Cluster randomised trials.
Although randomised controlled trials are the reference methodology to assess the effects of therapeutic interventions, for interventions that naturally occur in groups of individuals random allocation of participants may be inappropriate. In these cases, the unit of random allocation may be the group or cluster, rather than the individual. Clinical trials that randomly allocate groups or clusters of individuals are called cluster randomised trials. This article briefly presents the main implications of cluster randomisation with respect to the following methodological aspects: generalisability, concealment of allocation, comparability at baseline, blindness, loss of clusters and intra-class correlation.


A high-resolution C. elegans essential gene network based on phenotypic profiling of a complex tissue.
High-content screening for gene profiling has generally been limited to single cells. Here, we explore an alternative approach-profiling gene function by analyzing effects of gene knockdowns on the architecture of a complex tissue in a multicellular organism. We profile 554 essential C. elegans genes by imaging gonad architecture and scoring 94 phenotypic features. To generate a reference for evaluating methods for network construction, genes were manually partitioned into 102 phenotypic classes, predicting functions for uncharacterized genes across diverse cellular processes. Using this classification as a benchmark, we developed a robust computational method for constructing gene networks from high-content profiles based on a network context-dependent measure that ranks the significance of links between genes. Our analysis reveals that multi-parametric profiling in a complex tissue yields functional maps with a resolution similar to genetic interaction-based profiling in unicellular eukaryotes-pinpointing subunits of macromolecular complexes and components functioning in common cellular processes.


Selfish drive can trump function when animal mitochondrial genomes compete.
Mitochondrial genomes compete for transmission from mother to progeny. We explored this competition by introducing a second genome into Drosophila melanogaster to follow transmission. Competitions between closely related genomes favored those functional in electron transport, resulting in a host-beneficial purifying selection. In contrast, matchups between distantly related genomes often favored those with negligible, negative or lethal consequences, indicating selfish selection. Exhibiting powerful selfish selection, a genome carrying a detrimental mutation displaced a complementing genome, leading to population death after several generations. In a different pairing, opposing selfish and purifying selection counterbalanced to give stable transmission of two genomes. Sequencing of recombinant mitochondrial genomes showed that the noncoding region, containing origins of replication, governs selfish transmission. Uniparental inheritance prevents encounters between distantly related genomes. Nonetheless, in each maternal lineage, constant competition among sibling genomes selects for super-replicators. We suggest that this relentless competition drives positive selection, promoting change in the sequences influencing transmission.


[Incidental finding of inguinal hernia sac cancer].
The presence of cancer in a hernia sac is uncommon. The tumor can involve the hernia sac, the herniated mass or be external to the hernia sac. We report two cases with this condition. A 68 years old male was operated of a right inguinal hernia. During surgery, several white nodules were noted in the internal side of hernia sac. The same lesions were present in the mesentery. Pathological study revealed an adenocarcinoma. The primary tumor was not located and the patient died one and a half years after the procedure. A 62 years old male was operated due to an irreducible inguinal mass, seven months after a subtotal gastrectomy for gastric cancer. During the resection of the mass, metastasis implants in the mesenteric adipose tissue were noted. A mini laparotomy was performed and an extensive peritoneal tumor dissemination was found. The patient died two months after surgery.


Transcranial Doppler ultrasound in the evaluation of collateral blood flow in patients with internal carotid artery occlusion: correlation with cerebral angiography.
To determine the accuracy of transcranial Doppler (TCD) ultrasound for evaluation of collateral supply through the circle of Willis in patients with internal carotid artery (ICA) occlusion. The evaluation of the collateral pathways through the circle of Willis with TCD ultrasound and with cerebral angiography was compared in 40 patients (30 men, 10 women; mean age, 55 +/- 9 years) in a total of 44 ICA occlusions of which 43 had a suitable ipsilateral temporal bone window for TCD examination. By TCD, a patent anterior communicating artery is indicated by a reversal blood flow in the A1-segment of the anterior cerebral artery or by a prompt fall of blood velocity in the middle cerebral artery after compression of the nonoccluded contralateral carotid artery. In 42 of 43 instances of ICA occlusion, TCD and angiography agreed in the evaluation of a present or absent anterior communicating artery collateral supply. TCD's sensitivity was 95%, its specificity 100%. A collateral supply through the basilar artery was assumed with TCD when there was: (a) a basilar artery blood velocity of more than 70 cm/s; (b) a marked increase of basilar artery blood velocity after compression of the nonoccluded carotid artery; (c) an evident side-to-side asymmetry of the blood velocity of the posterior cerebral arteries with high blood velocity ipsilateral to the ICA occlusion. For evaluating the collateralization via the basilar artery, TCD and angiography agreed in 37 of 40 ICA occlusions. TCD's sensitivity was 87%, its specificity 95%. TCD is a reliable tool for the evaluation of the collateral supply in patients with ICA occlusions.


Early estimates of the indirect effects of the COVID-19 pandemic on maternal and child mortality in low-income and middle-income countries: a modelling study.
While the COVID-19 pandemic will increase mortality due to the virus, it is also likely to increase mortality indirectly. In this study, we estimate the additional maternal and under-5 child deaths resulting from the potential disruption of health systems and decreased access to food. We modelled three scenarios in which the coverage of essential maternal and child health interventions is reduced by 9·8-51·9% and the prevalence of wasting is increased by 10-50%. Although our scenarios are hypothetical, we sought to reflect real-world possibilities, given emerging reports of the supply-side and demand-side effects of the pandemic. We used the Lives Saved Tool to estimate the additional maternal and under-5 child deaths under each scenario, in 118 low-income and middle-income countries. We estimated additional deaths for a single month and extrapolated for 3 months, 6 months, and 12 months. Our least severe scenario (coverage reductions of 9·8-18·5% and wasting increase of 10%) over 6 months would result in 253 500 additional child deaths and 12 200 additional maternal deaths. Our most severe scenario (coverage reductions of 39·3-51·9% and wasting increase of 50%) over 6 months would result in 1 157 000 additional child deaths and 56 700 additional maternal deaths. These additional deaths would represent an increase of 9·8-44·7% in under-5 child deaths per month, and an 8·3-38·6% increase in maternal deaths per month, across the 118 countries. Across our three scenarios, the reduced coverage of four childbirth interventions (parenteral administration of uterotonics, antibiotics, and anticonvulsants, and clean birth environments) would account for approximately 60% of additional maternal deaths. The increase in wasting prevalence would account for 18-23% of additional child deaths and reduced coverage of antibiotics for pneumonia and neonatal sepsis and of oral rehydration solution for diarrhoea would together account for around 41% of additional child deaths. Our estimates are based on tentative assumptions and represent a wide range of outcomes. Nonetheless, they show that, if routine health care is disrupted and access to food is decreased (as a result of unavoidable shocks, health system collapse, or intentional choices made in responding to the pandemic), the increase in child and maternal deaths will be devastating. We hope these numbers add context as policy makers establish guidelines and allocate resources in the days and months to come. Bill & Melinda Gates Foundation, Global Affairs Canada.


Preparation of high-potency, non-aggregating insulins using a novel sulfation procedure.
The marked propensity of insulin to self-associate into large aggregates causes significant mechanical problems in insulin delivery devices and may also stimulate production of a tissue-amyloid A precursor in some patients. Although conventionally prepared sulfated insulin (SI) resists aggregation, clinical application has been limited by major insulin bioactivity losses that occur during synthesis. To eliminate this problem, insulin sulfation was carried out in the organic solvent dimethylformamide in the presence of condensing agents such as N,N'-dicyclohexyl carbodiimide (DCC) and a sulfate donor. With this new procedure, the degree of sulfation could be controlled over an eightfold range by varying the amount of condensing agent. The bioactivity of these new SI derivatives varied between 78% and 87% of unmodified insulin. Insulin aggregation, induced by passage through a syringe and needle, did not occur with derivatives having two or more sulfate moieties per insulin molecule. Diffusion velocity studies using "non-aggregated" insulin solutions demonstrated that aggregates were present in crystalline zinc and sodium porcine insulin. In contrast, SI having more than 0.5 mole sulfate per mole of insulin dialyzed as it were predominantly in the monomeric form. Results from the studies described in this report now provide the means for selectively designing and preparing specific high-potency, non-aggregating insulins, which may be necessary for optimal use of current and future insulin delivery devices.


Turbulent transfer in a deciduous forest.
Carbon dioxide, water vapor and other passive scalars are physically transferred between a plant canopy and the atmosphere by turbulence. Intense and intermittent sweep and ejection events transfer most of the mass. Although the capacity for turbulence to transfer material is high, mass transfer is coupled to the diffusive source or sink strength of the foliage and soil and is ultimately limited to a minimum level set by the supply of material, or the demand for it. The diffusive source/sink strength of material leaving or entering leaves and the soil is a function of many physical, biological and chemical attributes and processes. These attributes and processes include the amount and distribution of foliage, the leaf boundary layer and surface resistances, the turbulence and radiative regimes in the canopy, biochemical and photochemical reactions and the scalar concentration field within and above the canopy and inside leaves and the soil. Here we discuss how these factors contribute to turbulent transfer in a deciduous forest.


Sleep fears, sleep disturbance, and PTSD symptoms in minority youth exposed to Hurricane Katrina.
Posttraumatic stress disorder (PTSD) is common following the experience of a natural disaster and sleep disturbance is an important influence on its course in adults, but little research is available examining sleep and PTSD in youths. This study's objective was to evaluate the role of sleep disturbance and the developmentally influenced factor of fear of sleeping alone in the maintenance of posttraumatic stress (PTS) symptoms in youths. Deidentified data of 191 Hurricane Katrina survivors ages 8 to 15 were used in this study. We found cross-sectional relationships of sleep disturbance and fear of sleeping alone with PTS symptom severity. Longitudinal analysis also indicated that general sleep disturbance at 24 months (T1) was predictive of PTS symptoms severity at 30 months (T2) even after adjusting for PTS symptom severity at T1, age, sex, and continued disrepair to the home. These results have implications for intervention strategies among youth exposed to traumatic events.


