prognostic or predictive capacity of MSI status and the sidedness of tumors is warranted.


Development of hyperplastic polyps following argon plasma coagulation of gastric antral vascular ectasia.
The etiology of gastric antral vascular ectasia (GAVE) syndrome or gastric hyperplastic polyps (HPs) is not fully understood. We report a case of gastric HP arising in a patient treated with argon plasma coagulation (APC) for GAVE syndrome. Despite unclear etiologic progression, this and previously reported cases suggest a temporal relationship between the treatment of GAVE and HP. A 68-year-old male with a history of coronary artery disease, congestive heart failure and diabetes type II who initially presented with symptomatic anemia 2 weeks after starting aspirin and clopidogrel therapy. Diagnostic esophagogastroduodenoscopy (EGD) demonstrated diffuse GAVE. He was treated with 5 APC treatments, at 6-week intervals, over a 30 weeks period. 16 months after the initial APC treatment, an EGD performed secondary to persistent anemia demonstrated innumerable, large, bleeding polyps in the gastric antrum. Biopsy performed at that time confirmed hyperplastic gastric polyps. It has been proposed that HPs are regenerative lesions that arise at sites of severe mucosal injury. Our patient's treatment of GAVE with APC created significant mucosal injury, resulting in HP. Technique and genetic factors may have promoted hyperplastic changes during the regeneration of mucosa, at sites previously treated with APC. This case highlights the potential progression of GAVE to HP in a patient with persistent anemia after APC therapy.


Cloning and subcellular location of an Arabidopsis receptor-like protein that shares common features with protein-sorting receptors of eukaryotic cells.
Many receptors involved in clathrin-mediated protein transport through the endocytic and secretory pathways of yeast and animal cells share common features. They are all type I integral membrane proteins containing cysteine-rich lumenal domains and cytoplasmic tails with tyrosine-containing sorting signals. The cysteine-rich domains are thought to be involved in ligand binding, whereas the cytoplasmic tyrosine motifs interact with clathrin-associated adaptor proteins during protein sorting along these pathways. In addition, tyrosine-containing signals are required for the retention and recycling of some of these membrane proteins to the trans-Golgi network. Here we report the characterization of an approximately 80-kD epidermal growth factor receptor-like type I integral membrane protein containing all of these functional motifs from Arabidopsis thaliana (called AtELP for A. thaliana Epidermal growth factor receptor-Like Protein). Biochemical analysis indicates that AtELP is a membrane protein found at high levels in the roots of both monocots and dicots. Subcellular fractionation studies indicate that the AtELP protein is present in two membrane fractions corresponding to a novel, undefined compartment and a fraction enriched in vesicles containing clathrin and its associated adaptor proteins. AtELP may therefore serve as a marker for compartments involved in intracellular protein trafficking in the plant cell.


Identifying market risk for substandard and falsified medicines: an analytic framework based on qualitative research in China, Indonesia, Turkey and Romania.
Introduction: Substandard and falsified medicines undermine health systems. We sought to unravel the political and economic factors which drive the production of these products, and to explain how they reach patients. Methods: We conducted in-depth case studies in China, Indonesia, Turkey and Romania. We reviewed academic papers and press reports (n = 840), developing semi-structured questionnaires. We interviewed regulators, policy-makers, pharmaceutical manufacturers, physicians, pharmacists, patients and academics (n=88). We coded data using NVivo software, and developed an analytic framework to assess national risks for substandard and falsified medicines. We tested the framework against cases reported to the World Health Organization, from countries at all income levels. Results: We found that increasing political commitment to provision of universal health coverage has led to public procurement policies aimed at lowering prices of medical products. In response, legitimate, profit-driven pharmaceutical companies protect their margins by cutting costs, or withdrawing from less profitable markets, while distributors engage in arbitrage. Meanwhile, health providers sometimes protect profits by 'upselling' patients to medicines not covered by insurers. Cost-cutting can undermine quality assurance, leading to substandard or degraded medicines. Other responses contribute to shortages, irrational demand and high prices. All of these provide market opportunities for producers of falsified products; they also push consumers outside of the regular supply chain, providing falsifiers with easy access to customers. The analytic framework capturing these interactions explained cases in most high and middle-income settings; additional factors operate in the poorest countries. Conclusions: Most efforts to secure medicine quality currently focus on product regulation. However, our research suggests market mechanisms are key drivers for poor quality medicines, including where political commitments to universal health coverage are under-resourced. We have developed a framework to guide country-specific, system-wide analysis. This can flag risks and pinpoint specific actions to protect medicine quality, and thus health.


