Bone balance within a cortical BMU: local controls of bone resorption and formation.
Maintaining bone volume during bone turnover by a BMU is known as bone balance. Balance is required to maintain structural integrity of the bone and is often dysregulated in disease. Consequently, understanding how a BMU controls bone balance is of considerable interest. This paper develops a methodology for identifying potential balance controls within a single cortical BMU. The theoretical framework developed offers the possibility of a directed search for biological processes compatible with the constraints of balance control. We first derive general control constraint equations and then introduce constitutive equations to identify potential control processes that link key variables that describe the state of the BMU. The paper describes specific local bone volume balance controls that may be associated with bone resorption and bone formation. Because bone resorption and formation both involve averaging over time, short-term fluctuations in the environment are removed, leaving the control systems to manage deviations in longer-term trends back towards their desired values. The length of time for averaging is much greater for bone formation than for bone resorption, which enables more filtering of variability in the bone formation environment. Remarkably, the duration for averaging of bone formation may also grow to control deviations in long-term trends of bone formation. Providing there is sufficient bone formation capacity by osteoblasts, this leads to an extraordinarily robust control mechanism that is independent of either osteoblast number or the cellular osteoid formation rate. A complex picture begins to emerge for the control of bone volume. Different control relationships may achieve the same objective, and the 'integration of information' occurring within a BMU may be interpreted as different sets of BMU control systems coming to the fore as different information is supplied to the BMU, which in turn leads to different observable BMU behaviors.


A siderophore from Pseudomonas putida type A1: structural and biological characterization.
A siderophore from a root-colonizing, plant-beneficial fluorescent Pseudomonas (P. putida type A1) isolated from chickpea rhizosphere was studied. Culture conditions required for optimal production of the chromophore by the organism were standardized. The compound was purified by gel filtration, ion exchange and RP-HPLC chromatographic procedures. The purified compound exhibited siderophore activity for P. putida and antifungal activity on phytopathogens, Fusarium oxysporum f. sp. ciceri and Helminthosporium oryzae. Growth inhibition of the pathogens was observed under iron-deficient conditions. Complete acid hydrolysis of the compound revealed that it is a peptide containing Asx, Thr, Glx, Val, His, Lys, Ser and Gly. Spectral analysis revealed that it contains hydroxyquinoline-based chromophore in addition to an aromatic residue and the molecular weight of the compound was 1.5 kDa. EPR analysis of the peptide-chromophore-iron complex showed that the compound binds to iron and the bound iron was in the Fe(3+) oxidation state having a high spin d(5) system. The peptide-chromophore-iron complex takes a turn structure in solution as shown by circular dichroism spectroscopy, a feature which was hitherto not known for other siderophores. The siderophore studied here is unique in this respect but otherwise strikingly similar to other pseudobactin-type siderophores of plant growth-promoting and plant-deleterious pseudomonads. The possible functional significance of the compound is discussed in relation to the secondary structure described earlier for siderophores.


Characterization of the chlorosome antenna of the filamentous anoxygenic phototrophic bacterium Chloronema sp. strain UdG9001.
The absorption and fluorescence properties of chlorosomes of the filamentous anoxygenic phototrophic bacterium Chloronema sp. strain UdG9001 were analyzed. The chlorosome antenna of Chloronema consists of bacteriochlorophyll (BChl) d and BChl c together with gamma-carotene as the main carotenoid. HPLC analysis combined with APCI LC-MS/MS showed that the chlorosomal BChls comprise a highly diverse array of homologues that differ in both the degree of alkylation of the macrocycle at C-8 and/or C-12 and the alcohol moiety esterified to the propionic acid group at C-17. BChl c and BChl d from Chloronema were mainly esterified with geranylgeraniol (33% of the total), heptadecanol (24%), octadecenol (19%), octadecanol (14%), and hexadecenol (9%). Despite this pigment heterogeneity, fluorescence emission of the chlorosomes showed a single peak centered at 765 nm upon excitation at wavelengths ranging from 710 to 740 nm. This single emission, assigned to BChl c, indicates an energy transfer from BChl d to BChl c within the same chlorosome. Likewise, incubation of chlorosomes under reducing conditions caused a weak increase in fluorescence emission, which indicates a small redox-dependent fluorescence. Finally, protein analysis of Chloronema chlorosomes using SDS-PAGE and MALDI-TOF-MS revealed the presence of a chlorosomal polypeptide with a molecular mass of 5.7 kDa, resembling the CsmA protein found in Chloroflexus aurantiacus and Chlorobium tepidum chlorosomes. Several minor polypeptides were also detected but not identified. These results indicate that, compared with other members of filamentous anoxygenic phototrophic bacteria and green sulfur bacteria, Chloronema possesses an antenna system with novel features that may be of interest for further investigations.


TAL effector-mediated genome visualization (TGV).
The three-dimensional remodeling of chromatin within nucleus is being recognized as determinant for genome regulation. Recent technological advances in live imaging of chromosome loci begun to explore the biological roles of the movement of the chromatin within the nucleus. To facilitate better understanding of the functional relevance and mechanisms regulating genome architecture, we applied transcription activator-like effector (TALE) technology to visualize endogenous repetitive genomic sequences in mouse cells. The application, called TAL effector-mediated genome visualization (TGV), allows us to label specific repetitive sequences and trace nuclear remodeling in living cells. Using this system, parental origin of chromosomes was specifically traced by distinction of single-nucleotide polymorphisms (SNPs). This review will present our approaches to monitor nuclear dynamics of target sequences and highlights key properties and potential uses of TGV.


Too busy: why time is a health and environmental problem.
Time pressure is emerging as a modern malaise. It is linked to changes in working life, with longer work hours and faster work pace, and it is compounded in families; nowadays both parents must combine working with caring. Time pressure also challenges urban, health and environmental policy because many interventions have an unacknowledged time dimension. People need time to keep healthy, to exercise and to maintain strong social and family bonds. If urban designs or environmental solutions can reduce time demands they may directly improve health and social outcomes. However, where they increase time demands they may have unanticipated health costs, create disincentives for the uptake of interventions and disadvantage those who are most time poor.


Confusion over similar drug names. Problems and solutions.
Confusion over similar drug names is one of the reasons for errors in the prescribing or administration of drugs. The risks of such errors could be reduced by some simple measures. National and international agencies: Licensing authorities should exercise more control over the naming of new proprietary formulations; Nonproprietary names should be internationalised; New proprietary names should be internationalised; Common prefixes in names should be avoided if possible. Pharmaceutical manufacturers: Manufacturers should play their part in ensuring that new names are carefully chosen and internationalised; Over-the-counter formulations should be given unique names; Generic formulations should be marketed under their nonproprietary names, not new proprietary names. Doctors: Should inform patients about the nature and risks of their therapy; Should issue printed prescriptions if possible, or use clearly-penned block capitals in handwritten prescriptions. In most cases they should use nonproprietary names when prescribing. Abbreviations of drug names should never be used. Pharmacists: Should discuss the nature and risks of patients' therapy with them and check that they recognise the medicines they are taking; Should ask patients to hand in their old medicines containers when they fill a new prescription; In hospital, clinical pharmacists can help to check doctors' prescriptions and to liaise between doctors and nurses, advising on correct therapy. Special cases: Special care should be taken with sulphonylureas: manufacturers should produce distinctive formulations and pharmacists should keep them in a separate section in the dispensary.


Recurrent urinary tract infection in women and overactive bladder - Is there a relationship?
Overactive bladder (OAB) in women has similar symptomatology with other common urologic diseases such as recurrent urinary tract infection (UTI). Recent evidence showed that chronic low-grade bacterial bladder colonization might exacerbate OAB symptoms and could be the etiology of recurrent UTI. The high prevalence of lower urinary tract dysfunction is associated with OAB. Women with urgency urinary incontinence refractory to antimuscarinic therapy had more bacteria and a more diverse urinary microbiome. The bacterial reside in the superficial urothelial cells to form intracellular bacterial community and outbreak when the host innate immunity is low. Women with recurrent UTI are found to have highly prevalent voiding dysfunction and detrusor overactivity. These functional abnormalities will further damage the urothelial barrier integrity and create vulnerable to uropathogen invasion. The defective urinary microbiota is less common in women with recurrent UTI, suggesting that the normal flora in the urine might inhibit uropathogen growth and invasion. The defective urothelial barrier function, deficient basal proliferation, and deficient maturation might be owing to chronic suburothelial inflammation, resulting in activation of sensory nerves (causing OAB) and failure elimination of intracellular bacterial communities (causing recurrent UTI). Precision diagnosis and multidisciplinary treatment of the underlying pathophysiology of OAB and recurrent UTI is necessary.


The FANTASTIC FOUR proteins influence shoot meristem size in Arabidopsis thaliana.
Throughout their lives plants produce new organs from groups of pluripotent cells called meristems, located at the tips of the shoot and the root. The size of the shoot meristem is tightly controlled by a feedback loop, which involves the homeodomain transcription factor WUSCHEL (WUS) and the CLAVATA (CLV) proteins. This regulatory circuit is further fine-tuned by morphogenic signals such as hormones and sugars. Here we show that a family of four plant-specific proteins, encoded by the FANTASTIC FOUR (FAF) genes, has the potential to regulate shoot meristem size in Arabidopsis thaliana. FAF2 and FAF4 are expressed in the centre of the shoot meristem, overlapping with the site of WUS expression. Consistent with a regulatory interaction between the FAF gene family and WUS, our experiments indicate that the FAFs can repress WUS, which ultimately leads to an arrest of meristem activity in FAF overexpressing lines. The finding that meristematic expression of FAF2 and FAF4 is under negative control by CLV3 further supports the hypothesis that the FAFs are modulators of the genetic circuit that regulates the meristem. This study reports the initial characterization of the Arabidopsis thaliana FAF gene family. Our data indicate that the FAF genes form a plant specific gene family, the members of which have the potential to regulate the size of the shoot meristem by modulating the CLV3-WUS feedback loop.