Highly differentiated ZW sex microchromosomes in the Australian Varanus species evolved through rapid amplification of repetitive sequences.
Transitions between sex determination systems have occurred in many lineages of squamates and it follows that novel sex chromosomes will also have arisen multiple times. The formation of sex chromosomes may be reinforced by inhibition of recombination and the accumulation of repetitive DNA sequences. The karyotypes of monitor lizards are known to be highly conserved yet the sex chromosomes in this family have not been fully investigated. Here, we compare male and female karyotypes of three Australian monitor lizards, Varanus acanthurus, V. gouldii and V. rosenbergi, from two different clades. V. acanthurus belongs to the acanthurus clade and the other two belong to the gouldii clade. We applied C-banding and comparative genomic hybridization to reveal that these species have ZZ/ZW sex micro-chromosomes in which the W chromosome is highly differentiated from the Z chromosome. In combination with previous reports, all six Varanus species in which sex chromosomes have been identified have ZZ/ZW sex chromosomes, spanning several clades on the varanid phylogeny, making it likely that the ZZ/ZW sex chromosome is ancestral for this family. However, repetitive sequences of these ZW chromosome pairs differed among species. In particular, an (AAT)n microsatellite repeat motif mapped by fluorescence in situ hybridization on part of W chromosome in V. acanthurus only, whereas a (CGG)n motif mapped onto the W chromosomes of V. gouldii and V. rosenbergi. Furthermore, the W chromosome probe for V. acanthurus produced hybridization signals only on the centromeric regions of W chromosomes of the other two species. These results suggest that the W chromosome sequences were not conserved between gouldii and acanthurus clades and that these repetitive sequences have been amplified rapidly and independently on the W chromosome of the two clades after their divergence.


Children and youth with fetal alcohol spectrum disorders: summary of intervention recommendations after clinical diagnosis.
Children with fetal alcohol spectrum disorders (FASDs) present with a wide range of developmental disabilities; however, clinical standards of care after a diagnosis are not well established. This retrospective review summarizes the types of intervention recommendations generated by an interdisciplinary FASD diagnostic team for 120 children ages 0.2 to 16.5 years receiving an FASD diagnosis at the University of Washington FAS Diagnostic & Prevention Network Clinic. Intervention recommendations documented in a FASD diagnostic summary report and submitted to each patient's medical record were subject to masked review and content analysis. Intervention recommendations were compared across 3 FASD diagnostic groups and selected demographic variables. The results show the type and frequency of services, supports, and resources recommended to a clinical sample of children with FASD.


Possible mechanism of quadriceps femoris weakness in patients with ruptured anterior cruciate ligament.
The purpose of this study was to test the hypothesis that loss of afferent feedback due to rupture of anterior cruciate ligament (ACL) is the cause of quadriceps femoris (QF) weakness through gamma loop. Two experiments were designed to prove our hypothesis. In experiment 1, the maximal voluntary contraction (MVC) of knee extension and integrated electromyogram (I-EMG) of vastus medialis (VM), vastus lateralis (VL), and rectus femoris (RF) were measured in 13 patients with ruptured ACL and 7 healthy volunteers before and after injection of anesthetic agent into the knee. In experiment 2, MVC of knee extension and I-EMG of the VM, VL, and RF were measured in 13 patients with ruptured ACL, 7 knee-anesthetized healthy subjects, and 12 normal subjects, before and after 20-min vibration stimulation applied to the infrapatellar tendon. The results of experiment 1 revealed that injection of anesthetic agent into the knee capsule resulted in significant decrease of MVC and I-EMGs. In experiment 2, the mean percentage change of MVC in the control group was significantly lower than that in the other two groups. There was no significant difference between knee-anesthetized group and patients with ruptured ACL. The mean percentage change of I-EMG showed a pattern similar to that of MVC. Our results suggest that loss of feedback from mechanoreceptors in ACL is the underlying mechanism of weakness of QF in patients with ACL lesion. This conclusion is based on chronic suppression of recruitment of high-threshold motor units during voluntary contraction because ACL lesion leads to chronic reduction in Ia-feedback to muscles around the knee due to a lack of feedback from ACL to gamma motor neurons.


Multiple factors, including non-motor impairments, influence decision making with regard to exercise participation in Parkinson's disease: a qualitative enquiry.
To explore how the meaning of exercise and other factors interact and influence the exercise behaviour of individuals with Parkinson's disease (PD) enrolled in a 6-month minimally supervised exercise program to prevent falls, regardless of whether they completed the prescribed exercise or not. This qualitative study utilised in-depth semi-structured interviews analysed using grounded theory methodology. Four main themes were constructed from the data: adapting to change and loss, the influence of others, making sense of the exercise experience and hope for a more active future. Participation in the PD-specific physiotherapy program involving group exercise provided an opportunity for participants to reframe their identity of their "active" self. Three new influences on exercise participation were identified and explored: non-motor impairments of apathy and fatigue, the belief in a finite energy quota, and the importance of feedback. A model was developed incorporating the themes and influences to explain decision-making for exercise participation in this group. Complex and interacting issues, including non-motor impairments, need to be considered in order to enhance the development and ongoing implementation of effective exercise programmes for people with PD. Exercise participation can assist individuals to reframe their identity as they are faced with losses associated with Parkinson's disease and ageing. Non-motor impairments of apathy and fatigue may influence exercise participation in people with Parkinson's disease. Particular attention needs to be paid to the provision of feedback in exercise programs for people with Parkinson's disease as it important for their decision-making about continuing exercise.


Characterization of a copper-transport operon, copYAZ, from Streptococcus mutans.
A copper-transport (copYAZ) operon was cloned from the oral bacterium Streptococcus mutans JH1005. DNA sequencing showed that the operon contained three genes (copY, copA and copZ), which were flanked by a single promoter and a factor-independent terminator. copY encoded a small protein of 147 aa with a heavy-metal-binding motif (CXCX(4)CXC) at the C-terminus. CopY shared extensive homology with other bacterial negative transcriptional regulators. copA encoded a 742 aa protein that shared extensive homology with P-type ATPases. copZ encoded a 67 aa protein that also contained a heavy-metal-binding motif (CXXC) at the N-terminus. Northern blotting showed that a 3.2 kb transcript was produced by Cu2+-induced Strep. mutans cells, suggesting that the genes were synthesized as a polycistronic message. The transcriptional start site of the cop operon was mapped and shown to lie within the inverted repeats of the promoter-operator region. Strep. mutans wild-type cells were resistant to 800 microM Cu2+, whereas cells of a cop knock-out mutant were killed by 200 microM Cu2+. Complementation of the cop knock-out mutant with the cop operon restored Cu2+ resistance to wild-type level. The wild-type and the mutant did not show any differences in susceptibility to other heavy metals, suggesting that the operon was specific for copper. By using a chloramphenicol acetyltransferase reporter gene fusion, the cop operon was shown to be negatively regulated by CopY and could be derepressed by Cu2+.


Recent advances in Parkinson's disease genetics.
The last 5 years have seen rapid progress in Parkinson's disease (PD) genetics, with the publication of a series of large-scale genome wide association studies for PD, and evaluation of the roles of the LRRK2 and GBA genes in the aetiology of PD. We are beginning to develop a coherent picture of the interplay of Mendelian and non-Mendelian factors in PD. Pathways involved in mitochondrial quality control (mitophagy), lysosomal function and immune function are emerging as important in the pathogenesis of PD. These pathways represent a target for therapeutic intervention and a way in which the heterogeneity of disease cause, as well as disease mechanism, can be established. In the future, there is likely to be an individualised basis for the treatment of PD, linked to the identification of specific genetic factors.


Quick and Accurate Detection and Quantification of Magnaporthe oryzae in Rice Using Real-Time Quantitative Polymerase Chain Reaction.
Rice blast, caused by Magnaporthe oryzae, is one of the most severe fungal diseases in rice worldwide. In this study, we developed methods to quickly and accurately detect and quantify M. oryzae in the pure cultures of the fungus, rice plants, and rice seed by using SYBR Green I of the real-time quantitative polymerase chain reaction (qPCR). Results of absolute qPCR show that Magnaporthe oryzae can be detected at as low as 6.9 × 10-5 ng of genomic DNA. Results also show that all 10 varieties of rice seed examined in this study contain this fungus, indicating that M. oryzae is generally widespread in rice seed. We report the quantification of DNA of M. oryzae in rice leaves collected in the field, instead of in the lab, using relative qPCR by using rice actin gene as a housekeeping gene. Our results show great practical significance because we would know the potential fungal infection even before planting.