Time to re-appraise the role of alpha-1 adrenoceptor antagonists in the management of hypertension?
The role of alpha-1 adrenoceptor antagonists (alpha-blockers) in the management of hypertension continues to evolve. Recent data support their use as add-on therapy in uncontrolled hypertension when used in combination with all other major classes of antihypertensive drug and there is increasing evidence suggesting that they have modest but significant beneficial effects on lipid and glucose metabolism. The availability of extended-release formulations has contributed to an excellent tolerability profile. New data from an observational analysis of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) suggest that doxazosin gastrointestinal therapeutic system (GITS) used as a third-line antihypertensive agent lowered blood pressure and caused modest reductions in plasma lipids. Furthermore, use of doxazosin in ASCOT was not associated with an increased risk of heart failure, in contrast to the earlier finding of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Overall, currently available data support the use of alpha-blockers as safe, well tolerated and effective add-on antihypertensive drugs, which have additional favourable metabolic effects.


EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update.
To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost.


CRY1 Variations Impacts on the Depressive Relapse Rate in a Sample of Bipolar Patients.
A relevant part of the social and personal burden caused by Bipolar Disorder (BD) is related to depressive phases. Authors investigated the genetic impact of a set of variations located in CRY1, a gene involved in the control of the circadian rhythms, towards depressive episodes in a sample of bipolar patients from the STEP-BD sample. As a secondary analysis, CYR1 variations were analyzed as predictors of sleep disruption. 654 bipolar patients were included in the analysis. Data were available genome-wide. The part of the genome coding for the CRY1 was imputed and pruned according to standards in the field. 7 SNPs were available for the analysis. A correction for multitesting was applied and we had sufficient power (0.80) to detect a small-medium effect size (0.22) between two allelic frequencies each one represented by at least 300 subjects. Intronic rs10861688 was associated with the number of depressive events corrected for the times patients were assessed during the period of observation. In particular, AA subjects (n=21) had 4.46±3.15 events, AG (n=141) had 3.08±3.17 and GG (n=342) 2.65±2.97 (p=0.0048, beta=-0.22). No other significant associations were reported. We bring further evidence that genes involved in the regulation of circadian rhythms may be relevant to depressive bipolar phases. Independent confirmation analyses are mandatory.


Biochemical and functional characterization of recombinant fungal immunomodulatory proteins (rFIPs).
In this study, two novel FIPs have been identified and characterized. The first is FIP-nha, identified in the ascomycete Nectria haematococca, and as such, FIP-nha would be the first FIP to be identified outside the order of Basidiomycota. The second is LZ-9, an LZ-8 like protein identified in Ganoderma lucidum. Recombinant FIPs (rFIPs) were produced in Pichia pastoris and purified using His-affinity magnetic beads. The bioactive characteristics of FIP-nha and LZ-9 were compared to the well-known FIPs, LZ-8 from G. lucidum and FIP-fve from Flammulina velutipes, which were produced and purified using the same method. The produced rFIPs: rLZ-8, rLZ-9, rFIP-fve and rFIP-nha were investigated for their hemagglutinating activity which revealed that rLZ-8, rLZ-9 and rFIP-nha were able to agglutinate rabbit, mouse and sheep red blood cells while rFIP-fve only agglutinated rabbit red blood cells. None of the rFIPs were able to agglutinate human red blood cells unless the cells were trypsinized. In addition, all rFIPs were studied and compared to several lectins for their effect on Caco-2 intestinal cell layer integrity using transepithelial electrical resistance (TEER) measurement. rLZ-9 appeared to have the highest effect in lowering TEER, similar to one of the tested lectins. Testing of rFIPs for their activation of inflammation-related genes of THP-1 macrophages showed rFIP-fve to be the strongest inducer of pro-inflammatory cytokine transcription. These results indicate that each rFIP has a unique bioactive profile as well as each lectin, creating the basis for further studies to relate structure to biological activity.