NiCHE Platform: Nature-Inspired Catechol-Conjugated Hyaluronic Acid Environment Platform for Salivary Gland Tissue Engineering.
Recently, there has been growing interest in replacing severely damaged salivary glands with artificial salivary gland functional units created in vitro by tissue engineering approaches. Although various materials such as poly(lactic-co-glycolic acid), polylactic acid, poly(glycolic acid), and polyethylene glycol hydrogels have been used as scaffolds for salivary gland tissue engineering, none of them is effective enough to closely recapitulate the branched structural complexity and heterogeneous cell population of native salivary glands. Instead of discovering new biomaterial candidates, we synthesized hyaluronic acid-catechol (HACA) conjugates to establish a versatile hyaluronic acid coating platform named "NiCHE (nature-inspired catechol-conjugated hyaluronic acid environment)" for boosting the salivary gland tissue engineering efficacy of the previously reported biomaterials. By mimicking hyaluronic acid-rich niche in the mesenchyme of embryonic submandibular glands (eSMGs) with NiCHE coating on substrates including polycarbonate membrane, stiff agarose hydrogel, and polycaprolactone scaffold, we observed significantly enhanced cell adhesion, vascular endothelial and progenitor cell proliferation, and branching of in vitro-cultured eSMGs. High mechanical stiffness of the substrate is known to inhibit eSMG growth, but the NiCHE coating significantly reduced such stiffness-induced negative effects, leading to successful differentiation of progenitor cells to functional acinar and myoepithelial cells. These enhancement effects of the NiCHE coating were due to the increased proliferation of vascular endothelial cells via interaction between CD44 and surface-immobilized HAs. As such, our NiCHE coating platform renders any kind of material highly effective for salivary gland tissue culture by mimicking in vivo embryonic mesenchymal HA. Based on our results, we expect the NiCHE coating to expand the range of biomaterial candidates for salivary glands and other branching epithelial organs.


[The Brazilian Universal Health System and the delivery of nursing care in a Brazilian hospital].
There are few studies on the delivery of nursing services in hospitals participating in the Brazilian universal public health system (Sistema Unico de Saúde), which was put in place in 1988. This study, which examined possible changes in the delivery of these services since universal health care was implemented, was based on interviews carried out between July and September 1995 with 31 nurses working at a teaching hospital in the city of Ribeirão Preto, in the state of São Paulo. The nurses had begun working at the hospital between May 1980 and May 1987. Thematic analysis was used to assess their answers. According to the nurses, patients treated after the universal system was implemented have had more complex medical needs and a higher socioeconomic status. In addition, nurses reported an increase in the complexity of patient demands and in the variety of medical specialties offered by the hospital, as well as a decrease in the length of inpatient stays. Forty-six percent of the interviewees reported a change in the work done by nursing staff (for example, nurses have less time available for each patient). Not all of the problems the nurses mentioned are related to the public health system (understaffing is one example). It is essential that nurses examine national health policy and that they engage in the (re)construction of the practice of health care delivery. Nurses ought to understand the reality of their institutions and carry out a management process geared towards the expectations of patients and of health care workers.


Seven-channel fabry-perot spectrum analyzer used in laser scattering measurements.
A high resolution seven-channel Fabry-Perot interferometer spectrum analyzer is described that was used in laser scattering experiments on a theta-pinch plasma where the spectral width to be measured was of the order of 1 A. The resolution of the system was 0.2 A and covered a wavelength interval of 1.4 A. The interferometer was of the pressure tuned type, using dry nitrogen gas, to center the laser radiation on any given channel for wavelength calibration of the system. The Fabry-Perot plates had to be antireflection coated for proper performance of the system. A complete profile of the Doppler broadened scattered light is obtained in a single discharge, and a typical spectral profile is shown.


Neurofeedback helps to reveal a relationship between context reinstatement and memory retrieval.
Theories of mental context and memory posit that successful mental context reinstatement enables better retrieval of memories from the same context, at the expense of memories from other contexts. To test this hypothesis, we had participants study lists of words, interleaved with task-irrelevant images from one category (e.g., scenes). Following encoding, participants were cued to mentally reinstate the context associated with a particular list, by thinking about the images that had appeared between the words. We measured context reinstatement by applying multivariate pattern classifiers to fMRI, and related this to performance on a free recall test that followed immediately afterwards. To increase sensitivity, we used a closed-loop neurofeedback procedure, whereby higher classifier evidence for the cued category elicited increased visibility of the images from the studied context onscreen. Our goal was to create a positive feedback loop that amplified small fluctuations in mental context reinstatement, making it easier to experimentally detect a relationship between context reinstatement and recall. As predicted, we found that greater amounts of classifier evidence were associated with better recall of words from the reinstated context, and worse recall of words from a different context. In a second experiment, we assessed the role of neurofeedback in identifying this brain-behavior relationship by presenting context images again and manipulating whether their visibility depended on classifier evidence. When neurofeedback was removed, the relationship between classifier evidence and memory retrieval disappeared. Together, these findings demonstrate a clear effect of context reinstatement on memory recall and suggest that neurofeedback can be a useful tool for characterizing brain-behavior relationships.


Lifestyle change program engagement in real-world clinical practice: a mixed-methods analysis.
Participant engagement in structured lifestyle change programs (LCPs) is essential for adopting behaviors that promote weight loss; however, the challenges to, and facilitators that promote, engagement with such programs are not well understood. We conducted a mixed-methods study among real-world LCP participants to assess factors associated with program engagement and to examine the reasons for withdrawal. Using electronic health records (EHR), we identified LCP eligible participants between 2010 and 2017. Multivariable logistic regression was used to assess associations between program engagement and baseline characteristics. Semi-structured interviews with LCP participants were conducted and thematically analyzed to examine reasons for withdrawal. A total of 1,813 LCP participants were included. The median number of sessions attended was 10 of 21-25 sessions. Highest LCP engagement was associated with factors potentially related to self-efficacy/motivation, such as older age, higher baseline weight, prior healthcare utilization and an absence of a history of smoking or depression. Engagement was also negatively associated with being Non-Hispanic Black versus White. The qualitative analysis of the interviews revealed four general themes pertaining to participants' withdrawal: competing priorities, perceived program effectiveness, characteristics of the program, and facilitator-related factors. Taken together, results from this mixed-methods study suggest that motivation and self-efficacy are important for program engagement; future LCP enhancements should incorporate flexible formats that may help participants manage competing priorities and maximize personal and cultural relevance for all racial/ethnic groups, especially those who have not benefitted fully. Furthermore, participants should be encouraged to set realistic goals to manage expectations.


A Comparison of the Safety and Efficacy of HX575 (Epoetin Alfa Proposed Biosimilar) with Epoetin Alfa in Patients with End-Stage Renal Disease.
HX575 (biosimilar epoetin alfa) was approved in Europe in 2007 for the treatment of chronic kidney disease (CKD)-related anemia. This study assessed the clinical equivalence of HX575 with the US-licensed reference epoetin alfa (Epogen®/Procrit®, Amgen/Janssen) following subcutaneous (SC) administration in dialysis patients with CKD-related anemia. This randomized, double-blind, parallel-group, multicenter study (NCT01693029) was conducted at 49 US clinical sites. Eligible patients were aged ≥18 years, had end-stage renal disease, were on hemodialysis or peritoneal dialysis for ≥6 months (or ≥12 months in the case of a failed kidney transplant), and were receiving treatment with stable SC doses of epoetin alfa. Eligible patients also had mean hemoglobin (Hb) concentration between 9.0 and 11.5 g/dL during the screening period. The primary endpoint was the mean absolute change in Hb concentration between the screening/baseline period (week-4 to week-1) and the evaluation period (weeks 21 to 28). Hb values at the end of the evaluation period and the Hb change from baseline to evaluation period were similar between treatment groups. The estimated difference between groups in mean absolute change in Hb concentration was -0.093 g/dL, with 90% CI (-0.23 to 0.04) entirely within the pre-specified equivalence limits (-0.5 to 0.5 g/dL). The safety profile of each medicine was similar and as expected in dialysis patients, and neither method of treatment led to the development of neutralizing, clinically relevant antibodies. SC HX575 in dialysis patients with renal anemia was therapeutically equivalent to the reference medicine in terms of maintaining stable Hb levels and safety.


Highly near-IR emissive ytterbium(iii) complexes with unprecedented quantum yields.
The design of highly near-infrared (NIR) emissive lanthanide (Ln) complexes is challenging, owing to the lack of molecular systems with a high sensitization efficiency and the difficulty of achieving a large intrinsic quantum yield. Previous studies have reported success in optimizing individual factors and achieving high overall quantum yields, with the best yield being 12% for Yb(iii). Herein we report a series of highly NIR emissive Yb complexes, in which the Yb is sandwiched between an octafluorinated porphyrinate antenna ligand and a deuterated Kläui ligand, which allowed optimization of two factors in the same system, and one of the complexes had an unprecedented quantum yield of 63% (estimated uncertainty 15%) in CD2Cl2 with a long lifetime (τobs) of 714 μs. Systematic analysis of the structure-photophysical properties relationship suggested that porphyrinates are effective antenna ligands with a sensitization efficiency up to ca. 100% and that replacement of the high-energy C-H oscillators in porphyrinate and Kläui ligands significantly improves the intrinsic quantum yield up to 75% (τobs/τrad), both of which contribute to enhancing the NIR emission intensity of Yb(iii) up to 25-fold. Besides the high luminescence efficiency, these Yb complexes have other attractive features such as excitation in the visible range and large extinction coefficients which make these Yb(iii) complexes outstanding optical materials in the NIR region.