Large-scale field study on thin-layer capping of marine PCDD/F-contaminated sediments in Grenlandfjords, Norway: physicochemical effects.
A large-scale field experiment on in situ thin-layer capping was carried out in the polychlorinated dibenzodioxin and dibenzofuran (PCDD/F) contaminated Grenlandsfjords, Norway. The main focus of the trial was to test the effectiveness of active caps (targeted thickness of 2.5 cm) consisting of powdered activated carbon (AC) mixed into locally dredged clean clay. Nonactive caps (targed thickness of 5 cm) consisting of clay without AC as well as crushed limestone were also tested. Fields with areas of 10,000 to 40,000 m(2) were established at 30 to 100 m water depth. Auxiliary shaken laboratory batch experiments showed that 2% of the applied powdered AC substantially reduced PCDD/F porewater concentrations, by >90% for tetra-, penta- and hexa-clorinated congeners to 60-70% for octachlorinated ones. In-situ AC profiles revealed that the AC was mixed into the sediment to 3 to 5 cm depth in 20 months. Only around 25% of the AC was found inside the pilot fields. Sediment-to-water PCDD/F fluxes measured by in situ diffusion chambers were significantly lower at the capped fields than at reference fields in the same fjord, reductions being largest for the limestone (50-90%) followed by clay (50-70%), and the AC + clay (60%). Also reductions in overlying aqueous PCDD/F concentrations measured by passive samplers were significant in most cases (20-40% reduction), probably because of the large size of the trial fields. The AC was less effective in the field than in the laboratory, probably due to prolonged sediment-to-AC mass transfer times for PCDD/Fs and field factors such as integrity of the cap, new deposition of contaminated sediment particles, and bioturbation. The present field data indicate that slightly thicker layers of limestone and dredged clay can show as good physicochemical effectiveness as thin caps of AC mixed with clay, at least for PCDD/Fs during the first two years after cap placement.


Coping with chronic complex regional pain syndrome: advice from patients for patients.
To explore what advice people currently living with chronic complex regional pain syndrome would offer to another person coming to terms with a diagnosis of chronic complex regional pain syndrome. Semi-structured interviews with 21 adults (5 male) living with chronic complex regional pain syndrome who had completed a complex regional pain syndrome rehabilitation programme were conducted. Effectively self-managing complex regional pain syndrome required individuals to play an active role. This could only be achieved if they felt they had sufficient control. Means of attaining control involved attaining a level of acceptance, becoming well-informed and accessing the right kind of support. The advice offered by patients for patients largely reflected that offered by healthcare professionals. One area where there was a conflict concerned sleep hygiene. Our study provides support both for the argument put forward by Redman that without appropriate preparation and support, self-management is ineffective, and that by Skuladottir and Hallsdottir that the main challenge of the chronic pain trajectory is that of retaining a sense of control. The clinical implications of this are discussed.


In vitro development of in vitro-matured porcine oocytes following chemical activation or in vitro fertilization.
Porcine cumulus-oocyte complexes were cultured in BSA-free Whitten's medium or modified Medium 199, each supplemented with porcine follicular fluid (PFF) and hormonal supplements (OMWM and OMM199, respectively) for 20 h; they then were cultured without hormonal supplements for an additional 20 (experiments 1 and 3) or 24 h (experiment 2). At the end of culture (experiment 1), the intracellular glutathione concentration was higher (p < 0.05) in oocytes matured in OMWM vs. OMM199. After activation by Ca2+ ionophore (experiment 2), the incidence of activation in the OMWM group was lower (p < 0.01) than in the OMM199 group. However, the incidence of pronuclear formation was higher (p < 0.01) in the OMWM group than in the OMM199 group at 8 h after activation. The percentage of embryos that developed to the morula stage was higher (p < 0.01) in the group matured in OMWM vs. OMM199 after 5 days of culture. After in vitro fertilization (experiment 3), the incidence of male pronuclear formation and the percentage of monospermic oocytes that formed one male and one female pronuclei were higher (p < 0.05) after maturation in OMWM vs. OMM199. The percentage of cleaved embryos that developed to the 8-cell and morula stages was higher (p < 0.05) in the OMWM group as compared to the OMM199 group. These results indicate that culture in modified Whitten's medium as compared with a standard medium (modified Medium 199) improves cytoplasmic maturation of porcine oocytes as evaluated by intracellular glutathione content, pronuclear formation, and development in vitro after artificial activation or fertilization in vitro.


KLRG1 binds cadherins and preferentially associates with SHIP-1.
The killer cell lectin-like receptor G1 (KLRG1) is a unique inhibitory receptor expressed on a phenotypically mature subset of resting NK cells as well as subsets of T cells in naive mice. In vivo, pathogenic immune system activation induces dramatic changes in the expression patterns of KLRG1 among the different cell subsets. In order to enhance our understanding of KLRG1 signaling properties and to clarify the functions of KLRG1 on these cells, we identified the broadly expressed N-cadherin molecule as a ligand for KLRG1. We further demonstrate that a second member of this superfamily of adhesion molecules, E-cadherin, binds to KLRG1. Additionally, we show that upon phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) tyrosine, KLRG1 recruits both SHIP-1 and SHP-2 but not SHP-1. We also delineate the key KLRG1 ITIM amino acid residues required for optimal association with these phosphatases. Finally, we demonstrate that KLRG1 engagement can inhibit sub-optimal TCR signaling. Taken together, our results indicate that KLRG1 may differentially regulate NK cell and T cell functions through the association with different ligands as well as the recruitment of distinct phosphatases.


Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy.
Muscle wasting is a debilitating consequence of fasting, inactivity, cancer, and other systemic diseases that results primarily from accelerated protein degradation by the ubiquitin-proteasome pathway. To identify key factors in this process, we have used cDNA microarrays to compare normal and atrophying muscles and found a unique gene fragment that is induced more than ninefold in muscles of fasted mice. We cloned this gene, which is expressed specifically in striated muscles. Because this mRNA also markedly increases in muscles atrophying because of diabetes, cancer, and renal failure, we named it atrogin-1. It contains a functional F-box domain that binds to Skp1 and thereby to Roc1 and Cul1, the other components of SCF-type Ub-protein ligases (E3s), as well as a nuclear localization sequence and PDZ-binding domain. On fasting, atrogin-1 mRNA levels increase specifically in skeletal muscle and before atrophy occurs. Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases.


Acclimation of Nannochloropsis gaditana to different illumination regimes: effects on lipids accumulation.
Algae are interesting potential sources of biodiesel, although research is still needed to develop efficient large scale productions. One major factor affecting productivity is light use efficiency. The effect of different light regimes on the seawater alga Nannochloropsis gaditana was accessed monitoring growth rate and photosynthetic performances. N. gaditana showed the capacity of acclimating to different light intensities, optimizing its photosynthetic apparatus to illumination. Thanks to this response, N. gaditana maintained similar growth rates under a wide range of irradiances, suggesting that this organism is a valuable candidate for outdoor productions in variable conditions. In the conditions tested here, without external CO(2) supply, light intensity alone was not found to be a major signal affecting lipids accumulation showing the absence of a direct regulatory link between the light stress and lipids accumulation. Strong illumination can nevertheless indirectly influences lipid accumulation if combined with other stresses or in the presence of excess CO(2).


Twelve-Minute Daily Yoga Regimen Reverses Osteoporotic Bone Loss.
Assess the effectiveness of selected yoga postures in raising bone mineral density (BMD). Ten-year study of 741 Internet-recruited volunteers comparing preyoga BMD changes with postyoga BMD changes. Dual-energy x-ray absorptiometric scans. Optional radiographs of hips and spine and bone quality study (7 Tesla). Bone mineral density improved in spine, hips, and femur of the 227 moderately and fully compliant patients. Monthly gain in BMD was significant in spine (0.0029 g/cm2, P = .005) and femur (0.00022 g/cm2, P = .053), but in 1 cohort, although mean gain in hip BMD was 50%, large individual differences raised the confidence interval and the gain was not significant for total hip (0.000357 g/cm2). No yoga-related serious injuries were imaged or reported. Bone quality appeared qualitatively improved in yoga practitioners. Yoga appears to raise BMD in the spine and the femur safely.


Participatory approaches involving community and healthcare providers in family planning/contraceptive information and service provision: a scoping review.
As efforts to address unmet need for family planning and contraception (FP/C) accelerate, voluntary use, informed choice and quality must remain at the fore. Active involvement of affected populations has been recognized as one of the key principles in ensuring human rights in the provision of FP/C and in improving quality of care. However, community participation continues to be inadequately addressed in large-scale FP/C programmes. Community and healthcare providers' unequal relationship can be a barrier to successful participation. This scoping review identifies participatory approaches involving both community and healthcare providers for FP/C services and analyzes relevant evidence. The detailed analysis of 25 articles provided information on 28 specific programmes and identified three types of approaches for community and healthcare provider participation in FP/C programmes. The three approaches were: (i) establishment of new groups either health committees to link the health service providers and users or implementation teams to conduct specific activities to improve or extend available health services, (ii) identification of and collaboration with existing community structures to optimise use of health services and (iii) operationalization of tools to facilitate community and healthcare provider collaboration for quality improvement. Integration of community and healthcare provider participation in FP/C provision were conducted through FP/C-only programmes, FP/C-focused programmes and/or as part of a health service package. The rationales behind the interventions varied and may be multiple. Examples include researcher-, NGO- or health service-initiated programmes with clear objectives of improving FP/C service provision or increasing demand for services; facilitating the involvement of community members or service users and, in some cases, may combine socio-economic development and increasing self-reliance or control over sexual and reproductive health. Although a number of studies reported increase in FP/C knowledge and uptake, the lack of robust monitoring and evaluation mechanisms and quantitative and comparable data resulted in difficulties in generating clear recommendations. It is imperative that programmes are systematically designed, evaluated and reported.


Long term cultivation of Namalva cells for interferon production: stable cytogenetic markers for identification of cells in spite of drastic chromosomal variation.
Namalva cells were propagated continuously over a period of up to 18 months. During this period the chromosomal status of the cell populations were investigated cytogenetically. The ability of the cells to produce interferons after induction with Sendai virus was monitored. In contrast to the drastic chromosomal variation observed, interferon production was remarkably stable. Comparison of the various cytogenetic data revealed the presence of marker chromosomes and chromosomal constellations which were excluded from the drift. Some of these are useful for unequivocal identification of Namalva cells during long term cultivation.


Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes.
Mesenchymal stem cells (MSCs) have emerged as excellent candidates for clinical application because of their capabilities of immunomodulatory and supporting hematopoiesis. Nevertheless, it is unclear whether the characteristics of MSCs are altered in diseased states. In this study, we obtained and expanded MSCs from bone marrow of patients with myelodysplastic syndromes (MDS). Our results showed that MSCs derived from MDS (MDS-MSCs) were similar to normal adult bone marrow derived MSCs in morphology, growth property, surface epitopes, and differentiation ability in vitro. In addition, MDS-MSCs had normal karyotype and ultrastructure. However, MDS-MSCs appeared to be impaired in immunomodulatory and supporting hematopoiesis function. Although, MDS-MSCs could express hematopoietic cytokines and support hematopoiesis in long term culture, Real time quantitative polymerase chain reaction showed that the expression of hematopoietic cytokines in MDS-MSCs was much lower than that of normal adult derived MSCs. Moreover, MDS-MSCs showed reduced hematopoiesis support function, as compared to their normal counterparts. Lastly, the capacity of MDS-MSCs to inhibit T lymphocyte activation and proliferation was impaired in vitro. These results indicate that MDS-MSCs have impaired immunomodulatory and hematopoiesis support functions, suggesting their critical role in the pathogenesis of MDS.


Adipose-derived stem cell: a better stem cell than BMSC.
To further study the proliferation and multi-differentiation potentials of adipose-derived stem cells (ADSCs), the cells were isolated with improved methods and their growth curves were achieved with cck-8. Surface protein expression was analyzed by flow cytometry to characterize the cell phenotype. The multi-lineage potential of ADSCs was testified by differentiating cells with adipogenic, chondrogenic, osteogenic, and myogenic inducers. The results showed that about 5 x 10(5) stem cells could be obtained from 400 to 600 mg adipose tissue. The ADSCs can be continuously cultured in vitro for up to 1 month without passage and they have several logarithmic growth phases during the culture period. Also, the flow cytometry analysis showed that ADSCs expressed high levels of stem cell-related antigens (CD13, CD29, CD44, CD105, and CD166), while did not express hematopoiesis-related antigens CD34 and CD45, and human leukocyte antigen HLA-DR was also negative. Moreover, stem cell-related transcription factors, Nanog, Oct-4, Sox-2, and Rex-1 were positively expressed in ADSCs. The expression of alkaline phosphatase (ALP) was detected in the early osteogenic induction and the calcified nodules were observed by von Kossa staining. Intracellular lipid droplets could be observed by Oil Red staining. Differentiated cardiomyocytes were observed by connexin43 fluorescent staining. In order to obtain more stem cells, we can subculture ADSCs every 14 days instead of the normal 5 days. ADSCs still keep strong proliferation ability, maintain their phenotypes, and have stronger multi-differentiation potential after 25 passages.


Potentially inappropriate prescribing according to STOPP and START and adverse outcomes in community-dwelling older people: a prospective cohort study.
This study aims to determine if potentially inappropriate prescribing (PIP) is associated with increased healthcare utilization, functional decline and reduced quality of life (QoL) in a community-dwelling older cohort. This prospective cohort study included participants aged ≥65 years from The Irish Longitudinal Study on Ageing (TILDA) with linked administrative pharmacy claims data who were followed up after 2 years. PIP was defined by the Screening Tool for Older Persons Prescriptions (STOPP) and Screening Tool to Alert doctors to Right Treatment (START). The association with number of emergency department (ED) visits and GP visits reported over 12 months was analyzed using multivariate negative binomial regression adjusting for confounders. Marginal structural models investigated the presence of time-dependent confounding. Of participants followed up (n = 1753), PIP was detected in 57% by STOPP and 41.8% by START, 21.7% reported an ED visit and 96.1% visited a GP (median 4, IQR 2.5-6). Those with any STOPP criterion had higher rates of ED visits (adjusted incident rate ratio (IRR) 1.30, 95% confidence interval (CI) 1.02, 1.66) and GP visits (IRR 1.15, 95%CI 1.06, 1.24). Patients with two or more START criteria had significantly more ED visits (IRR 1.45, 95%CI 1.03, 2.04) and GP visits (IRR 1.13, 95%CI 1.01, 1.27) than people with no criteria. Adjusting for time-dependent confounding did not affect the findings. Both STOPP and START were independently associated with increased healthcare utilization and START was also related to functional decline and QoL. Optimizing prescribing to reduce PIP may provide an improvement in patient outcomes.


CPU Isosurface Ray Tracing of Adaptive Mesh Refinement Data.
Adaptive mesh refinement (AMR) is a key technology for large-scale simulations that allows for adaptively changing the simulation mesh resolution, resulting in significant computational and storage savings. However, visualizing such AMR data poses a significant challenge due to the difficulties introduced by the hierarchical representation when reconstructing continuous field values. In this paper, we detail a comprehensive solution for interactive isosurface rendering of block-structured AMR data. We contribute a novel reconstruction strategy-the octant method-which is continuous, adaptive and simple to implement. Furthermore, we present a generally applicable hybrid implicit isosurface ray-tracing method, which provides better rendering quality and performance than the built-in sampling-based approach in OSPRay. Finally, we integrate our octant method and hybrid isosurface geometry into OSPRay as a module, providing the ability to create high-quality interactive visualizations combining volume and isosurface representations of BS-AMR data. We evaluate the rendering performance, memory consumption and quality of our method on two gigascale block-structured AMR datasets.


Cigarette smoking and male lung cancer in an area of very high incidence. I. Report of a case-control study in the West of Scotland.
Altogether 656 male lung cancer cases and 1312 age and sex matched controls were interviewed between 1976 and 1981 in a case-control study of cigarette smoking habits and lung cancer in Glasgow and the West of Scotland, an area with the highest recorded incidence in the world. The relative risk of lung cancer increased significantly for smokers whose consumption was below 20 cigarettes per day but did not rise significantly in those who smoked more than 20 cigarettes per day. Other smoking characteristics such as inhalation and tar yields of brands smoked did not explain this finding. Additionally, the relative risks observed at all levels of cigarette consumption were low in comparison with those in the published literature. By constructing an index of cigarette exposure which included the tar yields of brands smoked, an assessment of the risk of lung cancer in relation to tar exposure independent of amount smoked was derived. Only in smokers of less than 15 cigarettes per day was there a statistically significant reduction in risk of lung cancer associated with lower levels of tar yield.


Synaptic scaling in combination with many generic plasticity mechanisms stabilizes circuit connectivity.
Synaptic scaling is a slow process that modifies synapses, keeping the firing rate of neural circuits in specific regimes. Together with other processes, such as conventional synaptic plasticity in the form of long term depression and potentiation, synaptic scaling changes the synaptic patterns in a network, ensuring diverse, functionally relevant, stable, and input-dependent connectivity. How synaptic patterns are generated and stabilized, however, is largely unknown. Here we formally describe and analyze synaptic scaling based on results from experimental studies and demonstrate that the combination of different conventional plasticity mechanisms and synaptic scaling provides a powerful general framework for regulating network connectivity. In addition, we design several simple models that reproduce experimentally observed synaptic distributions as well as the observed synaptic modifications during sustained activity changes. These models predict that the combination of plasticity with scaling generates globally stable, input-controlled synaptic patterns, also in recurrent networks. Thus, in combination with other forms of plasticity, synaptic scaling can robustly yield neuronal circuits with high synaptic diversity, which potentially enables robust dynamic storage of complex activation patterns. This mechanism is even more pronounced when considering networks with a realistic degree of inhibition. Synaptic scaling combined with plasticity could thus be the basis for learning structured behavior even in initially random networks.


Polyamide platinum anticancer complexes designed to target specific DNA sequences.
Two new platinum complexes, trans-chlorodiammine[N-(2-aminoethyl)-4-[4-(N-methylimidazole-2-carboxamido)-N-methylpyrrole-2-carboxamido]-N-methylpyrrole-2-carboxamide]platinum(II) chloride (DJ1953-2) and trans-chlorodiammine[N-(6-aminohexyl)-4-[4-(N-methylimidazole-2-carboxamido)-N-methylpyrrole-2-carboxamido]-N-methylpyrrole-2-carboxamide]platinum(II) chloride (DJ1953-6) have been synthesized as proof-of-concept molecules in the design of agents that can specifically target genes in DNA. Coordinate covalent binding to DNA was demonstrated with electrospray ionization mass spectrometry. Using circular dichroism, these complexes were found to show greater DNA binding affinity to the target sequence: d(CATTGTCAGAC)(2), than toward either d(GTCTGTCAATG)(2,) which contains different flanking sequences, or d(CATTGAGAGAC)(2), which contains a double base pair mismatch sequence. DJ1953-2 unwinds the DNA helix by around 13 degrees , but neither metal complex significantly affects the DNA melting temperature. Unlike simple DNA minor groove binders, DJ1953-2 is able to inhibit, in vitro, RNA synthesis. The cytotoxicity of both metal complexes in the L1210 murine leukaemia cell line was also determined, with DJ1953-6 (34 microM) more active than DJ1953-2 (>50 microM). These results demonstrate the potential of polyamide platinum complexes and provide the structural basis for designer agents that are able to recognize biologically relevant sequences and prevent DNA transcription and replication.


[Assessment of a health program for the non-insured population].
Present the results of the evaluation of a program for the non-insured population of the four poorest states of the country implemented by the Ministry of Health of Mexico between 1991 and 1995. The effects of the program were evaluated in three areas: i) increase in health services coverage; ii) delivery of personal health services, and iii) changes in health conditions of the target population. The extension of coverage was measured by the increase in potential access due to the construction of health infrastructure projects and the use of additional health manpower, mainly primary health care workers. For the evaluation of the impact of the program on the delivery of services, three surveys were developed: one for service utilization, another one for accessibility, and a third for quality of care. The impact on health conditions was evaluated by changes in health indicators of children under five and women of reproductive age. The Program had a positive impact on coverage, accessibility and quality of services. Its impact on health conditions was also positive. However, these last changes cannot be attributed only to the program, but to the sum of several concurrent activities.