Positional clustering improves computational binding site detection and identifies novel cis-regulatory sites in mammalian GABAA receptor subunit genes.
Understanding transcription factor (TF) mediated control of gene expression remains a major challenge at the interface of computational and experimental biology. Computational techniques predicting TF-binding site specificity are frequently unreliable. On the other hand, comprehensive experimental validation is difficult and time consuming. We introduce a simple strategy that dramatically improves robustness and accuracy of computational binding site prediction. First, we evaluate the rate of recurrence of computational TFBS predictions by commonly used sampling procedures. We find that the vast majority of results are biologically meaningless. However clustering results based on nucleotide position improves predictive power. Additionally, we find that positional clustering increases robustness to long or imperfectly selected input sequences. Positional clustering can also be used as a mechanism to integrate results from multiple sampling approaches for improvements in accuracy over each one alone. Finally, we predict and validate regulatory sequences partially responsible for transcriptional control of the mammalian type A gamma-aminobutyric acid receptor (GABA(A)R) subunit genes. Positional clustering is useful for improving computational binding site predictions, with potential application to improving our understanding of mammalian gene expression. In particular, predicted regulatory mechanisms in the mammalian GABA(A)R subunit gene family may open new avenues of research towards understanding this pharmacologically important neurotransmitter receptor system.


Decline in rate of death from ischaemic heart disease in the United Kingdom.
The rates of death from ischaemic heart disease in the United Kingdom in the years after 1968 were studied to establish whether any general trend had occurred. A decline in the rates began after 1973-4, was greatest in those aged 35-44 years, and occurred among both men and women and in each of the regions of England and in Wales and Scotland. Total dietary fat intake had started to fall about five years earlier, and this may provide part of the explanation. Changes in smoking habits also occurred but were more difficult to relate to the pattern of change in the death rates. If a general decline in ischaemic heart disease has begun in the United Kingdom a case may be made for close monitoring of changes in lifestyle and medical practice in different demographic groups to try to find the explanation.


Effects of pre- or post-exercise low-level laser therapy (830 nm) on skeletal muscle fatigue and biochemical markers of recovery in humans: double-blind placebo-controlled trial.
The purpose of this study was to investigate the effect of low-level laser therapy (LLLT) before and after exercise on quadriceps muscle performance, and to evaluate the changes in serum lactate and creatine kinase (CK) levels. The study was randomized, double blind, and placebo controlled. A sample of 27 healthy volunteers (male soccer players) were divided into three groups: placebo, pre-fatigue laser, and post-fatigue laser. The experiment was performed in two sessions, with a 1 week interval between them. Subjects performed two sessions of stretching followed by blood collection (measurement of lactate and CK) at baseline and after fatigue of the quadriceps by leg extension. LLLT was applied to the femoral quadriceps muscle using an infrared laser device (830 nm), 0.0028 cm(2) beam area, six 60 mW diodes, energy of 0.6 J per diode (total energy to each limb 25.2 J (50.4 J total), energy density 214.28 J/cm(2), 21.42 W/cm(2) power density, 70 sec per leg. We measured the time to fatigue and number and maximum load (RM) of repetitions tolerated. Number of repetitions and time until fatigue were primary outcomes, secondary outcomes included serum lactate levels (measured before and 5, 10, and 15 min after exercise), and CK levels (measured before and 5 min after exercise). The number of repetitions (p=0.8965), RM (p=0.9915), and duration of fatigue (p=0.8424) were similar among the groups. Post-fatigue laser treatment significantly decreased the serum lactate concentration relative to placebo treatment (p<0.01) and also within the group over time (after 5 min vs. after 10 and 15 min, p<0.05 both). The CK level was lower in the post-fatigue laser group (p<0.01). Laser application either before or after fatigue reduced the post-fatigue concentrations of serum lactate and CK. The results were more pronounced in the post-fatigue laser group.