The Athlete Biological Passport: an integral element of innovative strategies in antidoping.
Concern for the health of athletes and integrity of sport resulted in the banning of specific substances although many years passed before analytical testing took place. Soon doping control programmes became synonymous with urine tests and adverse analytical findings. This system has its limits due to the detection window of prohibited substances, the timing of sample collections and the sophistication of some doping regimens. There have been a number of situations where these limits were demonstrated by athletes who proclaimed innocence based on passing their analytical tests only to later confess to doping. New strategies were called for to protect clean athletes. In the current World Anti-Doping Code, there are eight means to an Anti-Doping Rule Violation (ADRV). Article 2.2 states that the use of a prohibited substance may be established by any reliable means including witness statements, documentary evidence or evaluations of longitudinal profiling. In 2006, the World Anti-Doping Agency (WADA) with the support of some International Federations (IFs) gathered a group of experts to develop a harmonised programme on longitudinal profiling, or serial analysis of indirect biomarkers of doping, that was both scientifically and legally robust. This culminated in the WADA Athlete Biological Passport (ABP) Operating Guidelines and Technical Documents, published in 2009. The ABP is a paradigm that infers the use of prohibited substance (or method) by the monitoring of discriminant biomarkers over time. The haematological module detects blood manipulation by the use of erythropoietic stimulating agents or via blood transfusions. The steroidal module aims to identify endogenous anabolic androgenic steroids when administered exogenously and other indirect steroid doping substances or methods. Other ABP modules (endocrine, 'omics') are being developed. The term passport, first coined in 2000, is now defined in the ABP Guidelines as the longitudinal profile and all other relevant information including training, competitions and information derived from investigations. In the 2015 World Anti-Doping Code, investigations or enquiries gathered from other sources will play an even more prominent role.


c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias.
Leukemias expressing the constitutively activated tyrosine kinases (TK) BCR-ABL1 and FLT3/ITD activate signaling pathways that increase genomic instability through generation of reactive oxygen species (ROS), DNA double-strand breaks (DSB), and error-prone repair. The nonhomologous end-joining (NHEJ) pathway is a major pathway for DSB repair and is highly aberrant in TK-activated leukemias; an alternative form of NHEJ (ALT-NHEJ) predominates, evidenced by increased expression of DNA ligase IIIα (LIG3) and PARP1, increased frequency of large genomic deletions, and repair using DNA sequence microhomologies. This study, for the first time, demonstrates that the TK target c-MYC plays a role in transcriptional activation and subsequent expression of LIG3 and PARP1 and contributes to the increased error-prone repair observed in TK-activated leukemias. c-MYC negatively regulates microRNAs miR-150 and miR-22, which demonstrate an inverse correlation with LIG3 and PARP1 expression in primary and cultured leukemia cells and chronic myelogenous leukemia human patient samples. Notably, inhibition of c-MYC and overexpression of miR-150 and -22 decreases ALT-NHEJ activity. Thus, BCR-ABL1 or FLT3/ITD induces c-MYC expression, leading to genomic instability via augmented expression of ALT-NHEJ repair factors that generate repair errors. In the context of TK-activated leukemias, c-MYC contributes to aberrant DNA repair through downstream targets LIG3 and PARP1, which represent viable and attractive therapeutic targets.


A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence.
Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence. Previously, we demonstrated that plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of serine proteases, is an important biomarker and regulator of cellular senescence and aging. Here, we tested the hypothesis that pharmacological inhibition of cellular PAI-1 protects against stress- and aging-induced cellular senescence and delineated the molecular basis of protective action of PAI-1 inhibition. Results show that TM5441, a potent small molecule inhibitor of PAI-1, effectively prevents Doxorubicin-induced senescence in cardiomyocytes, fibroblasts and endothelial cells. TM5441 exerts its inhibitory effect on Doxorubicin-induced cellular senescence by decreasing reactive oxygen species generation, induction of antioxidants like catalase and suppression of stress-induced senescence cadre p53, p21, p16, PAI-1 and IGFBP3. Importantly, TM5441 also reduces replicative senescence of fibroblasts. Together these results for the first time demonstrate the efficacy of PAI-1 inhibitor in prevention of Doxorubicin-induced and replicative senescence in normal cells. Thus PAI-1 inhibitor may form an important adjuvant component of chemotherapy regimens, limiting not only Doxorubicin-induced cardiac senescence but also ameliorating the prothrombotic profile.


Mapping temporal-network percolation to weighted, static event graphs.
The dynamics of diffusion-like processes on temporal networks are influenced by correlations in the times of contacts. This influence is particularly strong for processes where the spreading agent has a limited lifetime at nodes: disease spreading (recovery time), diffusion of rumors (lifetime of information), and passenger routing (maximum acceptable time between transfers). We introduce weighted event graphs as a powerful and fast framework for studying connectivity determined by time-respecting paths where the allowed waiting times between contacts have an upper limit. We study percolation on the weighted event graphs and in the underlying temporal networks, with simulated and real-world networks. We show that this type of temporal-network percolation is analogous to directed percolation, and that it can be characterized by multiple order parameters.


Examination of water spray airborne coal dust capture with three wetting agents.
Water spray applications are one of the principal means of controlling airborne respirable dust in coal mines. Since many coals are hydrophobic and not easily wetted by water, wetting agents can be added to the spray water in an effort to improve coal wetting and assist with dust capture. In order to study wetting agent effects on coal dust capture, laboratory experiments were conducted with three wetting agents used by the coal industry on -325 mesh sized Pocahontas No. 3 coal dust. Significant differences in coal dust sink times were observed among the three wetting agents at water mixture concentrations of 0.05%, 0.1% and 0.2%. The best wetting agent as identified by the coal dust sink test was only tested at the lowest 0.05% water mixture concentration and was found to have a negligible effect on spray airborne dust capture. Water spray airborne dust capture results for all three wetting agents tested at a 0.2% water mixture concentration showed that all three wetting agents exhibit similar but small improvements in dust capture efficiency as compared with water. These results indicate that the coal dust sink test may not be a good predictor for the capture of airborne dust. Additional research is needed to examine if the coal dust sink test is a better predictor of wetting agent dust suppression effects during cutting, loading, conveying and dumping of coal products by comparison to airborne dust capture from sprays.


Tissue effects of and host response to human papillomavirus infection.
Human papillomaviruses are a heterogeneous group of DNA tumor viruses associated with hyperplastic (warts, condylomata), dysplastic (CIN and VIN), and malignant lesions (carcinomas) of squamous epithelium. Each HPV type is preferentially associated with specific clinical lesions and has an anatomic site preference for either cutaneous or mucosal squamous epithelium. Infection appears to begin in the basal cells. Early gene expression is associated with acanthosis, and late gene expression is associated with appearance of structural antigens and virions in nuclei of cells of the granular layer, usually koilocytotic cells. Malignant transformation of warts and papillomas appears to be related to a variety of factors: (1) infection by certain HPV types (HPV-5, HPV-8, HPV-16, HPV-18, HPV-31); (2) decreased cellular immunity to HPV-associated antigens; and (3) interaction with cofactors such as other microorganisms or sunlight. Spontaneous regression or successful treatment of the benign lesions appears to depend on either naturally acquired or iatrogenically related stimulation of HPV type-specific immunity. The humoral antibody response to HPV particles may be important in preventing infection. In contrast, the local events surrounding regression of warts and condylomata are primarily associated with specific cell-mediated immunity. Local cell-mediated immune responses, particularly cell-associated soluble mediators and stationary macrophage-like cells, may be especially important in the host's immune response to mucosal infections.


Cyclooxygenase polymorphisms and risk of cardiovascular events: the Atherosclerosis Risk in Communities (ARIC) study.
Cyclooxygenase-derived prostaglandins modulate cardiovascular disease risk. We genotyped 2212 Atherosclerosis Risk in Communities study participants (1,023 incident coronary heart disease (CHD) cases; 270 incident ischemic stroke cases; 919 non-cases) with available DNA for polymorphisms in PTGS1 and PTGS2. Using a case-cohort design, associations between genotype and CHD or stroke risk were evaluated using proportional hazards regression. In Caucasians, the reduced function PTGS1 -1006A variant allele was significantly more common among stroke cases compared to non-cases (18.2 versus 10.6%, P=0.027). In African Americans, the reduced function PTGS2 -765C variant allele was significantly more common in stroke cases (61.4 versus 49.4%, P=0.032). No significant relationships with CHD risk were observed. However, aspirin utilization appeared to modify the relationship between the PTGS2 G-765C polymorphism and CHD risk (interaction P=0.072). These findings suggest that genetic variation in PTGS1 and PTGS2 may be important risk factors for the development of cardiovascular disease events. Confirmation in independent populations is necessary.


Drug Treatment of Pulmonary Hypertension in Children.
Pulmonary arterial hypertension (PAH) is a rare disease in infants and children that is associated with significant morbidity and mortality. The disease is characterized by progressive pulmonary vascular functional and structural changes resulting in increased pulmonary vascular resistance and eventual right heart failure and death. In many pediatric patients, PAH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. PAH associated with developmental lung diseases such as bronchopulmonary dysplasia or congenital diaphragmatic hernia is increasingly more recognized in infants and children. Although treatment of the underlying disease and reversal of advanced structural changes have not yet been achieved with current therapy, quality of life and survival have improved significantly. Targeted pulmonary vasodilator therapies, including endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase type 5 inhibitors have resulted in hemodynamic and functional improvement in children. The management of pediatric PAH remains challenging as treatment decisions depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts. This article reviews the current drug therapies and their use in the management of PAH in children.


Self-association, cooperativity and supercooperativity of oxygen binding by hemoglobins.
Cooperative ligand binding by tetrameric vertebrate hemoglobins (Hbs) makes possible the delivery of oxygen at higher pressures than would otherwise occur. This cooperativity depends on changes in dimer-dimer interactions within the tetramer and is reflected in a 50 000-fold increase in the tetramer-dimer dissociation constant in human Hb upon oxygenation at pH 7.4, from approximately 2x10(-11)mol l-1 to approximately 10(-6)mol l-1. Hbs that undergo such ligand-dependent changes in association are widespread in non-vertebrates, where the mechanisms are very different from those in vertebrates. Oligomeric Hbs have been identified in organisms in five phyla (molluscs, echinoderms, annelids, phoronids and chordates) that dissociate to subunits upon oxidation of the heme iron and reassociate with the binding of ferric iron ligands such as CN-, N3- or NO2-. Thus, the valence and ligand state of the heme iron control the stability of a critical subunit interface. The broad distribution of this phenomenon suggests a common mechanism of communication between heme and interface that may be almost universal among non-vertebrate Hbs. This interaction may be similar to that known for the homodimeric Hb of the mollusc Scapharca inaequivalvis. Although muscle tissue Hbs or myoglobins (Mbs) are usually monomeric, with non-cooperative O2 binding, the radular muscles of gastropod molluscs and chitons have homodimeric Mbs that bind O2 cooperatively. Cooperative non-muscle tissue Hbs have also been identified. These include the neural Hb of the nemertean worm Cerebratulus lacteus and the Hb of the diving beetle Anisops assimilis, which exhibit deoxygenation-dependent self-association of monomers that is associated with high Hill coefficients. Calculations suggest that the 2-3 mmol l-1 concentration of Hb on a heme basis in the brain of Cerebratulus should substantially extend the time as an active predator in an anaerobic or hypoxic environment. Oxygen from the Hb of Anisops is delivered to a gas bubble and thereby controls the buoyant density. Many Hbs of amphibians, reptiles, birds and some embryonic mammals exhibit a further 'supercooperativity' of O2 binding which depends on reversible deoxygenation-dependent tetramer-tetramer association to form an assemblage with a very low affinity for O2. This phenomenon results in steeper O2-binding curves than exhibited by tetramers alone. The increased cooperativity should result in an increase in the amount of O2 delivered to the tissues and should be especially valuable for avian flight muscles.