Nephronophthisis-medullary cystic kidney disease: from bedside to bench and back again.
Medullary cystic kidney disease (MCKD) belongs with nephronophthisis (NPH) to the NPH-MCKD complex, a group of inherited tubulointerstitial nephritis which share some morphological and clinical features. Juvenile NPH, the most frequent variant of the complex, is a recessive disease with onset in childhood leading to end stage renal disease (ESRD) within the 2nd decade of life. The most frequent extrarenal involvement is tapeto-retinal degeneration. MCKD is a less frequent disease with dominant inheritance; it is recognized later in life, leading to ESRD at the age of 50 years, and may be associated with hyperuricemia and gout. In an early phase, both NPH and MCKD are pauci-symptomatic, major signs being confined to polyuria. Later in the course, clinical findings are related to the progressive renal insufficiency, such as anemia, uremic symptoms and, in NPH, growth retardation. On renal ultrasound, the kidneys present an increased medullary echogenicity with diminished cortico-medullary differentiation. Renal cysts may be present, usually at corticomedullary boundary. Due to the clinico-pathological identity, the two diseases were considered to be a single disorder, and the compromise appellation of NPH-MCKD complex was suggested. This unifying conception was subsequently refuted following the identification of MCKD dominant families. The recent advances of the molecular genetics changed the traditional classification of NPH-MCKD complex. The majority of cases of juvenile NPH are due to deletion of the NPHP1 gene on chromosome 2q13. Genes for infantile and adolescent NPH have been localized to chromosome 9q22-q31 and 3q22, respectively. A new locus, NPHP4, has been recently mapped on chromosome 1p36. Two genes predisposing to dominant MCKD, MCKD1 and MCKD2, have been localized to chromosome 1q21 and to chromosome 16p12. Moreover, a gene for familial juvenile hyperuricemic nephropathy (FJHN), a phenotype very similar to MCKD, was mapped to 16p12 in a region overlapping with the MCKD2 locus. The proof of the allelism between MCKD2 and FJHN has been recently provided by the identification of four novel uromodulin (UMOD) gene mutations, segregating with the disease phenotype in three families with FJHN and one with family with MCKD2. These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders.


Neural Encoding of Speech and Music: Implications for Hearing Speech in Noise.
Understanding speech in a background of competing noise is challenging, especially for individuals with hearing loss or deficits in auditory processing ability. The ability to hear in background noise cannot be predicted from the audiogram, an assessment of peripheral hearing ability; therefore, it is important to consider the impact of central and cognitive factors on speech-in-noise perception. Auditory processing in complex environments is reflected in neural encoding of pitch, timing, and timbre, the crucial elements of speech and music. Musical expertise in processing pitch, timing, and timbre may transfer to enhancements in speech-in-noise perception due to shared neural pathways for speech and music. Through cognitive-sensory interactions, musicians develop skills enabling them to selectively listen to relevant signals embedded in a network of melodies and harmonies, and this experience leads in turn to enhanced ability to focus on one voice in a background of other voices. Here we review recent work examining the biological mechanisms of speech and music perception and the potential for musical experience to ameliorate speech-in-noise listening difficulties.


Usefulness as guided bone regeneration membrane of the alginate membrane.
Alginate membrane is a new bioabsorbable, guided bone regeneration (GBR) membrane, which is placed directly on the surface of the bone defect. It is designed to drop a calcium chloride aqueous solution into the bone defect, which is filled with sodium alginate aqueous solution. Alginate membrane is an excellent agent for this procedure due to its close assimilation to the surface of the bone. In this study, we evaluated the short-term biocompatibility of alginate membrane in the bone defects of rat tibiae. GBR membrane availability was also examined. Consequently, we found that the healing process in bone defects covered with an alginate membrane was delayed in comparison with that of controls, however, the defect was restored to nearly original condition. In contrast, in the controls, bone defect repairs exhibited partitioning as a result of connective tissue involvement. Furthermore, we observed a relation between the sodium alginate concentration and the rate of absorption of the sodium alginate membrane. Absorption of a 1.5% sodium alginate membrane was slow. As a result, the compound was not absorbed completely and bone repairs resembled an hourglass. Moreover, the inflammatory response was absent surrounding the alginate membrane. The present findings suggested that the alginate membrane functions effectively as a GBR membrane. In addition, the alginate membrane derived from 3% calcium chloride and 1% sodium alginate was most suitable as a GBR membrane.


Review of Episiotomy and the Effect of its Risk Factors on Postepisiotomy Complications at the University of Port Harcourt Teaching Hospital.
This study aimed to determine the prevalence of episiotomy and postepisiotomy complications and to assess the relationship between the risk factors and postepisiotomy complications in the University of Port Harcourt Teaching Hospital. This was a descriptive longitudinal study, in which 403 consecutive women who had episiotomy in the labor ward were recruited for the study. They were followed up and reviewed at the postnatal clinic on the 1st and 6th weeks postdelivery. Data regarding age, marital status, occupation, educational status, address, parity, booking status, postepisiotomy complications, and the associated risk factors were entered adequately into a prestructured pro forma, and statistical analysis was done using statistical software (SPSS for Windows® version 19.0). t-test was used to explore the association of risk factors to postepisiotomy complications. The episiotomy rate was 22.1%. The prevalence of postepisiotomy complications was 52.1%. The mean age of the women was 23.8 (standard deviation ± 3.2) years. Seventy-two (34.3%) patients had perineal pain, which lasted for 72 h or more; 61 (29.1%) had difficulty in walking, while 37 (17.6%) had perineal discomfort. Four (1.9%) had wound infection and only one (0.4%) had wound dehiscence. The development of postepisiotomy complications was not statistically significantly associated with risk factors such as gestational age (T = 1.4, P = 0.1), packed cell volume on admission (T = 1.0, P = 0.2), duration of first stage of labor (T = 0.5, P = 0.1), duration of second stage of labor (T = 0.7, P = 0.3), duration of rupture of fetal membranes (T = 0.8, P = 0.4), delivery repair interval (T = 0.6, P = 0.2), estimated blood loss (T = 0.9, P = 0.2), duration of Sitz bath (T = 1.0, P = 0.2), duration of analgesic (T = 1.2, P = 0.1), duration of antibiotics (T = 1.3, P = 0.1), or the operator who performed or repaired the episiotomy (P = 0.2). The prevalence of episiotomy and postepisiotomy complications in this study was high. Necessary attention should be given to ensure adequate pain relief for all parturients who had episiotomy, and the policy of restrictive use of episiotomy should be fully implemented in the department in line with the best practices and evidence-based recommendations. This will further reduce the incidence of episiotomy rate as well complications that may arise from it and ensure a positive pregnancy experience for pregnant women.


Lyme disease following a dog bite--was there a tick?
Lyme disease is the most common tick borne infection in temperate zones and the reported incidence of the condition is increasing. Erythema migrans is one of the few clinical signs of Lyme disease and is usually indicative of recently acquired infection. A case is presented of Lyme disease with erythema migrans which followed shortly after a dog bite. The author is not aware of any previously reported similar case. The author considers that the development of Lyme disease in the case was most likely due to a coincidental tick bite which was not noticed by the patient but an alternative possibility is that the disease was activated from a latent form. Patients with Lyme disease may not give a history of tick bite and clinicians should be aware of this.


Near-infrared spectroscopy and skeletal muscle oxidative function in vivo in health and disease: a review from an exercise physiology perspective.
In most daily activities related to work or leisure, the energy for muscle work substantially comes from oxidative metabolism. Functional limitations or impairments of this metabolism can significantly affect exercise tolerance and performance. As a method for the functional evaluation of skeletal muscle oxidative metabolism, near-infrared spectroscopy (NIRS) has important strengths but also several limitations, some of which have been overcome by recent technological developments. Skeletal muscle fractional O2 extraction, the main variable which can be noninvasively evaluated by NIRS, is the result of the dynamic balance between O2 utilization and O2 delivery; it can yield relevant information on key physiological and pathophysiological mechanisms, relevant in the evaluation of exercise performance and exercise tolerance in healthy subjects (in normal and in altered environmental conditions) and in patients. In the right hands, NIRS can offer insights into the physiological and pathophysiological adaptations to conditions of increased O2 needs that involve, in an integrated manner, different organs and systems of the body. In terms of patient evaluation, NIRS allows determination of the evolution of the functional impairments, to identify their correlations with clinical symptoms, to evaluate the effects of therapeutic or rehabilitative interventions, and to gain pathophysiological and diagnostic insights.


Generalisation, decision making, and embodiment effects in mental rotation: A neurorobotic architecture tested with a humanoid robot.
Mental rotation, a classic experimental paradigm of cognitive psychology, tests the capacity of humans to mentally rotate a seen object to decide if it matches a target object. In recent years, mental rotation has been investigated with brain imaging techniques to identify the brain areas involved. Mental rotation has also been investigated through the development of neural-network models, used to identify the specific mechanisms that underlie its process, and with neurorobotics models to investigate its embodied nature. Current models, however, have limited capacities to relate to neuro-scientific evidence, to generalise mental rotation to new objects, to suitably represent decision making mechanisms, and to allow the study of the effects of overt gestures on mental rotation. The work presented in this study overcomes these limitations by proposing a novel neurorobotic model that has a macro-architecture constrained by knowledge held on brain, encompasses a rather general mental rotation mechanism, and incorporates a biologically plausible decision making mechanism. The model was tested using the humanoid robot iCub in tasks requiring the robot to mentally rotate 2D geometrical images appearing on a computer screen. The results show that the robot gained an enhanced capacity to generalise mental rotation to new objects and to express the possible effects of overt movements of the wrist on mental rotation. The model also represents a further step in the identification of the embodied neural mechanisms that may underlie mental rotation in humans and might also give hints to enhance robots' planning capabilities.