Common stressful life events and difficulties are associated with mental health symptoms and substance use in young adolescents.
Stressful life events are associated with mood disorders in adults in clinical settings. Less described in the literature is the association between common life stressors and a wide range of psychopathology in young adolescents. This study uses a large non-clinical sample of young adolescents to describe the associations among worry or stress about common life events/difficulties, mental health and substance use. Data on lifetime stress or worry about common life events/difficulties (i.e., romantic breakups, family disruption, interpersonal difficulties, and personal stress (health, weight, school work)), symptoms of depression, conduct disorder symptoms, and substance use were collected from 1025 grade 7 students (mean age 12.9 years; 45% male). The association between each source of stress and each mental health and substance use indicator was modeled in separate logistic regression analyses. The proportion of adolescents reporting worry or stress ranged from 7% for new family to 53% for schoolwork. Romantic breakup stress was statistically significantly associated with all the mental health and substance use indicators except illicit drug use. Family disruption was statistically significantly associated with depression symptoms, marijuana use, and cigarette use. Interpersonal difficulties stress was statistically significantly associated with depression symptoms. All sources of personal stress were statistically significantly related to depression symptoms. In addition, health-related stress was inversely related to binge drinking. Young adolescents may benefit from learning positive coping skills to manage worry or stress about common stressors and in particular, worry or stress related to romantic breakups. Appropriate management of mental health symptoms and substance use related to common stressful life events and difficulties may help reduce emerging psychopathology.


Surveillance for laboratory-confirmed sporadic cases of cyclosporiasis--United States, 1997-2008.
Cyclosporiasis is an enteric disease caused by the parasite Cyclospora cayetanensis. Cyclosporiasis is reported most commonly in tropical and subtropical regions. In the United States, outbreaks of cyclosporiasis associated with various types of imported fresh produce have been documented and described since the mid-1990s. No molecular tools are available for linking C. cayetanensis cases. National data regarding laboratory-confirmed sporadic cases (i.e., cases not linked to documented outbreaks) have not been summarized previously. This summary includes laboratory-confirmed sporadic cases that occurred during 1997-2008 and were reported to CDC by 2009. In January 1999, cyclosporiasis became a nationally notifiable disease, and, as of 2008, it was a reportable condition in 37 states, New York City (NYC), and the District of Columbia. For 1997-2008, CDC was notified of laboratory-confirmed cases via two active surveillance systems (the Cyclospora Sentinel Surveillance Network and the Foodborne Diseases Active Surveillance Network), two passive systems (the National Notifiable Diseases Surveillance System and the Public Health Laboratory Information System), and informal mechanisms (e.g., electronic mail). CDC was notified of 1,110 laboratory-confirmed sporadic cases of cyclosporiasis that occurred during 1997-2008. The overall population-adjusted incidence rates ranged from a low of 0.01 cases per 100,000 persons in 1997 to a high of 0.07 in 2002. Of the 1,110 cases, 849 (76.5%) were reported by seven states: 498 (44.9%) occurred in residents of Florida (228 cases), NYC (200 cases), and elsewhere in New York state (70 cases); and >50 cases were reported by each of five other states (Connecticut, Georgia, Massachusetts, New Jersey, and Pennsylvania). Overall, the case-patients' median age was 44 years (range: 3 months-96 years); 50.5% were female, 47.2% were male, and the sex was unknown for 2.3%. A total of 372 case-patients (33.5%) had a documented history of international travel during the 2-week period before symptom onset or diagnosis, 398 (35.9%) reported no international travel, and 340 (30.6%) had an unknown travel history. Some details about the travel were available for 317 (85.2%) of the case-patients with a known history of international travel; 142 (44.8%) had traveled to Mexico (60 persons), Guatemala (44 persons), or Peru (38 persons). Among the 398 case-patients classified as having domestically acquired cases, 124 persons (31.2%) lived in Florida, and 64 persons (16.1%) lived either in NYC (49 persons) or elsewhere in New York state (15 persons). The majority (278 [69.8%]) of onset or diagnosis dates for domestically acquired cases occurred during April-August. Approximately one third of cases occurred in persons with a known history of international travel who might have become infected while traveling outside the continental United States. Domestically acquired cases were concentrated in time (spring and summer) and place (eastern and southeastern states): some of these cases probably were outbreak associated but were not linked to other cases, in part because of a lack of molecular tools. Surveillance for cases of cyclosporiasis and research to develop molecular methods for linking seemingly sporadic cases should remain U.S. public health priorities, in part to facilitate identification and investigation of outbreaks and to increase understanding of the biology of Cyclospora and the epidemiology of cyclosporiasis. Unidentified, uninvestigated cases and outbreaks represent missed opportunities to identify vehicles of infection, modes of contamination, and preventive measures. Travelers to known areas of endemicity should be advised that food and water precautions for Cyclospora are similar to those for other enteric pathogens, except that this parasite is unlikely to be killed by routine chemical disinfection or sanitizing methods. The diagnosis of cyclosporiasis should be considered for persons with persistent or remitting-relapsing diarrheal illness, and testing for Cyclospora should be requested explicitly.


