Phylo SI: a new genome-wide approach for prokaryotic phylogeny.
The evolutionary history of all life forms is usually represented as a vertical tree-like process. In prokaryotes, however, the vertical signal is partly obscured by the massive influence of horizontal gene transfer (HGT). The HGT creates widespread discordance between evolutionary histories of different genes as genomes become mosaics of gene histories. Thus, the Tree of Life (TOL) has been questioned as an appropriate representation of the evolution of prokaryotes. Nevertheless a common hypothesis is that prokaryotic evolution is primarily tree-like, and a routine effort is made to place new isolates in their appropriate location in the TOL. Moreover, it appears desirable to exploit non-tree-like evolutionary processes for the task of microbial classification. In this work, we present a novel technique that builds on the straightforward observation that gene order conservation ('synteny') decreases in time as a result of gene mobility. This is particularly true in prokaryotes, mainly due to HGT. Using a 'synteny index' (SI) that measures the average synteny between a pair of genomes, we developed the phylogenetic reconstruction tool 'Phylo SI'. Phylo SI offers several attractive properties such as easy bootstrapping, high sensitivity in cases where phylogenetic signal is weak and computational efficiency. Phylo SI was tested both on simulated data and on two bacterial data sets and compared with two well-established phylogenetic methods. Phylo SI is particularly efficient on short evolutionary distances where synteny footprints remain detectable, whereas the nucleotide substitution signal is too weak for reliable sequence-based phylogenetic reconstruction. The method is publicly available at http://research.haifa.ac.il/ssagi/software/PhyloSI.zip.


Divergence of two families of repeated DNA in wood and field mice of the genus Apodemus (Muridae, Rodentia).
The nDNA of six species of a wood and field mice of the genus Apodemus (2n = 48): peninsulae, sylvaticus, flavicollis, microps, speciosus, agrarius, grey rat Rattus norvegicus as well, and house mouse Mus musculus were studied using EcoRI and HindIII restriction endonucleases with an agarose and polyacrylamide gel electrophoresis and a microdensitometry. It is shown for dispersed sequences that a quarter of 1.85 kb EcoRI genus specific family of repeated DNA is constant but a quarter of 1.35 kb EcoRI repeats, which are specific for more large taxon unit, is variable. The HindIII satDNA of the various species differs in the length of monomer, size of more representative multimer and digestion of the monomers by the same endonuclease of restriction; HindIII satDNA quantity correlates with 1.35 kb EcoRI repeat content. Some nonidentified components are found in Apodemus genomes. The possible ways evaluation of the repetitive DNA are briefly discussed. It was supposed that the evolutionary age of the wood mice is directly proportional to the length of HindIII multimer and inversely proportional to the amount of HIndIII satDNA with a 1.35 kb EcoRI repeats.


A Comprehensive Spatial Mapping of Muscle Synergies in Highly Variable Upper-Limb Movements of Healthy Subjects.
Recently, muscle synergy analysis has become a standard methodology for extracting coordination patterns from electromyographic (EMG) signals, and for the evaluation of motor control strategies in many contexts. Most previous studies have characterized upper-limb muscle synergies across a limited set of reaching movements. With the aim of future uses in motor control, rehabilitation and other fields, this study provides a comprehensive characterization of muscle synergies in a large set of upper-limb tasks and also considers inter-individual and environmental variability. Sixteen healthy subjects performed upper-limb hand exploration movements for a comprehensive mapping of the upper-limb workspace, which was divided into several sectors (Frontal, Right, Left, Horizontal, and Up). EMGs from representative upper-limb muscles and kinematics were recorded to extract muscle synergies and explore the composition, repeatability and similarity of spatial synergies across subjects and movement directions, in a context of high variability of motion. Even in a context of high variability, a reduced set of muscle synergies may reconstruct the original EMG envelopes. Composition, repeatability and similarity of synergies were found to be shared across subjects and sectors, even if at a lower extent than previously reported. Extending the results of previous studies, which were performed on a smaller set of conditions, a limited number of muscle synergies underlie the execution of a large variety of upper-limb tasks. However, the considered spatial domain and the variability seem to influence the number and composition of muscle synergies. Such detailed characterization of the modular organization of the muscle patterns for upper-limb control in a large variety of tasks may provide a useful reference for studies on motor control, rehabilitation, industrial applications, and sports.


The existence of tubulo-cisternal endoplasmic reticulum in rat hepatocytes.
Rat livers were fixed by perfusion with glutaraldehyde via the portal vein and postfixed with a mixture of osmium tetroxide and potassium ferricyanide. Subsurface cisterns and vesicles were demonstrated, and, from serial sections, it appears that these organelles are part of large, fenestrated cisterns situated parallel to and at a distance of 20-40 nm from the lateral plasma membrane. Some of the cisterns possessed ribosomes on the surface facing the interior of the cell and, at points, they were continuous with the endoplasmic reticulum. From the lateral cisterns, tubules approached the plasma membrane facing the space of Disse and the sinusoid. A network of tubules was found in the vicinity of the bile canaliculus; a part of it lay close to the canalicular plasma membrane. Serial sectioning revealed that this network was continuous with the lateral cisterns via the endoplasmic reticulum. This morphology resembles that of tubulo-cisternal endoplasmic reticulum of such transporting epithelia as the choroid plexus and the renal proximal tubules.