Time to unravel the conceptual confusion of authenticity and fidelity and their contribution to learning within simulation-based nurse education. A discussion paper.
High-fidelity patient simulation is a method of education increasingly utilised by educators of nursing to provide authentic learning experiences. Fidelity and authenticity, however, are not conceptually equivalent. Whilst fidelity is important when striving to replicate a life experience such as clinical practice, authenticity can be produced with low fidelity. A challenge for educators of undergraduate nursing is to ensure authentic representation of the clinical situation which is a core component for potential success. What is less clear is the relationship between fidelity and authenticity in the context of simulation based learning. Authenticity does not automatically follow fidelity and as a result, educators of nursing cannot assume that embracing the latest technology-based educational tools will in isolation provide a learning environment perceived authentic by the learner. As nursing education programmes increasingly adopt simulators that offer the possibility of representing authentic real world situations, there is an urgency to better articulate and understand the terms fidelity and authenticity. Without such understanding there is a real danger that simulation as a teaching and learning resource in nurse education will never reach its potential and be misunderstood, creating a potential barrier to learning. This paper examines current literature to promote discussion within nurse education, concluding that authenticity in the context of simulation-based learning is complex, relying on far more than engineered fidelity.


Cytotoxic and Antibacterial Cervinomycins B1-4 from a Streptomyces Species.
AntiSMASH analysis of genome DNA of Streptomyces CPCC 204980, a soil isolate with potent antibacterial activity, revealed a gene cluster for polycyclic xanthones. A subsequent chemical study confirmed that the microorganism produced polycyclic xanthone cervinomycin A2 (1) and the new congeners cervinomycins B1-4 (2-5). The structures of 1-5 were determined by comprehensive analyses of MS and NMR data, which indicated that 2-5 featured a common dihydro-D ring in the polycyclic xanthone core moiety of their molecules. 2-5 are toxic to human cancer cells and active against Gram-positive bacteria.


Patient with ankylosing spondylitis and scleroderma renal crisis.
We report a 56-year-old man with a history of ankylosing spondylitis and systemic scleroderma. The patient had been diagnosed with ankylosing spondylitis 20 years ago and had been receiving treatment with NSAIDs and anti TNFα drugs. He referred to our rheumatology department for Raynaud's phenomenon, arthralgias and weight loss. Physical examination revealed stiffness of the skin with difficulty in pinching (mainly at lower extremities, from knee to ankle). Soon after his first visit to our department, he developed renal scleroderma crisis with abrupt increase in blood pressure, decline in renal function, and microangiopathic haemolytic anaemia in accordance with positive antinuclear autoantibodies and positive anti-topoisomerase I antibody (anti-Scl70). This is one of the few reports in the literature of coexistence of ankylosing spondylitis and systemic scleroderma. A genetic correlation seems to be an explanation in some patients who carry one or two susceptibility alleles to both diseases. Thus, this might be the case of a 'genetic trap' in which distinct genes are cooperating to favour the susceptibility to two different HLA-associated systemic autoimmune diseases.


Heterogeneous hydrosilylation reaction catalysed by platinum complexes immobilized on bipyridine-periodic mesoporous organosilicas.
The utility of a bipyridine periodic mesoporous organosilica, BPy-PMO, as a support material of a hydrosilylation catalyst was investigated in the hydrosilylation of phenylacetylene with trimethoxysilane. [PtMe2(BPy-PMO)] (1) exhibited a moderate catalytic activity, whereas the reaction was successfully catalysed by [PtMe2(BPy-PMO-TMS)] (2) bearing end-capped TMS groups on the surface. Spectroscopic analyses of 2 revealed that the porous structure of BPy-PMO-TMS remained almost unchanged through the reaction. The hot filtration test supported the nonleaching property of 2, thereby exhibiting good reusability without the loss of the product yields.


A disease-associated mutation in fibrillin-1 differentially regulates integrin-mediated cell adhesion.
Fibrillins serve as scaffolds for the assembly of elastic fibers that contribute to the maintenance of tissue homeostasis and regulate growth factor signaling in the extracellular space. Fibrillin-1 is a modular glycoprotein that includes 7 latent transforming growth factor β (TGFβ)-binding protein-like (TB) domains and mediates cell adhesion through integrin binding to the RGD motif in its 4th TB domain. A subset of missense mutations within TB4 cause stiff skin syndrome (SSS), a rare autosomal dominant form of scleroderma. The fibrotic phenotype is thought to be regulated by changes in the ability of fibrillin-1 to mediate integrin binding. We characterized the ability of each RGD-binding integrin to mediate cell adhesion to fibrillin-1 or a disease-causing variant. Our data show that 7 of the 8 RGD-binding integrins can mediate adhesion to fibrillin-1. A single amino acid substitution responsible for SSS (W1570C) markedly inhibited adhesion mediated by integrins α5β1, αvβ5, and αvβ6, partially inhibited adhesion mediated by αvβ1, and did not inhibit adhesion mediated by α8β1 or αIIbβ3. Adhesion mediated by integrin αvβ3 depended on the cell surface expression level. In the SSS mutant background, the presence of a cysteine residue in place of highly conserved tryptophan 1570 alters the conformation of the region containing the exposed RGD sequence within the same domain to differentially affect fibrillin's interactions with distinct RGD-binding integrins.


Combining feature- and correspondence-based methods for visual object recognition.
We present an object recognition system built on a combination of feature- and correspondence-based pattern recognizers. The feature-based part, called preselection network, is a single-layer feedforward network weighted with the amount of information contributed by each feature to the decision at hand. For processing arbitrary objects, we employ small, regular graphs whose nodes are attributed with Gabor amplitudes, termed parquet graphs. The preselection network can quickly rule out most irrelevant matches and leaves only the ambiguous cases, so-called model candidates, to be verified by a rudimentary version of elastic graph matching, a standard correspondence-based technique for face and object recognition. According to the model, graphs are constructed that describe the object in the input image well. We report the results of experiments on standard databases for object recognition. The method achieved high recognition rates on identity and pose. Unlike many other models, it can also cope with varying background, multiple objects, and partial occlusion.


Role of aspirin in primary prevention of cardiovascular disease.
The benefits of aspirin therapy for the secondary prevention of cardiovascular disease clearly outweigh the risks of bleeding, and low-dose aspirin is uniformly recommended in this setting. However, no clear consensus exists about whether, and if so in whom, aspirin therapy is appropriate for the primary prevention of cardiovascular disease. Three trials of low-dose aspirin versus placebo in three populations at increased risk of myocardial infarction or ischaemic stroke in the absence of established cardiovascular disease were reported in 2018. The ASPREE trial in elderly people was terminated early for futility because aspirin had no effect on disability-free survival but significantly increased the risk of major haemorrhage and, unexpectedly, all-cause mortality. In the ASCEND trial in patients with diabetes mellitus and no evidence of vascular disease, aspirin significantly reduced serious vascular events but increased major bleeding. In the ARRIVE trial in people with multiple risk factors for cardiovascular disease, aspirin had no effect on major cardiovascular events but increased gastrointestinal bleeding. The aim of this Review is to place these new results in the context of previous evidence on aspirin for the primary prevention of cardiovascular disease and to appraise whether the new evidence is likely to enable the more targeted use of aspirin in particular individuals for whom the net benefit is both clinically worthwhile and statistically definite.


Complete lack of vitamin C intake generates pulmonary emphysema in senescence marker protein-30 knockout mice.
Vitamin C (VC) is a potent antioxidant and plays an essential role in collagen synthesis. As we previously reported, senescence marker protein-30 (SMP30) knockout (KO) mice cannot synthesize VC due to the genetic disruption of gluconolactonase (i.e., SMP30). Here, we utilized SMP30 KO mice deprived of VC and found that VC depletion caused pulmonary emphysema due to oxidative stress and a decrease of collagen synthesis by the third month of age. We grew SMP30 KO mice and wild-type (WT) mice on VC-free chow and either VC water [VC(+)] or plain water [VC(-)] after weaning at 4 wk of age. Morphometric findings and reactive oxygen species (ROS) in the lungs were evaluated at 3 mo of age. No VC was detected in the lungs of SMP30 KO VC(-) mice, but their ROS increased 50.9% over that of the VC(+) group. Moreover, their collagen content in the lungs markedly decreased, and their collagen I mRNA decreased 82.2% compared with that of the WT VC(-) group. In the SMP30 KO VC(-) mice, emphysema developed [21.6% increase of mean linear intercepts (MLI) and 42.7% increase of destructive index compared with VC(+) groups], and the levels of sirtuin 1 (Sirt1) decreased 16.8%. However, VC intake increased the MLI 16.2% and thiobarbituric acid reactive substances 22.2% in WT mice, suggesting that an excess of VC can generate oxidative stress and may be harmful during this period of lung development. These results suggest that VC plays an important role in lung development through affecting oxidant-antioxidant balance and collagen synthesis.