Assessment strategies for municipal selective waste collection schemes.
An important strategy to promote a strong sustainable growth relies on an efficient municipal waste management, and phasing out waste landfilling through waste prevention and recycling emerges as a major target. For this purpose, effective collection schemes are required, in particular those regarding selective waste collection, pursuing a more efficient and high quality recycling of reusable materials. This paper addresses the assessment and benchmarking of selective collection schemes, relevant to guide future operational improvements. In particular, the assessment is based on the monitoring and statistical analysis of a core-set of performance indicators that highlights collection trends, complemented with a performance index that gathers a weighted linear combination of these indicators. This combined analysis underlines a potential tool to support decision makers involved in the process of selecting the collection scheme with best overall performance. The presented approach was applied to a case study conducted in Oporto Municipality, with data gathered from two distinct selective collection schemes.


Proteomic analysis of Clostridium thermocellum core metabolism: relative protein expression profiles and growth phase-dependent changes in protein expression.
Clostridium thermocellum produces H2 and ethanol, as well as CO2, acetate, formate, and lactate, directly from cellulosic biomass. It is therefore an attractive model for biofuel production via consolidated bioprocessing. Optimization of end-product yields and titres is crucial for making biofuel production economically feasible. Relative protein expression profiles may provide targets for metabolic engineering, while understanding changes in protein expression and metabolism in response to carbon limitation, pH, and growth phase may aid in reactor optimization. We performed shotgun 2D-HPLC-MS/MS on closed-batch cellobiose-grown exponential phase C. thermocellum cell-free extracts to determine relative protein expression profiles of core metabolic proteins involved carbohydrate utilization, energy conservation, and end-product synthesis. iTRAQ (isobaric tag for relative and absolute quantitation) based protein quantitation was used to determine changes in core metabolic proteins in response to growth phase. Relative abundance profiles revealed differential levels of putative enzymes capable of catalyzing parallel pathways. The majority of proteins involved in pyruvate catabolism and end-product synthesis were detected with high abundance, with the exception of aldehyde dehydrogenase, ferredoxin-dependent Ech-type [NiFe]-hydrogenase, and RNF-type NADH:ferredoxin oxidoreductase. Using 4-plex 2D-HPLC-MS/MS, 24% of the 144 core metabolism proteins detected demonstrated moderate changes in expression during transition from exponential to stationary phase. Notably, proteins involved in pyruvate synthesis decreased in stationary phase, whereas proteins involved in glycogen metabolism, pyruvate catabolism, and end-product synthesis increased in stationary phase. Several proteins that may directly dictate end-product synthesis patterns, including pyruvate:ferredoxin oxidoreductases, alcohol dehydrogenases, and a putative bifurcating hydrogenase, demonstrated differential expression during transition from exponential to stationary phase. Relative expression profiles demonstrate which proteins are likely utilized in carbohydrate utilization and end-product synthesis and suggest that H2 synthesis occurs via bifurcating hydrogenases while ethanol synthesis is predominantly catalyzed by a bifunctional aldehyde/alcohol dehydrogenase. Differences in expression profiles of core metabolic proteins in response to growth phase may dictate carbon and electron flux towards energy storage compounds and end-products. Combined knowledge of relative protein expression levels and their changes in response to physiological conditions may aid in targeted metabolic engineering strategies and optimization of fermentation conditions for improvement of biofuels production.