Levels and associations among self-esteem, fertility distress, coping, and reaction to potentially being a genetic carrier in women with diminished ovarian reserve.
To measure the level of distress and its relationship with other psychologic factors in women with diminished ovarian reserve (DOR) who participated in a fragile X genetics study. Longitudinal data analyzed with structural equation modeling. Four U.S. private and academic fertility centers. Sixty-two infertile patients with DOR. None. Fertility Problem Inventory, Coping Scale for Infertile Couples, Rosenberg Self-Esteem, Health Orientation Scale. Nineteen percent had low fertility distress, 56% had average fertility distress, and 24% had high fertility distress. Thirty-six percent self-reported a "favorable" or "very favorable" emotional response to potentially being a fragile X carrier (termed "emotions"), 53% were "ambivalent," and 11% had an unfavorable reaction. Three months after learning that they were not a carrier, these percentages were 91%, 9%, and 0%, respectively. Emotions at this second time point were significantly more positive than at pretesting. At baseline, higher self-esteem was a significant predictor of reduced fertility distress both directly and indirectly through emotions. Fertility distress was not associated with coping. Self-esteem, fertility distress, pretesting emotions, and coping were unrelated to posttesting emotions. The potential of having an explanation for one's DOR condition may have a beneficial impact on women's psychologic states during the process of genetic testing, and this appeared to be especially true for women with higher self-esteem. Psychologic interventions targeted to women with low self-esteem may reduce distress and improve reactions to genetic testing.


Facilitating transfer through incorrect examples and explanatory feedback.
This article examines whether studying correct versus incorrect examples produces differential learning. A prediction that follows from behaviourism is that learning should be best from studying correct examples. A contrasting prediction is that incorrect examples can highlight a concept's properties that are missing in the example, and thereby enable concept learning. We test these ideas across two experiments, wherein subjects were shown hypothetical study scenarios and were asked to determine whether each was a true experiment. In Experiment 1, some subjects were only presented correct examples, some were only presented incorrect examples, and others were presented both. In addition, example type was crossed with feedback type: Some subjects were given explanatory feedback and some were not given any feedback; a control condition was also included, wherein subjects were not shown any study scenarios. All subjects completed a posttest involving novel scenarios; some questions asked subjects to indicate whether they were true experiments (classification questions), and some asked them to specify what was lacking in the design or to indicate how it could be fixed (application questions). Experiment 2 used a similar design, but compared explanatory feedback with corrective feedback. In both experiments, as long as some form of feedback was provided, subjects in the mixed example condition achieved the best classification performance. Furthermore, subjects in the incorrect and mixed example conditions performed best on application questions, particularly when explanatory feedback was provided. These findings offer insights into the mechanisms that might underlie learning from incorrect examples.


Validity of intraoperative gross examination of myometrial invasion in patients with endometrial cancer: a meta-analysis.
The current recommended endometrial cancer surgical treatment is abdominal extrafascial total hysterectomy with bilateral salpingo-oophorectomy followed by pelvic lymphadenectomy if >50% myometrial invasion is estimated by intraoperative gross examination (IGE). This meta-analysis aims to quantify evidence regarding the validity/predictive value of IGE staging compared with final histology. Meta-analysis of studies published until October 2011. Systematic search, according to PRISMA guidelines, of the six major medical literature databases - Medline, Scopus, EMBASE, Google Scholar, Ovid, Cochrane. Sixteen eligible studies including 2567 endometrial cancer patients. Pooled sensitivity/specificity, accuracy, negative/positive predictive value (NPV/PPV) and diagnostic odds ratio (DOR) of IGE were calculated and the summary receiver operator characteristic (sROC) curve was constructed. A meta-regression analysis was used to explore the role of potential modifiers of sensitivity and specificity. Pooled diagnostic measures of IGE indices. Results. Sixteen studies (15 retrospective, one prospective) meeting the inclusion criteria were qualitatively analyzed. Pooled IGE estimates were: sensitivity = 0.75 (95%CI: 0.72-0.78), specificity = 0.92 (95%CI 0.90-0.94), accuracy = 0.87 (95%CI 0.86-0.88), NPV = 0.89 (95%CI 0.87-0.92), PPV = 0.80 (95%CI 0.76-0.84) and DOR = 36.9 (95%CI 28.7-47.4). No significant modifiers were identified for sensitivity or specificity. The synthesized measures presented here for the first time showed that accuracy, sensitivity and specificity of IGE were 87, 75 and 92%, respectively, which indicates that IGE is useful for estimating depth of myometrial invasion and staging of endometrial cancer in clinical practice. The degree to which the relatively low values of some of its performance indicators could be improved remains to be elucidated in order for the values to be comparable with those from frozen section biopsies.


A community-based epidemiologic study of health sequelae of exposure to hydrofluoric acid.
An accident at an oil refinery in Texas City, Texas, released around 40,000 lb of hydrogen fluoride, exposing the community to the highly toxic and corrosive substance. A population-based epidemiologic study was conducted to evaluate the impact of the accident on the health of the community. Exposure assessment was done using a multipronged approach through a door-to-door survey of 10,811 individuals. A symptom survey resulting in 1994 completed interviews was conducted with a stratified random sample selected from the exposure study database. The sampling was balanced with respect to age, gender, and predisposition across the three ordinal exposure categories. The results show a strong dose relationship (P < 10(-4)) between the exposure and symptoms reported following the accident and 2 years later, most notably breathing and eye symptoms. However, substantial improvement in health was reported over the 2-year period regardless of the level of exposure. Problems of recall bias and behavioral sensitization are considered and it is recognized that the study may have overestimated the effect. It is also recognized that the study may not have completely unraveled the relative importance of exposure and host response in health outcome, since the two were probably conflated in the exposure measure. Nevertheless, the independence of predisposition and reported level of exposure, the magnitude of effect and its consistency, the unmistakable dose response, the large sample size, and the mutual corroboration of various findings make it difficult to dismiss the interpretation that the hydrofluoric acid exposure indeed caused health problems in the community that continued for at least 2 years after the accident.


Herbal medicine research and global health: an ethical analysis.
Governments, international agencies and corporations are increasingly investing in traditional herbal medicine research. Yet little literature addresses ethical challenges in this research. In this paper, we apply concepts in a comprehensive ethical framework for clinical research to international traditional herbal medicine research. We examine in detail three key, underappreciated dimensions of the ethical framework in which particularly difficult questions arise for international herbal medicine research: social value, scientific validity and favourable risk-benefit ratio. Significant challenges exist in determining shared concepts of social value, scientific validity and favourable risk-benefit ratio across international research collaborations. However, we argue that collaborative partnership, including democratic deliberation, offers the context and process by which many of the ethical challenges in international herbal medicine research can, and should be, resolved. By "cross-training" investigators, and investing in safety-monitoring infrastructure, the issues identified by this comprehensive framework can promote ethically sound international herbal medicine research that contributes to global health.


The antibiotic monensin causes cell cycle disruption of Toxoplasma gondii mediated through the DNA repair enzyme TgMSH-1.
Monensin is a polyether ionophore antibiotic that is widely used in the control of coccidia in animals. Despite its significance in veterinary medicine, little is known about its mode of action and potential mechanisms of resistance in coccidian parasites. Here we show that monensin causes accumulation of the coccidian Toxoplasma gondii at an apparent late-S-phase cell cycle checkpoint. In addition, experiments utilizing a monensin-resistant T. gondii mutant show that this effect of monensin is dependent on the function of a mitochondrial homologue of the MutS DNA damage repair enzyme (TgMSH-1). Furthermore, the same TgMSH-1-dependent cell cycle disruption is observed with the antiparasitic ionophore salinomycin and the DNA alkylating agent methyl nitrosourea. Our results suggest a novel mechanism for the mode of action of monensin and salinomycin on coccidial parasites, in which the drug activates an MSH-1-dependent cell cycle checkpoint by an unknown mechanism, ultimately leading to the death of the parasite. This model would indicate that cell cycle disruption is an important mediator of drug susceptibility and resistance to ionophoric antibiotics in coccidian parasites.


Influence of GLP-1 on myocardial glucose metabolism in healthy men during normo- or hypoglycemia.
Glucagon-like peptide-1 (GLP-1) may provide beneficial cardiovascular effects, possibly due to enhanced myocardial energetic efficiency by increasing myocardial glucose uptake (MGU). We assessed the effects of GLP-1 on MGU in healthy subjects during normo- and hypoglycemia. We included eighteen healthy men in two randomized, double-blinded, placebo-controlled cross-over studies. MGU was assessed with GLP-1 or saline infusion during pituitary-pancreatic normo- (plasma glucose (PG): 4.5 mM, n = 10) and hypoglycemic clamps (PG: 3.0 mM, n = 8) by positron emission tomography with (18)fluoro-deoxy-glucose ((18)F-FDG) as tracer. In the normoglycemia study mean (± SD) age was 25±3 years, and BMI was 22.6±0.6 kg/m(2) and in the hypoglycemia study the mean age was 23±2 years with a mean body mass index of 23±2 kg/m(2). GLP-1 did not change MGU during normoglycemia (mean (+/- SD) 0.15+/-0.04 and 0.16+/-0.03 µmol/g/min, P = 0.46) or during hypoglycemia (0.16+/-0.03 and 0.13+/-0.04 µmol/g/min, P = 0.14). However, the effect of GLP-1 on MGU was negatively correlated to baseline MGU both during normo- and hypoglycemia, (P = 0.006, r(2) = 0.64 and P = 0.018, r(2) = 0.64, respectively) and changes in MGU correlated positively with the level of insulin resistance (HOMA 2IR) during hypoglycemia, P = 0.04, r(2) = 0.54. GLP-1 mediated an increase in circulating glucagon levels at PG levels below 3.5 mM and increased glucose infusion rates during the hypoglycemia study. No differences in other circulating hormones or metabolites were found. While GLP-1 does not affect overall MGU, GLP-1 induces changes in MGU dependent on baseline MGU such that GLP-1 increases MGU in subjects with low baseline MGU and decreases MGU in subjects with high baseline MGU. GLP-1 preserves MGU during hypoglycemia in insulin resistant subjects. ClinicalTrials.gov registration numbers: NCT00418288: (hypoglycemia) and NCT00256256: (normoglycemia).


Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients.
Agents for the treatment of HIV-1-infected patients with resistance to current antiretroviral (ART) drugs are needed. TMC114-C202 was a randomized, partially blinded, dose-finding study in treatment-experienced HIV-1-infected patients with one or more primary protease inhibitor (PI) mutations and HIV-1 RNA > 1000 copies/ml. Patients were randomized to receive one of four TMC114 doses given with ritonavir (TMC114/r) or investigator-selected control PI drug(s) (CPI); all received an optimized background regimen. The primary intent-to-treat analysis compared the proportion of patients achieving a >or= 1 log10 copies/ml HIV-1 RNA reduction at week 24 between the treatment arms using the time-to-loss of virological response algorithm. For 278 patients at baseline, mean HIV-1 RNA was 4.7 log10 copies/ml, median CD4 cell count was 106 cells/mul; HIV-1 isolates had a median of three primary PI mutations and a median fold change in lopinavir susceptibility of 80. Discontinuation rates were 23% for TMC114/r versus 64% for CPI. More patients in each TMC114/r dose group achieved >or= 1.0 log10 copies/ml reduction in HIV-1 RNA than in the CPI group (45-62% versus 14%; P <or= 0.003): patients taking TMC114/r twice daily had the greatest responses. HIV-1 RNA was < 50 copies/ml in 18-39% of TMC114/r patients versus 7% CPI (P < 0.001 for highest dose). Mean CD4 cell count increased by 59-75 versus 12 cells/mul (TMC114/r versus CPI: P <or= 0.005). Overall adverse event rates were similar in both arms, without significant differences among TMC114/r groups. TMC114/r treatment resulted in greater virological and immunological responses in ART-experienced patients compared with CPI at 24 weeks.


Effect of Kimchi Fermentation on Oxalate Levels in Silver Beet (Beta vulgaris var. cicla).
Total, soluble and insoluble oxalates were extracted and analyzed by high performance liquid chromatography (HPLC) following the preparation of kimchi using silver beet (Beta vulgaris var. cicla) stems and leaves. As silver beet contains high oxalate concentrations and consumption of high levels can cause the development of kidney stones in some people, the reduction of oxalate during preparation and fermentation of kimchi was investigated. The silver beet stems and leaves were soaked in a 10% brine solution for 11 h and then washed in cold tap water. The total, soluble and insoluble oxalate contents of the silver beet leaves were reduced by soaking in brine, from 4275.81 ± 165.48 mg/100 g to 3709.49 ± 216.51 mg/100 g fresh weight (FW). Fermenting the kimchi for 5 days at 19.3 ± 0.8 °C in 5 L ceramic jars with a water airtight seal resulted in a mean 38.50% reduction in total oxalate content and a mean 22.86% reduction in soluble oxalates. The total calcium content was essentially the same before and after the fermentation of the kimchi (mean 296.1 mg/100 g FW). The study showed that fermentation of kimchi significantly (p < 0.05) reduced the total oxalate concentration in the initial mix from 609.32 ± 15.69 to 374.71 ± 7.94 mg/100 g FW in the final mix which led to a 72.3% reduction in the amount of calcium bound to insoluble oxalate.


Ritual uses of palms in traditional medicine in sub-Saharan Africa: a review.
Palms (Arecaceae) are prominent elements in African traditional medicines. It is, however, a challenge to find detailed information on the ritual use of palms, which are an inextricable part of African medicinal and spiritual systems. This work reviews ritual uses of palms within African ethnomedicine. We studied over 200 publications on uses of African palms and found information about ritual uses in 26 of them. At least 12 palm species in sub-Saharan Africa are involved in various ritual practices: Borassus aethiopum, Cocos nucifera, Dypsis canaliculata, D. fibrosa, D. pinnatifrons, Elaeis guineensis, Hyphaene coriacea, H. petersiana, Phoenix reclinata, Raphia farinifera, R. hookeri, and R. vinifera. In some rituals, palms play a central role as sacred objects, for example the seeds accompany oracles and palm leaves are used in offerings. In other cases, palms are added as a support to other powerful ingredients, for example palm oil used as a medium to blend and make coherent the healing mixture. A better understanding of the cultural context of medicinal use of palms is needed in order to obtain a more accurate and complete insight into palm-based traditional medicines.


No measurable "cleaning" of polychlorinated biphenyls from Rainbow Trout in a 9 week depuration study with dietary exposure to 40% polyethylene microspheres.
Persistent hydrophobic chemicals sorbed to plastic can be transferred to fish and other aquatic organisms upon ingestion. However, ingestion of plastic could also lead to enhanced elimination of these chemicals if the plastic is less contaminated than the fish. Here, we attempted to measure the influence of ingestion of uncontaminated polyethylene microspheres on the depuration rates of polychlorinated biphenyls (PCBs) in an in vivo fish feeding experiment. Rainbow trout were given feed contaminated with PCBs for two consecutive days, then clean feed for three days to allow for egestion of the contaminated food. A control group of fish were then fed ordinary food pellets and a treatment group were fed pellets that additionally contained 40% by weight polyethylene microspheres. Condition factors and growth rates in both groups were similar, indicating no negative effect of the plastic microspheres on the nutritional status of the fish. Fish were sampled after zero, three, six and nine weeks, homogenized, solvent-extracted and analyzed by GC/MS. PCB concentrations declined in both groups at a rate consistent with growth dilution. There was no significant difference in the elimination rate constants between the control and treatment group, indicating that ingestion of uncontaminated plastic did not cause a measurable enhancement of depuration of PCBs by the fish in this study.


Characterization of substrate binding and catalysis in the potential antibacterial target N-acetylglucosamine-1-phosphate uridyltransferase (GlmU).
N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) catalyzes the first step in peptidoglycan biosynthesis in both Gram-positive and Gram-negative bacteria. The products of the GlmU reaction are essential for bacterial survival, making this enzyme an attractive target for antibiotic drug discovery. A series of Haemophilus influenzae GlmU (hiGlmU) structures were determined by X-ray crystallography in order to provide structural and functional insights into GlmU activity and inhibition. The information derived from these structures was combined with biochemical characterization of the K25A, Q76A, D105A, Y103A, V223A, and E224A hiGlmU mutants in order to map these active-site residues to catalytic activity of the enzyme and refine the mechanistic model of the GlmU uridyltransferase reaction. These studies suggest that GlmU activity follows a sequential substrate-binding order that begins with UTP binding noncovalently to the GlmU enzyme. The uridyltransferase active site then remains in an open apo-like conformation until N-acetylglucosamine-1-phosphate (GlcNAc-1-P) binds and induces a conformational change at the GlcNAc-binding subsite. Following the binding of GlcNAc-1-P to the UTP-charged uridyltransferase active site, the non-esterified oxygen of GlcNAc-1-P performs a nucleophilic attack on the alpha-phosphate group of UTP. The new data strongly suggest that the mechanism of phosphotransfer in the uridyltransferase reaction in GlmU is primarily through an associative mechanism with a pentavalent phosphate intermediate and an inversion of stereochemistry. Finally, the structural and biochemical characterization of the uridyltransferase active site and catalytic mechanism described herein provides a basis for the structure-guided design of novel antibacterial agents targeting GlmU activity.


Dimethyltryptamine: Endogenous Role and Therapeutic Potential.
N, N-dimethyltryptamine (DMT) is an indole alkaloid produced by a number of plants and animals, including humans. Its psychoactive effects were first described in 1956 by Stephen Szára, but have been exploited for centuries by South American indigenous populations in the form of ayahuasca. In the present review, we assess the state of the art regarding a putative role for endogenous DMT and potential clinical applications of ayahuasca and DMT. A review assessing the pharmacological profile of DMT and its clinical effects in humans was performed using the PubMed data base until 5 August 2018 with the words: ayahuasca and N,N-dimethyltryptamine. While the role of endogenous DMT remains unclear, ayahuasca has promising results in anxiety, depression and substance dependence. Since ayahuasca has a good safety profile, it is crucial to conduct further research aimed at developing new treatments for psychiatric disorders.


Experiences of ICU survivors in a low middle income country- a multicenter study.
Stressful patient experiences during the intensive care unit (ICU) stay is associated with reduced satisfaction in High Income Countries (HICs) but has not been explored in Lower and Middle Income Countries (LMICs). This study describes the recalled experiences, stress and satisfaction as perceived by survivors of ICUs in a LMIC. This follow-up study was carried out in 32 state ICUs in Sri Lanka between July and December 2015.ICU survivors' experiences, stress factors encountered and level of satisfaction were collected 30 days after ICU discharge by a telephone questionnaire adapted from Granja and Wright. Of 1665 eligible ICU survivors, 23.3% died after ICU discharge, 49.1% were uncontactable and 438 (26.3%) patients were included in the study. Whilst 78.1% (n = 349) of patients remembered their admission to the hospital, only 42.3% (n = 189) could recall their admission to the ICU. The most frequently reported stressful experiences were: being bedridden (34.2%), pain (34.0%), general discomfort (31.7%), daily needle punctures (32.9%), family worries (33.6%), fear of dying and uncertainty in the future (25.8%). The majority of patients (376, 84.12%) found the atmosphere of the ICU to be friendly and calm. Overall, the patients found the level of health care received in the ICU to be "very satisfactory" (93.8%, n = 411) with none of the survivors stating they were either "dissatisfied" or "very dissatisfied". In common with HIC, survivors were very satisfied with their ICU care. In contrast to HIC settings, specific ICU experiences were frequently not recalled, but those remembered were reported as relatively stress-free. Stressful experiences, in common with HIC, were most frequently related to uncertainty about the future, dependency, family, and economic concerns.