Genetic Basis of Maize Resistance to Multiple Insect Pests: Integrated Genome-Wide Comparative Mapping and Candidate Gene Prioritization.
Several species of herbivores feed on maize in field and storage setups, making the development of multiple insect resistance a critical breeding target. In this study, an association mapping panel of 341 tropical maize lines was evaluated in three field environments for resistance to fall armyworm (FAW), whilst bulked grains were subjected to a maize weevil (MW) bioassay and genotyped with Diversity Array Technology's single nucleotide polymorphisms (SNPs) markers. A multi-locus genome-wide association study (GWAS) revealed 62 quantitative trait nucleotides (QTNs) associated with FAW and MW resistance traits on all 10 maize chromosomes, of which, 47 and 31 were discovered at stringent Bonferroni genome-wide significance levels of 0.05 and 0.01, respectively, and located within or close to multiple insect resistance genomic regions (MIRGRs) concerning FAW, SB, and MW. Sixteen QTNs influenced multiple traits, of which, six were associated with resistance to both FAW and MW, suggesting a pleiotropic genetic control. Functional prioritization of candidate genes (CGs) located within 10-30 kb of the QTNs revealed 64 putative GWAS-based CGs (GbCGs) showing evidence of involvement in plant defense mechanisms. Only one GbCG was associated with each of the five of the six combined resistance QTNs, thus reinforcing the pleiotropy hypothesis. In addition, through in silico co-functional network inferences, an additional 107 network-based CGs (NbCGs), biologically connected to the 64 GbCGs, and differentially expressed under biotic or abiotic stress, were revealed within MIRGRs. The provided multiple insect resistance physical map should contribute to the development of combined insect resistance in maize.


NTP Technical Report on the metabolism, toxicity and predicted carcinogenicity of diazoaminobenzene (CAS No. 136-35-6).
Diazoaminobenzene is used as an intermediate, complexing agent, and polymer additive. It is also an impurity in certain color additives used in cosmetics, food products, and pharmaceuticals. Diazoaminobenzene was selected for metabolism and toxicity studies based on the potential for worker exposure from its use in laboratories, positive Salmonella typhimurium gene mutation data, its presence as an impurity in foods and cosmetics, and the lack of adequate toxicity data. Several structural analogues and presumed metabolites of diazoaminobenzene are carcinogenic, providing evidence for the possible carcinogenicity of diazoaminobenzene. The chemical structure of diazoaminobenzene suggested that it would be metabolized into aniline and benzene; therefore, metabolism and disposition studies were performed in male and female F344/N rats and male B6C3F1 mice administered a single oral, dermal, or intravenous dose of diazoaminobenzene. Electron spin resonance (ESR) studies were conducted to assess the possible formation of a phenyl radical from the reduction of diazoaminobenzene by components of the cytochrome P450 mixed-function oxidase (P450) system in microsomes or by gut microflora in anaerobic cecal incubations. Bile duct-cannulated male F344/N rats were administered diazoaminobenzene and 5,5-dimethyl-1- pyrroline-N-oxide (DMPO) for in vivo determination of the DMPO-phenyl radical. 16-Day toxicity studies were performed to identify target organs of diazoaminobenzene following dermal application to male and female F344/N rats and B6C3F1 mice. In the disposition and metabolism studies, oral doses of 20 mg/kg to male and female rats and male mice were readily absorbed and excreted mainly in the urine, with exhalation of volatile organics accounting for about 1% of the dose. The only volatile metabolite detected in the breath was benzene, and all the metabolites in the urine were those previously shown to result from the metabolism of benzene and aniline in rats and mice. While dermal doses to rats and mice (2 and 20 mg/cm2) were only slightly absorbed, benzene and aniline metabolites were nonetheless detected in the urine. High circulating levels of benzene, aniline, and their metabolites were detected in the blood of rats administered 20 mg/kg diazoaminobenzene as early as 15 minutes after exposure. At 24 hours after dosing, diazoaminobenzene was detected at low levels (<1%) in the adipose tissue, blood, kidney, liver, muscle, skin, and spleen. Metabolites of benzene and aniline were also formed in an in vitro study using human liver slices. In the ESR spin-trapping experiments, the ESR spectrum of the DMPO-phenyl radical was detected when diazoaminobenzene was incubated with microsomes or P450 reductase, DMPO, and NADPH, or when incubated with cecal contents and DMPO. The DMPO-phenyl radical spectrum was not attenuated by the P450 inhibitor, 1-aminobenzotriazole, or carbon monoxide suggesting that P450s were not required. In in vivo experiments in which rats were administered diazoaminobenzene and DMPO, the DMPO-phenyl radical adduct was detected in bile within 1 hour after treatment. In the 16-day toxicity studies, groups of five male and five female F344/N rats and B6C3F1 mice received dermal applications of 0, 12.5, 25, 50, 100, or 200 mg diazoaminobenzene/kg body weight. Animals were evaluated for absolute and relative organ weights, for hematological effects, and for gross and microscopic lesions. No mortality occurred in rats. However, most male mice exposed to concentrations of 50 mg/kg or greater and female mice exposed to 200 mg/kg died. Body weights of male and female rats and female mice were less than those of the vehicle controls. Similar chemical-related toxicities were observed in both species. Clinical pathology data indicated a chemical-related methemoglobinemia and Heinz body formation in male and female rats and mice. Analysis of organ weights indicated possible chemical-related effects in the thymus, heart, spleen, kidney, and liver of rats and/or mice. Increases in the incidences of several skin lesionseral skin lesions, including hyperplasia of the epidermis and hair follicles, and inflammation in rats and mice and ulceration in female mice were observed. Other nonneoplastic lesions that were considered to be related to diazoaminobenzene administration were atrophy of the thymus, mandibular and/or mesenteric lymph nodes, and white pulp of the spleen, as well as splenic hematopoietic cell proliferation in rats and mice. In mice, there were increased incidences of atrial thrombosis, and necrosis was observed in the renal tubules and liver. Diazoaminobenzene was mutagenic in S. typhimurium strains TA98, TA100, and TA1537 with induced rat or hamster liver S9 enzymes; no activity was noted in strain TA1535, with or without S9. In vivo, two gavage administrations of either diazoaminobenzene or benzene induced highly significant increases in micronucleated polychromatic erythrocytes in bone marrow of male B6C3F1 mice at all doses tested. Diazoaminobenzene is metabolized to the known carcinogens benzene and aniline. Further evidence of this metabolism is that some toxic effects associated with aniline (methemoglobinemia) and benzene (atrophy of the lymphoid tissue) were identified. Based on these results, it is predicted that diazoaminobenzene is a carcinogen.


Data-driven visual tracking in retinal microsurgery.
In the context of retinal microsurgery, visual tracking of instruments is a key component of robotics assistance. The difficulty of the task and major reason why most existing strategies fail on in-vivo image sequences lies in the fact that complex and severe changes in instrument appearance are challenging to model. This paper introduces a novel approach, that is both data-driven and complementary to existing tracking techniques. In particular, we show how to learn and integrate an accurate detector with a simple gradient-based tracker within a robust pipeline which runs at framerate. In addition, we present a fully annotated dataset of retinal instruments in in-vivo surgeries, which we use to quantitatively validate our approach. We also demonstrate an application of our method in a laparascopy image sequence.


Vision of the hand and environmental context in human prehension.
Previous findings on the role of visual contact with the hand in the control of reaching and grasping have been contradictory. Some studies have shown that such contact is largely irrelevant, while more recent ones have emphasised its importance. In contrast, information arising from the surrounding environment has received relatively little attention in the study of prehensile actions. In order to identify the roles of both sources of information, we made kinematic comparisons between three conditions. In the first, reaching was performed in a dimly lit room and compared with a second condition in which reaches in the dark, but with the thumb and first finger illuminated, were made to a luminous object. This contrast allows the effects of environmental context to be identified. A comparison between the second and a third condition, in which both vision of the hand and the environment was removed, but the object was still visually available, enabled the assessment of how and when vision of the hand plays a role. Removing environmental cues had effects both early and late in the reach, while vision of the hand was only crucial in the period after peak deceleration. In addition, removal of both sources of information resulted in larger grip apertures. Differences and similarities between our findings and those of other studies are discussed, as is the ongoing debate about the relative importance of visual feedback of the hand in the control and co-ordination of prehensile actions. We conclude with suggestions for further research based on the set-up used in the present study.


Minimal relapse risk and early normalization of survival for patients with Burkitt lymphoma treated with intensive immunochemotherapy: an international study of 264 real-world patients.
Non-endemic Burkitt lymphoma (BL) is a rare germinal centre B-cell-derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic-based and population-based lymphoma registries from six countries were used to identify 264 real-world patients. The median age was 47 years and the majority had advanced-stage disease and elevated LDH. Treatment protocols were R-CODOX-M/IVAC (47%), R-hyper-CVAD (16%), DA-EPOCH-R (11%), R-BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two-year overall survival and event-free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two-year relapse risk was 6% but diminished to 0·6% for patients reaching 12 months of post-remission event-free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0·4 (95% CI: -0·7 to 2) months. In conclusion, real-world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow-up strategies with increased focus on survivorship and less focus on routine disease surveillance.


No treatment versus 24 or 60 weeks of antiretroviral treatment during primary HIV infection: the randomized Primo-SHM trial.
The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI). Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1∶1∶1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1∶1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count < 350 cells/mm(3) or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log(10) copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log(10) copies/ml in the 24- and 60-wk treatment arms (between groups: p < 0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0-1.8) y compared to 3.0 (1.9-4.2) and 1.8 (0.5-3.0) y in the 24- and 60-wk treatment arms (log rank test, p < 0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25-0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32-0.95]) were associated with time to (re)start of cART. In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection.