EDNRB/EDN3 and Hirschsprung disease type II.
The study of vertebrate pigmentary anomalies has greatly improved our understanding of melanocyte biology. One such disorder, Waardenburg syndrome (WS), is a mendelian trait characterized by hypopigmentation and sensorineural deafness. It is commonly subdivided into four types (WS1-4), defined by the presence or absence of additional symptoms. WS type 4 (WS4), or Shah-Waardenburg syndrome, is also known as Hirschsprung disease Type II (HSCR II) and is characterized by an absence of epidermal melanocytes and enteric ganglia. Mutations in the genes encoding the endothelin type-B receptor (EDNRB) and its physiological ligand endothelin 3 (EDN3) are now known to account for the majority of HSCR II patients. Null mutations in the mouse genes Ednrb and Edn3 have identified a key role for this pathway in the normal development of melanocytes and other neural crest-derived lineages. The pleiotropic effects of genes in this pathway, on melanocyte and enteric neuron development, have been clarified by the embryologic identification of their common neural crest (NC) ancestry. EDNRB and EDN3 are transiently expressed in crest-derived melanoblast and neuroblast precursors, and in the surrounding mesenchymal cells, respectively. The influence of EDNRB-mediated signaling on the emigration, migration, proliferation, and differentiation of melanocyte and enteric neuron precursors, in vivo and in vitro has recently been the subject of great scrutiny. A major emergent theme is that EDN3-induced signaling prevents the premature differentiation of melanocyte and enteric nervous system precursors and is essential between 10 and 12.5 days post-coitum. We review the present understanding of pigment cell development in the context of EDNRB/EDN3--a receptor-mediated pathway with pleiotropic effects.


Blood neurofilament light chain as a biomarker of MS disease activity and treatment response.
To assess the value of blood neurofilament light chain (NfL) as a biomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting multiple sclerosis. We measured NfL in blood samples from 589 patients with relapsing-remitting multiple sclerosis (from phase 3 studies of fingolimod vs placebo, FREEDOMS and interferon [IFN]-β-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes. At baseline, NfL levels (pg/mL) were higher in patients than in healthy controls (30.5 and 27.0 vs 16.9, p = 0.0001) and correlated with T2 lesion load and number of gadolinium-enhancing T1 lesions (p < 0.0001, both). Baseline NfL levels, treatment, and number of new or enlarging T2 lesions during the studies predicted NfL levels at the end of study (all p < 0.01). High vs low baseline NfL levels were associated (estimate [95% confidence interval]) with an increased number of new or enlarging T2 lesions (ratio of mean: 2.64 [1.51-4.60]; p = 0.0006), relapses (rate ratio: 2.53 [1.67-3.83]; p < 0.0001), brain volume loss (difference in means: -0.78% [-1.02 to -0.54]; p < 0.0001), and risk of confirmed disability worsening (hazard ratio: 1.94 [0.97-3.87]; p = 0.0605). Fingolimod significantly reduced NfL levels already at 6 months (vs placebo 0.73 [0.656-0.813] and IFN 0.789 [0.704-0.884]), which was sustained until the end of the studies (vs placebo 0.628 [0.552-0.714] and IFN 0.794 [0.705-0.894]; p < 0.001, both studies at all assessments). Blood NfL levels are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic value. Our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response.


Communicative Signals Promote Object Recognition Memory and Modulate the Right Posterior STS.
Detection of communicative signals is thought to facilitate knowledge acquisition early in life, but less is known about the role these signals play in adult learning or about the brain systems supporting sensitivity to communicative intent. The current study examined how ostensive gaze cues and communicative actions affect adult recognition memory and modulate neural activity as measured by fMRI. For both the behavioral and fMRI experiments, participants viewed a series of videos of an actress acting on one of two objects in front of her. Communicative context in the videos was manipulated in a 2 × 2 design in which the actress either had direct gaze (Gaze) or wore a visor (NoGaze) and either pointed at (Point) or reached for (Reach) one of the objects (target) in front of her. Participants then completed a recognition memory task with old (target and nontarget) objects and novel objects. Recognition memory for target objects in the Gaze conditions was greater than NoGaze, but no effects of gesture type were seen. Similarly, the fMRI video-viewing task revealed a significant effect of Gaze within right posterior STS (pSTS), but no significant effects of Gesture. Furthermore, pSTS sensitivity to Gaze conditions was related to greater memory for objects viewed in Gaze, as compared with NoGaze, conditions. Taken together, these results demonstrate that the ostensive, communicative signal of direct gaze preceding an object-directed action enhances recognition memory for attended items and modulates the pSTS response to object-directed actions. Thus, establishment of a communicative context through ostensive signals remains an important component of learning and memory into adulthood, and the pSTS may play a role in facilitating this type of social learning.