Sex Trafficking Related Knowledge, Awareness, and Attitudes among Adolescent Female Students in Nepal: A Cross-Sectional Study.
Sex trafficking has been a long-standing concern in Nepal. Very little has been achieved, however, in terms of actual reduction in the number of victims despite numerous anti-sex trafficking programs. This situation may be attributable to a lack of empirical evidence upon which to formulate anti-sexual trafficking interventions. This study aimed to assess sex trafficking-related knowledge, awareness and attitudes, and factors associated with sex trafficking awareness and attitudes towards the victims of sex trafficking and/or anti-sex trafficking campaigns among adolescent female students in Nepal. A cross-sectional study was conducted between August-September 2013 among 292 adolescent female students (>10 years old) using systematic random sampling from three high schools in Sindhupalchowk district, Nepal. As an initial step, descriptive analyses were employed to characterize the data and multivariate logistic regression analyses were used to explore factors associated with sex trafficking awareness and related attitudes. Seventy-six percent of sampled students reported that they were aware of sex trafficking and 94.6% indicated media (i.e., radio or television) as the primary sources of their knowledge. Fifty-one percent mentioned relatives/friends as mediators of sex trafficking, 60.4% reported promise for better jobs as the primary attraction behind sex trafficking, and 48.6% mentioned adolescent females as the most vulnerable group for sex trafficking. Over half (56.8%) of the respondents had positive attitudes towards the victims of sex trafficking and/or anti-sex trafficking campaigns. Age (OR = 3.38, 95% CI:2.51-4.55), parents' occupation (OR = 3.89, 95% CI:1.58-9.58), and having a radio/TV at home (OR = 6.67, 95% CI:3.99-9.54) were significantly associated with awareness, whereas being younger (OR = 0.67, 95% CI:0.55-0.79) and having joint-family (OR = 2.67, 95% CI:1.49-4.80) were significantly associated with having a positive attitudes towards the victims of sex trafficking and/or anti-sex trafficking campaigns. Findings presented have important implications for anti-trafficking programs, in particular those designed to educate the adolescent females who are at most-risk of sex trafficking. Educational programs need to include specific interventions to improve knowledge and attitudes towards sex trafficking among adolescent females in Nepal.


Transduction of terminally differentiated neurons by avian sarcoma virus.
Recent studies have demonstrated that avian sarcoma virus (ASV) can transduce cycle-arrested cells. Here, we have assessed quantitatively the transduction efficiency of an ASV vector in naturally arrested mouse hippocampal neurons. This efficiency was determined by comparing the number of transduced cells after infection of differentiated neurons versus dividing progenitor cells. The results indicate that ASV is able to transduce these differentiated neurons efficiently and that this activity is not the result of infection of residual dividing cells. The transduction efficiency of the ASV vector was found to be intermediate between the relatively high and low efficiencies obtained with human immunodeficiency virus type 1 and murine leukemia virus vectors, respectively.


Forcing ferromagnetic coupling between rare-earth-metal and 3d ferromagnetic films.
Using density functional calculations, we have studied the magnetic properties of nanocomposites composed of rare-earth-metal elements in contact with 3d transition metals (Fe and Cr). We demonstrate the possibility to obtain huge magnetic moments in such nanocomposites, of order 10mu(B)/rare-earth-metal atom, with a potential to reach the maximum magnetic moment of Fe-Co alloys at the top of the so-called Slater-Pauling curve. A first experimental proof of concept is given by thin-film synthesis of Fe/Gd and Fe/Cr/Gd nanocomposites, in combination with x-ray magnetic circular dichroism.


Respite needs of families receiving palliative care.
The care of a child with a life-limiting condition proves an emotional, physical and financial strain on the family that provides care for their child. Respite care is one way which allows carers to receive some relief and support in the context of this burden of care. The provision of and the requirements for respite in this context is poorly understood. This survey aims to describe the types of respite care families receive, the respite that they would ideally receive and the barriers that prevent this. A cohort of 34 families cared for by the Paediatric Palliative Care Service in Queensland were approached to participate in a 20-question survey about their current respite preferences for future respite, with 20 surveys returned. Three of the families (15%) reported receiving no respite in the previous 12 months. Families who received respite received a combination of formal respite (a structured care provider) and informal respite (family or friends). Ten families (50%) reported that they would want the time of respite changed. Barriers to receiving adequate respite included complexity of care of the child, financial barriers and lack of a respite provider. There is disparate provision of respite care with the main perceived barrier to attaining 'ideal respite' being the lack of a provider able to meet the complex care needs of their child. The provision of respite across diversity in geography; medical condition; social and cultural needs remains a challenge.