Incidence and biochemical parameters of dermatophilosis in Nigerian cattle breeds from livestock markets, Oyo state, Nigeria.
Dermatophilosis is one of the major economically important diseases of cattle in Nigeria. Managing the condition has been very challenging and re-occurrence has been reported with moderate to high morbidity and mortality. The incidence and biochemical features of cattle with dermatophilosis was conducted in June to December 2016 across the four geopolitical zones of Oyo state, Nigeria. Clinical diagnosis were made based on appearance of dermatophilosis lesion, breeds morphologically characterized, ageing were based on rostral dentition and severity based on the extent and nature of the lesion. Biochemical analysis was based on standard procedure as prescribed by Fortress International. Fifty cattle were found to be infected with clinical dermatophilosis during the period of the study. Twenty four (48%) in Ibadan zone, 14 (28%) in Oyo/Ogbomosho, 8 (16%) in Oke-ogun and 4 (8%) in Ibarapa zone. Breeds distribution across the zones showed 28 (56%) White Fulani, 5 (10%) Sokoto Gudali, 3 (6%) Adamawa Gudali, 7 (14%) Red Bororo, 5 (10%) Cross breeds while the Kuri was 2 (4%). Regarding animal ages, less than 2 years old were 2 animals (4%) while the adults were 48 animals (96%) and they fall under the categories of 2-2½ years of age, 3-3½ years of age and those which are over 3½ years of age. The different levels of severity were categorized into mild (20 (40%)), moderate (23 (46%)) and severe (7 (14%)) .The best parameters were seen in White Fulani, while the least were seen in Adamawa Gudali. The age group in the category of 3 - 3½ years had most of the best serum values while the least values were seen in animals less than 2 years of age. Cattle exhibiting mild lesions had most of the best serum values and the least values were observed in cattle with severe lesions. No significant difference (p > 0.05) was observed in the mean values for the various parameters studied among the breeds, age, and severity of condition.


ART influences HIV persistence in the female reproductive tract and cervicovaginal secretions.
The recently completed HIV prevention trials network study 052 is a landmark collaboration demonstrating that HIV transmission in discordant couples can be dramatically reduced by treating the infected individual with antiretroviral therapy (ART). However, the cellular and virological events that occur in the female reproductive tract (FRT) during ART that result in such a drastic decrease in transmission were not studied and remain unknown. Here, we implemented an in vivo model of ART in BM/liver/thymus (BLT) humanized mice in order to better understand the ability of ART to prevent secondary HIV transmission. We demonstrated that the entire FRT of BLT mice is reconstituted with human CD4+ cells that are shed into cervicovaginal secretions (CVS). A high percentage of the CD4+ T cells in the FRT and CVS expressed CCR5 and therefore are potential HIV target cells. Infection with HIV increased the numbers of CD4+ and CD8+ T cells in CVS of BLT mice. Furthermore, HIV was present in CVS during infection. Finally, we evaluated the effect of ART on HIV levels in the FRT and CVS and demonstrated that ART can efficiently suppress cell-free HIV-RNA in CVS, despite residual levels of HIV-RNA+ cells in both the FRT and CVS.


The role of the pediatrician in the oral health of children: A national survey.
To assess pediatricians' knowledge, attitudes, and professional experience regarding oral health, and to determine willingness to incorporate fluoride varnish into their practices. Poor and minority children suffer disproportionately from dental caries and have limited access to dental care. In a recent analysis of national survey data, the General Accounting Office reported that poor children had 5 times more untreated decay than did children from higher income families. Untreated decay can lead to problems with eating, speaking, and attending to learning. Children who are poor suffer 12 times the number of restricted activity days because of dental problems, compared with more affluent children. Despite higher rates of dental decay, poor children had one half the number of dental visits compared with higher income children in 1996. Medicaid's Early Periodic Screening Diagnosis and Treatment (EPSDT) program is intended to provide regular dental screenings and appropriate treatment but has apparently played a limited role in improving access to dental care for poor children. According to a report by the Office of the Inspector General of the Department of Health and Human Services, only 20% of children under 21 years of age, who were enrolled in Medicaid and eligible for EPSDT, actually received preventive dental services. By increasing their involvement in oral health prevention during well-child care visits, pediatricians may be able to play an important role in improving the dental health of their patients who have difficulty obtaining access to professional dental care. However, it is unclear to what degree pediatricians are knowledgeable about preventive oral health and the extent to which they may already be participating in prevention and assessment. Also, little is known about the incidence of dental problems in pediatric practice, and whether pediatricians perceive barriers to their patients' receiving professional dental care. Finally, it is important to know how pediatricians value the promotion of oral health and whether they would be willing to take on additional activities aimed at its improvement. We addressed these questions in a national survey of pediatricians. We surveyed a national sample of 1600 pediatricians randomly selected from the American Medical Association Master File to assess their knowledge, current practice, and opinion on their role in the promotion of oral health; experience with dental decay among patients and in referring patients for professional dental care; and willingness to apply fluoride varnish. Of 1386 eligible survey recipients, 862 returned surveys for a response rate of 62%. Respondents reported seeing dental problems regularly. Two thirds of respondents observed caries in their school-aged patients at least once a month. Of the respondents, 55% reported difficulty achieving successful dental referrals for their uninsured patients and 38% reported difficulty referring their Medicaid patients. More than 90% of the respondents agreed that they had an important role in identifying dental problems and counseling families on the prevention of caries. Moreover, respondents were interested in increasing their involvement: 74% expressed a willingness to apply fluoride varnish in their practices. One half of the respondents, however, reported no previous training in dental health issues during medical school or residency, and only 9% correctly answered all 4 knowledge questions. Access to dental care and unmet dental health needs are serious, under addressed problems for poor and minority children in the United States. In promoting preventive oral health, pediatricians benefit all children and particularly the underserved. We know of 2 states, Washington and North Carolina, that have acknowledged, through the provision of reimbursement, that pediatricians have a unique opportunity at well-child care visits to provide caries prevention c


The development of a single-use, capsule-free multi-breath tobramycin dry powder inhaler for the treatment of cystic fibrosis.
The aerosol performance and delivery characteristics of tobramycin for the treatment of respiratory infection were evaluated using the Orbital™, a multi-breath, high dose, dry powder inhaler (DPI). Micronised tobramycin was prepared and tested in the Orbital and in the commercially available TOBI Podhaler (Novartis AG). Furthermore, the TOBI Podhaler formulation containing tobramycin as Pulmospheres was tested in both the commercial Podhaler device (T-326) and Orbital for comparison. By varying the puck geometry of the Orbital, it was possible to deliver equivalent doses of micronised tobramycin (114.09±5.86mg) to that of the Podhaler Pulmosphere product (116.01±2.59mg) over 4 sequential simulated breaths (60Lmin-1 for 4s) without the need for multiple capsules. In general, the aerosol performance of the micronised tobramycin from the Orbital was higher than the T-326 Podhaler device, with fine particle fraction (FPF) of 44.99%±1.09% and 37.03%±0.86%, respectively. When testing the Pulmosphere powder in the two devices, the T-326 had marginally better performance with a FPF of 68.77%±2.10% compared to 61.30%±3.45%. This is to be expected since the TOBI Podhaler and Pulmosphere are an optimised powder and device combination. The Orbital was shown to be capable of delivering high efficiency, high dose antibiotic therapy for inhalation without the need for the use of multiple capsules as used in current devices. This approach may pave the way for a number of antibiotic therapies and medicaments where high dose respiratory deposition is required.


Psychiatric diagnoses in patients previously overdiagnosed with bipolar disorder.
In a previous article from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we reported that bipolar disorder is often overdiagnosed in psychiatric outpatients. An important question not examined in that article was what diagnoses were given to the patients who had been overdiagnosed with bipolar disorder. In the present report from the MIDAS project, we examined whether there was a particular diagnostic profile associated with bipolar disorder overdiagnosis. Eighty-two psychiatric outpatients reported having been previously diagnosed with bipolar disorder that was not confirmed when they were interviewed with the Structured Clinical Interview for DSM-IV (SCID). Psychiatric diagnoses were compared in these 82 patients and in 528 patients who were not previously diagnosed with bipolar disorder. Patients were interviewed by a highly trained diagnostic rater who administered a modified version of the SCID for DSM-IV Axis I disorders and the Structured Interview for DSM-IV Personality for DSM-IV Axis II disorders. This study was conducted from May 2001 to March 2005. The most frequent lifetime diagnosis in the 82 patients previously diagnosed with bipolar disorder was major depressive disorder (82.9%, n = 68). The patients overdiagnosed with bipolar disorder were significantly more likely to be diagnosed with borderline personality disorder compared to patients who were not diagnosed with bipolar disorder (24.4% vs 6.1%; P < .001). A previous diagnosis of bipolar disorder was also associated with significantly higher lifetime rates of major depressive disorder (P < .01), posttraumatic stress disorder (P < .05), impulse control disorders (P < .05), and eating disorders (P < .05), although only the association with impulse control disorders remained significant after controlling for the presence of borderline personality disorder. Psychiatric outpatients overdiagnosed with bipolar disorder were characterized by more Axis I and Axis II diagnostic comorbidity in general, and borderline personality disorder in particular.


Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.
Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93-1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94-1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93-1·05; p=0·79). In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. UK Research and Innovation (Medical Research Council) and National Institute of Health Research.


Preparation, characterization, in vitro release and degradation of cathelicidin-BF-30-PLGA microspheres.
Cathelicidin-BF-30 (BF-30), a water-soluble peptide isolated from the snake venom of Bungarus fasciatus containing 30 amino acid residues, was incorporated in poly(D,L-lactide-co-glycolide) (PLGA) 75∶25 microspheres (MS) prepared by a water in oil in water W/O/W emulsification solvent extraction method. The aim of this work was to investigate the stability of BF-30 after encapsulation. D-trehalose was used as an excipient to stabilize the peptide. The MS obtained were mostly under 2 µm in size and the encapsulation efficiency was 88.50±1.29%. The secondary structure of the peptide released in vitro was determined to be nearly the same as the native peptide using Circular Dichroism (CD). The ability of BF-30 to inhibit the growth of Escherichia coli was also maintained. The cellular relative growth and hemolysis rates were 92.16±3.55% and 3.52±0.45% respectively.