Salbutamol modulation of ion transport in sheep parietal pleura is protein dependent.
The formation of pleural effusion during pulmonary edema is an important physiological mechanism of resolution of alveolar flooding. In cases of pulmonary edema resulting from acute respiratory distress syndrome (ARDS) these effusions are exudative, having high protein load. To this end, the effect of salbutamol in the presence of protein, on the ion transport properties of the sheep parietal pleura was investigated by Ussing chamber experiments. Our results show that salbutamol increases ion transport in the presence of protein in sheep parietal pleura by stimulation of β(2)-adrenergic receptors since this effect was completely abolished by the specific β(2)-adrenergic blocker, ICI-118551. This finding may be of importance regarding the acceleration of the resolution of protein-rich pleural effusions occurring in cases of ARDS.


BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years.
In this phase 2 multicenter trial, we evaluated the efficacy of the combination of bortezomib, dexamethasone, and rituximab (BDR) in 59 previously untreated symptomatic patients with Waldenström macroglobulinemia (WM), most of which were of advanced age and with adverse prognostic factors. BDR consisted of a single 21-day cycle of bortezomib alone (1.3 mg/m2 IV on days 1, 4, 8, and 11), followed by weekly IV bortezomib (1.6 mg/m2 on days 1, 8, 15, and 22) for 4 additional 35-day cycles, with IV dexamethasone (40 mg) and IV rituximab (375 mg/m2) on cycles 2 and 5, for a total treatment duration of 23 weeks. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response). After a minimum follow-up of 6 years, median progression-free survival was 43 months and median duration of response for patients with at least partial response was 64.5 months. Overall survival at 7 years was 66%. No patient had developed secondary myelodysplasia, whereas transformation to high-grade lymphoma occurred in 3 patients who had received chemoimmunotherapy after BDR. Thus, BDR is a very active, fixed-duration, chemotherapy-free regimen, inducing durable responses and with a favorable long-term toxicity profile (www.ClinicalTrials.gov #NCT00981708).


Orthodontic treatment need and timing: Assessment of evolutive malocclusion conditions and associated risk factors.
Orthodontic treatment need indexes are indispensable tools for collecting aepidemiological information, to define the need for clinical intervention on a graduated risk scale and to monitor the evolution of clinical conditions over time. The purpose of this research is to evaluate the prevalence of malocclusion and associated risk factors, and to compare the prevalence of malocclusion related to children's growth. Investigating the correlation between malocclusion and dental occlusion development is crucial to define orthodontic timing and the most suitable treatment modalities. A cross-sectional, multi-center, observational study was carried out throughout Italy: 4,422 patients aged between 2 and 13 years were visited. The patients were divided into two age groups: one composed of patients aged 2 -7 years, and one of children between 8 and 13 years of age. The prevalence data were classified according to the items of the Baby ROMA (first group, deciduous/early mixed dentition) and ROMA Index (second group, late mixed/permanent dentition). Pearson's Chi-square test was applied for the calculation of statistical significance in the comparison of prevalence data between the two age groups (P <0.05). The need for orthodontic treatment among Italian children is high. In the sample aged between 2 and 7 years, the most frequent malocclusions are the moderate and severe open bite (23%), moderate and severe Class II (21.2%), deep bite (18.8%), cross bite (16.5%), Class III (7.7%), and crowding (5.1%). In the sample aged between 8 and 13 years the most frequent malocclusions are crowding (50.8 %), Class II (33.1%), deep bite (19.2%) crossbite (18.1%), Class III (9.1%), open bite (6.6%), facial or mandibular asymmetries (3.3%), and functional asymmetries (3.2%). It was found a statistically significant variation of the different malocclusion conditions according to age. The study confirms that some risk factors occur during growth, and worsen the malocclusion. Therefore, it is important to reduce this risk of worsening by counteracting those factors with an early orthodontic intervention. Some malocclusions are less affected by environmental risk factors. In these case it would be better defer treatment until adolescence.


Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor.
The phosphatase PTP4A3 is an attractive anticancer target, but knowledge of its exact role in cells remains incomplete. A potent, structurally novel inhibitor of the PTP4A family was obtained by photooxygenation of a less active, electron-rich thienopyridone (1). Iminothienopyridinedione 13 displays increased solution stability and is readily obtained by two new synthetic routes that converge in the preparation of 1. The late-stage photooxygenation of 1 to give 13 in high yield highlights the potential of this reaction to modify the structure and properties of a biological lead compound and generate value for expanding the scope of an SAR investigation. Analog 13 should become a valuable tool for further exploration of the role of PTP4A3 in tumor progression.