Xenopsin, neurotensin, neurotensin(8-13) and N-acetyl-neurotensin(8-13) inhibit vascular leakage in rats after tissue injury.
Swelling, edema and leakage of proteins from the vascular compartment are immediate inflammatory responses of living tissues to local injury. Xenopsin, neurotensin (NT), NT(8-13) and NAcNT(8-13) administered to male rats anesthetized with sodium pentobarbital 60 mg/kg i.p. inhibited swelling and edema in the paw induced by immersion in 58 degrees water for 1 min. The ED50 values for xenopsin. NT, NAcNT(8-13) and NT(8-13) for reducing heat-induced edema were 0.9, 1.5, 1.9 and 2.1 nmol/kg i.v., respectively. NAcNT(8-13) was chosen as a prototype for further studies because, compared to NT, it had minimal hypotensive effects. NAcNT(8-13), 4 nmol/kg i.v., injected 10 min before mechanical injury to muscle, produced by a 4 cm midline surgical incision in the rectus abdominis, or before freeze injury to the cortex, produced by applying a cold probe (-50 degrees C) to the skull for 4 min, reduced vascular leakage, measured as area of Monastral blue staining of the injured tissues. NAcNT(8-13), 4 nmol/kg i.v., also attenuated pulmonary edema induced by epinephrine bitartrate 10 micrograms/kg i.v. The ability of NAcNT(8-13) to inhibit vascular leakage was not linked to its transient hypotensive effects and it was not blocked by alpha-helical-CRF(9-41), a putative CRF receptor antagonist, or by chlorpheniramine, a H1-histamine receptor antagonist.


Identification of tubulin as the molecular target of proapoptotic pyrrolo-1,5-benzoxazepines.
We have demonstrated previously that certain members of a series of novel pyrrolo-1,5-benzoxazepine (PBOX) compounds potently induce apoptosis in a variety of human chemotherapy-resistant cancer cell lines and in primary ex vivo material derived from cancer patients. A better understanding of the molecular mechanisms underlying the apoptotic effects of these PBOX compounds is essential to their development as antineoplastic therapeutic agents. This study sought to test the hypothesis that proapoptotic PBOX compounds target the microtubules. We show that a representative proapoptotic PBOX compound, PBOX-6, induces apoptosis in both the MCF-7 and K562 cell lines. An accumulation of cells in G2/M precedes apoptosis in response to PBOX-6. PBOX-6 induces prometaphase arrest and causes an accumulation of cyclin B1 levels and activation of cyclin B1/CDK1 kinase in a manner similar to that of two representative antimicrotubule agents, nocodazole and paclitaxel. Indirect immunofluorescence demonstrates that both PBOX-6 and another pro-apoptotic PBOX compound, PBOX-15, cause microtubule depolymerization in MCF-7 cells. They also inhibit the assembly of purified tubulin in vitro, whereas a nonapoptotic PBOX compound (PBOX-21) has no effect on either the cellular microtubule network or on the assembly of purified tubulin. This suggests that the molecular target of the pro-apoptotic PBOX compounds is tubulin. PBOX-6 does not bind to either the vinblastine or the colchicine binding site on tubulin, suggesting that it binds to an as-yet-uncharacterised novel site on tubulin. The ability of PBOX-6 to bind tubulin and cause microtubule depolymerization confirms it as a novel candidate for antineoplastic therapy.


A combined therapeutic approach in stroke rehabilitation: A review on non-invasive brain stimulation plus pharmacotherapy.
Stroke is a leading cause of disability in the United States. Available treatments for stroke have only a modest effect on motor rehabilitation and about 50-60% of stroke patients remain with some degree of motor impairment after standard treatment. Non-invasive brain stimulation (NIBS) techniques have been proposed as adjuvant treatments to physical therapy for motor recovery after stroke. High frequency rTMS and anodal tDCS can be delivered over the affected motor cortex in order to increase cortical excitability and induce brain plasticity with the intention to enhance motor learning and achieve functional goals in stroke patients. Similarly, low frequency rTMS and cathodal tDCS can be delivered to the unaffected motor cortex to reduce interhemispheric inhibition and hinder maladaptive plasticity. The use of several drugs such as amphetamines, selective serotonin reuptake inhibitors (SSRIs), levodopa and cholinergic agents have been also proposed to enhance the motor function. Given that both NIBS and pharmacotherapy might provide some treatment effect independently for motor rehabilitation in stroke and with the rationale that they could work in a synergistic fashion, we believe that a combined therapy- NIBS plus pharmacotherapy- canlead to better outcomes than one or the other alone. In this paper we review the literature that support the potential use of a combined approach in stroke recovery and present the studies that have already investigated this idea.


First Report of Fludioxonil Resistance in Botrytis cinerea from a Strawberry Field in Virginia.
Gray mold caused by Botrytis cinerea Pers.:Fr. is one of the most economically important diseases of cultivated strawberry (Fragaria × ananassa) worldwide. Control of gray mold mainly depends on fungicides, including the phenylpyrrole fludioxonil, which is currently marketed in combination with cyprodinil as Switch 62.5WG (Syngenta Crop Protection, Research Triangle Park, Raleigh, NC). In 2012, 790 strains of B. cinerea were collected from 76 strawberry fields in eight states, including Arkansas, Florida, Georgia, Kansas, Maryland, North Carolina, South Carolina, and Virginia. Strains were collected from sporulating flowers and fruit and sensitivity to fludioxonil was determined using a conidial germination assay as previously described (2). Only one isolate from a farm located in Westmoreland County, Virginia, grew on medium amended with the discriminatory dose of 0.1 μg/ml fludioxonil and was therefore considered low resistant. The isolate did not grow on 10 μg/ml. All other 789 isolates did not grow at either of the two doses. This assay was repeated twice with a single-spore culture of the same strain. In both cases, residual growth was observed on the fludioxonil-amended medium of 0.1 μg/ml. The single spore isolate was confirmed to be B. cinerea Pers. using cultural and molecular tools as described previously (1). To assess resistance in vivo, commercially grown ripe strawberry fruit were rinsed with sterile water, dried, placed into plastic boxes (eight strawberries per box for each of the three replicates per treatment), and sprayed 4 h prior to inoculation with either water or 2.5 ml/liter of fludioxonil (Scholar SC, Syngenta) to runoff using a hand mister. This dose reflects the rate recommended for gray mold control according to the Scholar label. Each fruit was stabbed at three equidistant points, each about 1 cm apart and 1 cm deep using a syringe tip. Wounds were injected with a 30-μl droplet of conidia suspension (106 spores/ml) of either 5 sensitive or the resistant isolate. Control fruit were inoculated with water. After inoculation, the fruit were kept at 22°C for 4 days. In two independent experiments, sensitive and low resistant isolates were indistinguishable in pathogenicity on detached, unsprayed fruit. The low resistant isolate developed gray mold disease on all treated and untreated fruit (100% disease incidence) as determined by the absence or presence of gray mold symptoms. The sensitive isolates only developed disease on untreated fruit. The EC50 values, determined in microtiter assays with concentrations of 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 μg/ml fludioxonil, were 0.01 μg/ml for the sensitive isolates and 0.26 μg/ml for the resistant isolate. To our knowledge, this is the first report of fludioxonil resistance in B. cinerea from strawberry in North America. Our monitoring results indicate that resistance is emerging 10 years after the introduction of fludioxonil and stress the importance of chemical rotation for gray mold control. References: (1) X. P. Li et al. Plant Dis. 96:1634, 2012. (2) R. W. S. Weber and M. Hahn. J. Plant Dis. Prot. 118:17, 2011.


Heavy-machinery traffic impacts methane emissions as well as methanogen abundance and community structure in oxic forest soils.
Temperate forest soils are usually efficient sinks for the greenhouse gas methane, at least in the absence of significant amounts of methanogens. We demonstrate here that trafficking with heavy harvesting machines caused a large reduction in CH(4) consumption and even turned well-aerated forest soils into net methane sources. In addition to studying methane fluxes, we investigated the responses of methanogens after trafficking in two different forest sites. Trafficking generated wheel tracks with different impact (low, moderate, severe, and unaffected). We found that machine passes decreased the soils' macropore space and lowered hydraulic conductivities in wheel tracks. Severely compacted soils yielded high methanogenic abundance, as demonstrated by quantitative PCR analyses of methyl coenzyme M reductase (mcrA) genes, whereas these sequences were undetectable in unaffected soils. Even after a year after traffic compression, methanogen abundance in compacted soils did not decline, indicating a stability of methanogens here over time. Compacted wheel tracks exhibited a relatively constant community structure, since we found several persisting mcrA sequence types continuously present at all sampling times. Phylogenetic analysis revealed a rather large methanogen diversity in the compacted soil, and most mcrA gene sequences were mostly similar to known sequences from wetlands. The majority of mcrA gene sequences belonged either to the order Methanosarcinales or Methanomicrobiales, whereas both sites were dominated by members of the families Methanomicrobiaceae Fencluster, with similar sequences obtained from peatland environments. The results show that compacting wet forest soils by heavy machinery causes increases in methane production and release.


The history and current state of drug abuse in Japan.
Drug abuse in Japan began after World War II and has been characterized by three epidemics of methamphetamine abuse; in addition, solvent abuse has been prominent for a long time. Since 1995, with the beginning of the third epidemic of methamphetamine abuse, drug abuse or dependence in Japan changed, with a marked decrease in solvent abuse, stabilization of methamphetamine abuse, an increase in the abuse of such drugs as cannabis or 3,4-methylenedioxymethamphetamine (which do not have high potential of causing drug-induced psychosis), and the emergence of designer drugs. Furthermore, the abuse of medical drugs such as Ritalin became a major issue in 2007. These changes reveal an increase in the abuse of drugs that do not as easily produce a psychotic state, underlain with a shift from personal conduct that leads to arrest to conduct that does not. Japan, therefore, needs to deal with drug abuse and dependence using not only a medical model, but also a criminal model as well.


COVID-19 and Extracellular Vesicles: An Intriguing Interplay.
The outbreak of severe acute respiratory syndrome β-coronavirus 2 (SARS-CoV-2) has the potential to become a long-lasting global health crisis. The number of people infected with the novel coronavirus has surpassed 22 million globally, resulting in over 700,000 deaths with more than 15 million people having recovered (https://covid19.who.int). Enormous efforts are underway for rapid vaccine and treatment developments. Amongst the many ways of tackling the novel coronavirus disease 2019 (COVID-19) pandemic, extracellular vesicles (EVs) are emerging. EVs are lipid bilayer-enclosed structures secreted from all types of cells, including those lining the respiratory tract. They have established roles in lung immunity and are involved in the pathogenesis of various lung diseases, including viral infection. In this review, we point out the roles and possible contribution of EVs in viral infections, as well as ongoing EV-based approaches for the treatment of COVID-19, including clinical trials. Key Messages: EVs share structural similarities to viruses and recent findings demonstrate that viruses exploit EVs for cellular exit and EVs exploit viral entry mechanisms for cargo delivery. Moreover, EV-virus interplay could be exploited for future antiviral drug and vaccine development. EV-based therapies, especially the mesenchymal stem cell-derived EVs, are being intensively studied for the treatment of COVID-19.


Women's needs for CAM information to manage menopausal symptoms.
To identify the information needs of women regarding complementary and alternative medicine (CAM) treatment options to alleviate menopausal symptoms. Self-administered questionnaires were mailed to women responding to notices posted in family physicians' offices and a women's health center. Survey questions addressed preferred topics, formats and sources of information; experiences with information searching; and what signified good, trustworthy information. The women in this study (n = 413) indicated several challenges including a lack of time to gather information, gaps in, and lack of, relevant information, and poor information quality. They expressed interest in information about the menopausal process, conventional and CAM treatment options, and the safety of treatments. Personal consultation with health-care professionals was the preferred way for obtaining information. The majority of women preferred evidence-based information but there was also a substantial number of women who chose to rely on 'softer' evidence such as personal accounts. These results suggested two different subgroups; however, the data indicate that these are not mutually exclusive since many respondents showed a preference for both types of information. Women feel they are not sufficiently informed to make safe decisions regarding CAM treatment options to alleviate menopausal symptoms. Family physicians are a trusted information source and have an important role in providing women with that information. Brochures containing evidence-based information and a list of newsletters or books that include personal accounts, available in physician's offices and during personal consultations at women's health centers, are offered as a possible solution. A website is another possibility for distributing this information.


Stillbirths: economic and psychosocial consequences.
Despite the frequency of stillbirths, the subsequent implications are overlooked and underappreciated. We present findings from comprehensive, systematic literature reviews, and new analyses of published and unpublished data, to establish the effect of stillbirth on parents, families, health-care providers, and societies worldwide. Data for direct costs of this event are sparse but suggest that a stillbirth needs more resources than a livebirth, both in the perinatal period and in additional surveillance during subsequent pregnancies. Indirect and intangible costs of stillbirth are extensive and are usually met by families alone. This issue is particularly onerous for those with few resources. Negative effects, particularly on parental mental health, might be moderated by empathic attitudes of care providers and tailored interventions. The value of the baby, as well as the associated costs for parents, families, care providers, communities, and society, should be considered to prevent stillbirths and reduce associated morbidity.


Reduced loss through improved fabrication for single air interface bends in polymer waveguides.
We have previously demonstrated high efficiency small-area 45 degrees single air interface waveguide bends in a perfluorocyclobutyl (PFCB) material system [Opt. Express 12, 5314 (2004)]. In this paper we show how the loss per bend can be decreased through improved bend interface position accuracy and sidewall smoothness. This is achieved with electron-beam lithography (EBL) in a scanning electron microscope (SEM) at the cost of increased fabrication complexity compared to our previous work based on a UV contact mask aligner. Using the EBL-based fabrication process, the measured loss per bend decreases from 0.33 dB/bend to 0.124 dB/bend (97.2% bend efficiency) for TE polarization (electric field in plane) and from 0.30 dB/bend to 0.166 dB/bend (96.2% bend efficiency) for TM polarization (electric field out of plane). Since the alignment accuracy and patterning capability within a single exposure field for our low-end electron-beam lithography approach is comparable to what is achievable in high-end stepper tools, the significance of this work is that very low loss air trench bends in low refractive index and low refractive index contrast waveguide materials should be achievable using a conventional high volume microfabrication toolset.


Legitimating a nuclear critic: John Gofman, radiation safety, and cancer risks.
Whether low-level ionizing radiation has an effect on humans has been a polarizing issue for the last fifty years. The epicenter of this controversy has been the validity of the linear non-threshold dose-response model, according to which any amount of radiation, however small, causes damage to human genes and health. In the late 1960s and early 1970s, the nuclear scientist and medical researcher John Gofman (1918-2007) played a pivotal role in the debate. Historical accounts have treated Gofman as a radical antinuclear scientist whose unscientific arguments put enormous political pressure on the nuclear power industry and regulatory agencies. Gofman's bitter struggle with the Atomic Energy Commission, which funded his research at Lawrence Livermore National Laboratory, partly accounts for this view. However, my analysis of Gofman's involvement in the low-level radiation debate shows how he also helped shift the focus in radiation safety from the risks of genetic damage or leukemia to somatic or cancer risks. His arguments led to the introduction of the linear non-threshold radiation model as a means of numerically estimating cancer risks. This was a watershed event in radiation-safety science and politics. Gofman's case sheds light on the process by which a scientist could secure legitimation even when his technical arguments threatened the government's interests. I conclude that it also points to an open issue in the history of antinuclear scientists, or of other politically active scientists or technology critics: treating them as critics should not preclude historians from treating them as scientists.


Modulation of Cortical Activity by High-Frequency Whole-Body Vibration Exercise: An fNIRS Study.
Whole-body vibration (WBV) has shown many positive effects on the human body in rehabilitation and clinical settings in which vibration has been used to elicit muscle contractions in spastic and paretic muscles. The purpose of this study was to investigate whether WBV exercise (WBVe) differently modulates the cortical activity associated with motor and prefrontal function based on its frequency. A total of 18 healthy male adults (mean age: 25.3 [2.4] y) participated in this study and performed WBVe (Galileo Advanced plus; Novotec Medical, Pforzheim, Germany) under 3 different vibration frequency conditions (4-mm amplitude with 10-, 20-, and 27-Hz frequencies) and a control condition (0-mm amplitude with 0-Hz frequency). Each condition consisted of 2 alternating tasks (squatting and standing) every 30 seconds for 5 repetitions. All subjects performed the 4 conditions in a randomized order. Cortical activation during WBVe was measured by relative changes in oxygenated hemoglobin concentration over the primary motor cortex, premotor cortex, supplementary motor area, and prefrontal and somatosensory cortices using functional near-infrared spectroscopy. Oxygenated hemoglobin concentration was higher during the 27-Hz vibration condition than the control and 10-Hz vibration conditions. Specifically, these changes were pronounced in the bilateral primary motor cortex (P < .05) and right prefrontal cortex (P < .05). In contrast, no significant changes in oxygenated hemoglobin concentration were observed in any of the cortical areas during the 10-Hz vibration condition compared with the control condition. This study provides evidence that the motor network and prefrontal cortical areas of healthy adult males can be activated by 27-Hz WBVe. However, WBVe at lower frequencies did not induce significant changes in cortical activation.


Splenectomised and spleen intact Aotus monkeys' immune response to Plasmodium vivax MSP-1 protein fragments and their high activity binding peptides.
Two E. coli expressed recombinant polypeptides (rPvMSP-1(14) and rPvMSP-1(20)) contained in the 33kDa fragment, located within Plasmodium vivax merozoite surface protein (PvMSP-1) 42kDa C-terminal region, and a cocktail of high reticulocyte binding synthetic peptides located within these fragments, were evaluated for immunogenicity and protective immune responses in splenectomised and spleen intact Aotus nancymaae monkeys. Thirty splenectomised monkeys who had been previously immunised with either rPvMSP-1(14), rPvMSP-1(20), or a mixture of both recombinant fragments were intravenously challenged with the heterologous P. vivax VCG-1 strain (as determined by DNA sequencing); full protection was observed in five monkeys and low parasitaemia levels were obtained in eight more monkeys. Splenectomised control monkey group rapidly developed high parasitaemia levels, while no significant parasitaemia was obtained in the non-splenectomised control group. Although PvMSP-1 42 and 33kDa fragments were recognised by Western Blot and whole parasites by IFAT when tested with immune monkey sera, no correlation between protection and antibody titres by IFAT and ELISA was observed, suggesting that protection is not being solely mediated by a humoral immune response. This data showed that partial protection against a heterologous strain challenge was best achieved when immunising with a rPvMSP-1(14)-rPvMSP-1(20) mixture (2 were fully protected and 4 with low parasitaemia out of 12) suggesting for the first time, that these fragments could be good candidates for inclusion in a P. vivax multi-stage, multi-antigen vaccine.


Multiple sclerosis and Natalizumab.
Natalizumab (NTZ), defined as "the first of a new class of drugs known as elective adhesion molecule inhibitors" was developed at the beginning of 2003 to treat relapsing-remitting multiple sclerosis (MS) and was approved in the United States in November 2004. In February 2005, the production of NTZ was suspended by Producer Firms on account of the occurrence of two serious adverse events: two patients who had been taking NTZ manifested a progressive multifocal leukoencephalopathy; the patients showed progressive neurologic deterioration, initially believed to be a worsening of the pre-existing condition of MS. In March 2006, the Advisory Panel of the Food and Drug Administration voted unanimously in favor of the return of NTZ on the market with the majority of the panel also recommending that NTZ be considered the first choice of treatment in MS. NTZ should only be administered to patients who are not taking other medicines for MS and only in highly specialized centers. Inhibiting the adhesion of the circulating immune-competent cells to the vascular endothelium and reducing the precipitation of the circulating immune complexes (CICs) into the central nervous system, NTZ causes the level of the CICs to rise to values that inhibit the production of the antibodies (above all of the immunoglobulin Ms); because of the relative lack of antibodies, the pertussis toxins, no longer complexed, attack the nerve epithelia directly. We must conclude that 1) in remittent MS, between one attack and another (successive re-infection of bordetella pertussis) there are no CICs that can precipitate into the central nervous system, and thus the treatment with NTZ is useless and superfluous; 2) in chronic-progressive MS, the final result of the treatment with NTZ will be that of transforming MS into lateral amyotrophic sclerosis or progressive multifocal leukoencephalopathy; 3) in progressive MS, however, NTZ can be of considerable use in the first 2 months of antibiotic treatment to prevent the formation of new patches or the re-activation of previous ones. With the halt of toxin production (no bordetella pertussis strains resistant to erythrocyne exist) and continuing administration of the antibiotic on a long-term basis, there will be no further need of NTZ.