Markers of biological stress and mucosal immunity during a week leading to competition in adolescent swimmers.
In this study we examined changes in the salivary concentrations of immunoglobulin A (sIgA), cortisol (sC), testosterone (sT), and testosterone-to-cortisol ratio (T/C) in 21 competitive swimmers, 11-15 years old, during a week leading to competition as compared to a control (noncompetition) week. No day-to-day changes or significant differences between weeks were observed for sIgA (47.9 ± 4.4 versus 54.9 ± 5.2 μg/mL for control versus competition week, resp.), sC (2.7 ± 0.2 versus 2.5 ± 0.2 ng/mL for control versus competition week, resp.), and T/C ratio (83.4 ± 7.0 versus 77.9 ± 7.7 for control versus competition week, resp.). In contrast, sT was significantly lower during the week of competition (154.5 ± 11.3 pg/mL) as compared to the control week (181.3 ± 11.5 pg/mL) suggesting that the swimmers were in a catabolic state, although this did not have a negative effect on their performance. In conclusion, salivary cortisol did not change between the two weeks, and thus competition stress was relatively low, and mucosal immunity was unaffected in these young athletes prior to competition.


Alteration of Coagulation Test Results and Vaginal Bleeding Associated With the Use of Feverfew (Tanacetum parthenium).
Tanacetum parthenium (feverfew) is a member of the daisy family; it is used to prevent and treat migraine and rheumatoid arthritis. It has a long history of use as a traditional and folk medicine in Chinese, Greek, Indian and Arabic medicine, having been used for hundreds of years. The term feverfew comes from the Latin word febrifugia and means fever reducer. However, Short term use of feverfew (up to 4 months) is considered safe in adults. According to a few clinical trials, Tanacetum parthenium was not associated with serious adverse events but rather with mild and reversible events. Adverse events leading to withdrawals were mainly of a gastrointestinal nature. There is no major safety issue. Nevertheless, we report one case of a 36-year-old woman with known migraine who visited the obstetrics and gynecology clinic upon developing vaginal bleeding, prolonged duration of the menstrual cycle, and reddish skin without bruising. The patient suffered from these symptoms over a period of 3 months prior to the clinic visit. Based on history, the patient began taking 800 mg capsules of feverfew three times per day 9 months ago. We applied the Naranjo scale in our case, and it indicated that a probable relationship exists between feverfew and vaginal bleeding. Feverfew should be used cautiously by patients planning elective surgery, having coagulant disorders or taking antithrombotic drugs.


Research opportunities for cancer associated with indoor air pollution from solid-fuel combustion.
Indoor air pollution (IAP) derived largely from the use of solid fuels for cooking and heating affects about 3 billion people worldwide, resulting in substantial adverse health outcomes, including cancer. Women and children from developing countries are the most exposed populations. A workshop was held in Arlington, Virginia, 9-11 May 2011, to better understand women's and children's potential health effects from IAP in developing countries. Workshop participants included international scientists, manufacturers, policy and regulatory officials, community leaders, and advocates who held extensive discussions to help identify future research needs. Our objective was to identify research opportunities regarding IAP and cancer, including research questions that could be incorporated into studies of interventions to reduce IAP exposure. In this commentary, we describe the state of the science in understanding IAP and its associations with cancer and suggest research opportunities for improving our understanding of the issues. Opportunities for research on IAP and cancer include studies of the effect of IAP on cancers other than lung cancer; studies of genetic factors that modify susceptibility; studies to determine whether the effects of IAP are mediated via germline, somatic, and/or epigenetic changes; and studies of the effects of IAP exposure via dermal and/or oral routes. IAP from indoor coal use increases the risk of lung cancer. Installing chimneys can reduce risk, and some genotypes, including GSTM1-null, can increase risk. Additional research is needed regarding the effects of IAP on other cancers and the effects of different types of solid fuels, oral and dermal routes of IAP exposure, genetic and epigenetic mechanisms, and genetic susceptibility.