Contribution of postmortem multidetector CT scanning to identification of the deceased in a mass disaster: Experience gained from the 2009 Victorian bushfires.
CT scanning of the deceased is an established technique performed on all individuals admitted to VIFM over the last 5 years. It is used primarily to assist pathologists in determining cause and manner of death but is also invaluable for identification of unknown deceased individuals where traditional methods are not possible. Based on this experience, CT scanning was incorporated into phase 2 of the Institute's DVI process for the 2009 Victorian bushfires. All deceased individuals and fragmented remains admitted to the mortuary were CT scanned in their body bags using established protocols. Images were reviewed by 2 teams of 2 radiologists experienced in forensic imaging and the findings transcribed onto a data sheet constructed specifically for the DVI exercise. The contents of 255 body bags were examined in the 28 days following the fires. 164 missing persons were included in the DVI process with 163 deceased individuals eventually identified. CT contributed to this identification in 161 persons. In 2 cases, radiologists were unable to recognize commingled remains. CT was utilized in the initial triage of each bag's contents. If radiological evaluation determined that bodies were incomplete then this information was provided to search teams who revisited the scenes of death. CT was helpful in differentiation of human from non-human remains in 8 bags, recognition of human/animal commingling in 10 bags and human commingling in 6 bags. In 61% of cases gender was able to be determined on CT using a novel technique of genitalia detection and in all but 2 cases this was correct. Age range was able to be determined on CT in 94% with an accuracy of 76%. Specific identification features detected on CT included the presence of disease (14 disease entities in 13 cases), medical devices (26 devices in 19 cases) and 274 everyday metallic items associated with the remains of 135 individuals. CT scanning provided useful information prior to autopsy by flagging likely findings including the presence of non-human remains, at the time of autopsy by assisting in the localization of identifying features in heavily disfigured bodies, and after autopsy by retrospective review of images for clarification of issues that arose at the time of pathologist case review. In view of the success of CT scanning in this mass disaster, DVI administrators should explore the incorporation of CT services into their disaster plans.


Drug users in contact with general practice.
A group of heroin users who are in contact with a general practice in north west Edinburgh are described. The study group was younger and included more women than previous studies. These people used a large variety of drugs and mainly purchased them locally. Frequent and often prolonged abstinent periods occurred with no prescribed opiate treatment. The group had experienced a high rate of drug related medical disorders. All these points raise the possibility that opiate users who are known to general practitioners may be a distinctly different population from those who attend drug dependency clinics. The frequency of remission and the prevalence of polydrug use have profound implications for planning and evaluating an effective medical response.


Automatic Cell Segmentation by Adaptive Thresholding (ACSAT) for Large-Scale Calcium Imaging Datasets.
Advances in calcium imaging have made it possible to record from an increasingly larger number of neurons simultaneously. Neuroscientists can now routinely image hundreds to thousands of individual neurons. An emerging technical challenge that parallels the advancement in imaging a large number of individual neurons is the processing of correspondingly large datasets. One important step is the identification of individual neurons. Traditional methods rely mainly on manual or semimanual inspection, which cannot be scaled for processing large datasets. To address this challenge, we focused on developing an automated segmentation method, which we refer to as automated cell segmentation by adaptive thresholding (ACSAT). ACSAT works with a time-collapsed image and includes an iterative procedure that automatically calculates global and local threshold values during successive iterations based on the distribution of image pixel intensities. Thus, the algorithm is capable of handling variations in morphological details and in fluorescence intensities in different calcium imaging datasets. In this paper, we demonstrate the utility of ACSAT by testing it on 500 simulated datasets, two wide-field hippocampus datasets, a wide-field striatum dataset, a wide-field cell culture dataset, and a two-photon hippocampus dataset. For the simulated datasets with truth, ACSAT achieved >80% recall and precision when the signal-to-noise ratio was no less than ∼24 dB.


Duodenal Hemorrhage from Pancreatic Cancer Infiltration Controlled through Combination Therapy with Gemcitabine and S-1.
2.6% of pancreatic cancer patients have the primary manifestation of gastrointestinal bleeding. It is not feasible to stop the duodenal hemorrhage caused by the pancreatic cancer infiltration. A 43-year-old woman who was diagnosed as having pancreatic cancer with multiple hepatic metastases and duodenal infiltration was administered gemcitabine and S-1 combination therapy. During the chemotherapy, initially, bleeding occurred due to duodenal infiltration. However, we continued the chemotherapy and duodenal infiltration was markedly reduced in size and did not rebleed. Aggressive chemotherapy contributed to maintenance of performance status as well as improvement of quality of life for the patient.


Gender differences in clinical presentation and 1-year outcomes in atrial fibrillation.
Our objective was to examine gender differences in clinical presentation, management and prognosis of atrial fibrillation (AF) in a contemporary cohort. In 6412 patients, 39.7% women, of the PREvention oF thromboembolic events - European Registry in Atrial Fibrillation, we examined gender differences in symptoms, risk factors, therapies and 1-year incidence of adverse outcomes. Men with AF were on average younger than women (mean±SD: 70.1±10.7 vs 74.1±9.7 years, p<0.0001). Women more frequently had at least one AF-related symptom at least occasionally compared with men (95.4% in women, 89.8% in men, p<0.0001). Prescription of oral anticoagulation was similar, with an increase of non-vitamin K antagonist oral anticoagulants from 5.9% to 12.6% in women and from 6.2% to 12.6% in men, p<0.0001 for both.Men were more frequently treated with electrical cardioversion and ablation (20.6% and 6.3%, respectively) than women (14.9% and 3.3%, respectively), p<0.0001. Women had 65% (OR: 0.35; 95% CI (0.22 to 0.56)) lower age-adjusted and country-adjusted odds of coronary revascularisation, 40% (OR: 0.60; (0.38 to 0.93)) lower odds of acute coronary syndrome and 20% (OR: 0.80; (0.68 to 0.96)) lower odds of heart failure at 1 year. There were no statistically significant gender differences in 1-year stroke/transient ischaemic attack/arterial thromboembolism and major bleeding events. In a 'real-world' European AF registry, women were more symptomatic but less likely to receive invasive rhythm control therapy such as electrical cardioversion or ablation. Further study is needed to confirm that these differences do not disadvantage women with AF.


Spectrally-bounded continuous-wave supercontinuum generation in a fiber with two zero-dispersion wavelengths.
A common issue in fiber-based supercontinuum (SC) generation under continuous-wave pumping is that the spectral width of the resulting source is related to the input power of the pump laser used. An increase of the input pump power leads to an increase of the spectral width obtained at the fiber output, and therefore, the average power spectral density (APSD) over the SC spectrum does not grow according to the input power. For some applications it would be desired to have a fixed spectral width in the SC and to increase the average PSD proportionally to the input pump power. In this paper we demonstrate experimentally that SC generation under continuous-wave (CW) pumping can be spectrally bounded by using a fiber with two zero-dispersion wavelengths (ZDWs). Beyond a certain pump power, the spectral width of the SC source remains fixed, and the APSD of the SC grows with the pump power. In our experiment we generate a reasonably flat, spectrally-bounded SC spanning from 1550 nm to 1700 nm. The spectra l width of the source is shown to be constant between 3 and 6 W of pump power. Over this range, the increase in input power is directly translated in an increase in the output APSD. The experimental results are confirmed by numerical simulations, which also highlight the sensitivity of this configuration to variations in the fiber dispersion curve. We believe that these results open the way for tailoring the spectral width of high-APSD CW SC by adjusting the fiber dispersion.


Immunological dysfunction in HIV-1-infected individuals caused by impairment of adenosine deaminase-induced costimulation of T-cell activation.
The cell surface association between CD26 and adenosine deaminase (ADA) has a costimulatory function during T-cell activation. Several studies have revealed correlations among CD4(+) CD26(+) T-cell depletion, increased serum levels of ADA, and the evolution of human immunodeficiency virus (HIV) infection, implicating CD26 and ADA in HIV disease progression. In this context, we aimed to determine whether ADA costimulation could be altered during HIV infection. ADA costimulation was investigated in cells from HIV-infected patients (n = 36) in terms of proliferation and cytokine secretion. An effect of ADA on T-cell proliferation was found in HIV-1-infected patients and correlated positively with the CD4(+) percentage and the nadir CD4 count and negatively with viral load, demonstrating that the response depends on the immunological status of the patient. The robust ADA-induced increase in cytokine production [interferon (IFN)-gamma, interleukin (IL)-6 and IL-10] was markedly reduced in T cells from HIV-1-infected subjects. To eliminate some of the variables associated with immunological defects in HIV-1-infected patients, anti-CD3 plus ADA assays with T cells from healthy volunteers were performed in the presence of recombinant glycoprotein 120 (gp120). It was found that gp120 was responsible for the impairment of the ADA-CD26 interaction and consequently of the ADA-induced effect on both costimulation and cytokine production. The gp120-mediated disruption of the CD26-ADA interaction is a novel mechanism that might explain, at least in part, the altered immunological features observed in HIV-1-infected patients and may have significant relevance in AIDS pathogenesis.


Population structure, genetic variability, and gene flow of the bean leaf beetle, Cerotoma trifurcata, in the Midwestern United States.
Bean leaf beetle, Cerotoma trifurcata (Forster) (Coleoptera: Chrysomelidae), is a common pest of soybean in the Midwest United States. However, there are currently no reports on the genetic variability of C. trifurcata. This study examined 15-30 individuals from 25 sample locations to estimate genetic variability and gene flow within and among C. trifurcata from across the Mid- west. Amplified fragment length polymorphism generated 175 markers for analyses. Results from analysis of molecular variance (AMOVA) indicated that the majority of genetic variation was from within samples; only a small amount of the total variation was attributed to the variation among the samples. The GST for the entire C. trifurcata population indicated that the majority of genetic variation was found within the samples, further supporting the AMOVA results. The estimated average gene flow among the C. trifurcata samples was 1.83. The Mantel test revealed no indication of correlation between geographical and genetic distance for all the C. trifurcata samples. These findings show that C. trifurcata in the Midwest are genetically heterogeneous and part of a large, interbreeding population.