Isocratic high-performance liquid chromatographic resolution of glutethimide enantiomers and their 4-hydroxyglutethimide metabolites using cellulose tribenzoate chiral stationary phase.
Glutethimide (2-ethyl-2-phenylglutarimide) enantiomers and their corresponding 4-hydroxyglutethimide metabolites (RS and RR) are separated using newly developed commercially available cellulose tris(4-methylphenyl benzoate) ester (Chiralcel OJ) chiral stationary phase and hexane-ethanol or hexane-2-propanol as the mobile phase. The effects of ethanol or 2-propanol concentration in the mobile phase and of column temperature on retention and enantioselectivity of glutethimide enantiomers are also demonstrated. Maximum resolutions of 14.23 and 7.09 are obtained for glutethimide and their 4-hydroxyglutethimide metabolites, respectively, with hexane-ethanol (60:40) at 23 degrees C and a flow rate of 1 mL/min.


The equivalence of multi-axis spine systems: Recommended stiffness limits using a standardized testing protocol.
The complexity of multi-axis spine testing often makes it challenging to compare results from different studies. The aim of this work was to develop and implement a standardized testing protocol across three six-axis spine systems, compare them, and provide stiffness and phase angle limits against which other test systems can be compared. Standardized synthetic lumbar specimens (n=5), comprising three springs embedded in polymer at each end, were tested on each system using pure moments in flexion-extension, lateral bending, and axial rotation. Tests were performed using sine and triangle waves with an amplitude of 8Nm, a frequency of 0.1Hz, and with axial preloads of 0 and 500N. The stiffness, phase angle, and R2 value of the moment against rotation in the principal axis were calculated at the center of each specimen. The tracking error was adopted asa measure of each test system to minimize non-principal loads, defined as the root mean squared difference between actual and target loads. All three test systems demonstrated similar stiffnesses, with small (<14%) but significant differences in 4 of 12 tests. More variability was observed in the phase angle between the principal axis moment and rotation, with significant differences in 10 of 12 tests. Stiffness and phase angle limits were calculated based on the 95% confidence intervals from all three systems. These recommendations can be used with the standard specimen and testing protocol by other research institutions to ensure equivalence of different spine systems, increasing the ability to compare in vitro spine studies.


Current state of the art imaging approaches for colorectal liver metastasis.
One of the most common cancers worldwide, colorectal cancer (CRC) has been associated with significant morbidity and mortality and therefore represents an enormous burden to the health care system. Recent advances in CRC treatments have provided patients with primary and metastatic CRC a better long-term prognosis. The presence of synchronous or metachronous metastasis has been associated, however, with worse survival. The most common site of metastatic disease is the liver. A variety of treatment modalities aimed at targeting colorectal liver metastases (CRLM) has been demonstrated to improve the prognosis of these patients. Loco-regional approaches such as surgical resection and tumor ablation (operative and percutaneous) can provide patients with a chance at long-term disease control and even cure in select populations. Patient selection is important in defining the most suitable treatment option for CRLM in order to provide the best possible survival benefit while avoiding unnecessary interventions and adverse events. Medical imaging plays a crucial role in evaluating the characteristics of CRLMs and disease resectability. Size of tumors, proximity to adjacent anatomical structures, and volume of the unaffected liver are among the most important imaging parameters to determine the suitability of patients for surgical management or other appropriate treatment approaches. We herein provide a comprehensive overview of current-state-of-the-art imaging in the management of CRLM, including staging, treatment planning, response and survival assessment, and post-treatment surveillance. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are two most commonly used techniques, which can be used solely or in combination with functional imaging modalities such as positron emission tomography (PET) and diffusion weighted imaging (DWI). Providing up-to-date evidence on advantages and disadvantages of imaging modalities and tumor assessment criteria, the current review offers a practice guide to assist providers in choosing the most suitable imaging approach for patients with CRLM.


Maturation and maintenance of cholinergic medial septum neurons require glucocorticoid receptor signaling.
Glucocorticoids have been shown to influence trophic processes in the nervous system. In particular, they seem to be important for the development of cholinergic neurons in various brain regions. Here, we applied a genetic approach to investigate the role of the glucocorticoid receptor (GR) on the maturation and maintenance of cholinergic medial septal neurons between P15 and one year of age by using a mouse model carrying a CNS-specific conditional inactivation of the GR gene (GRNesCre). The number of choline acetyltransferase and p75NTR immuno-positive neurons in the medial septum (MS) was analyzed by stereology in controls versus mutants. In addition, cholinergic fiber density, acetylcholine release and cholinergic key enzyme activity of these neurons were determined in the hippocampus. We found that in GRNesCre animals the number of medial septal cholinergic neurons was significantly reduced during development. In addition, cholinergic cell number further decreased with aging in these mutants. The functional GR gene is therefore required for the proper maturation and maintenance of medial septal cholinergic neurons. However, the loss of cholinergic neurons in the medial septum is not accompanied by a loss of functional cholinergic parameters of these neurons in their target region, the hippocampus. This pinpoints to plasticity of the septo-hippocampal system, that seems to compensate for the septal cell loss by sprouting of the remaining neurons.


The menstrual cycle, personality, and academic performance.
Considerable research supports the widespread complaint of mood and behavioral changes during the menstrual cycle. However, there is little evidence of effects on intellectual performance, even though students commonly complain of it. We studied the results obtained by 244 female medical and paramedical students in all examinations taken during one year. In view of suspected correlations between personality characteristics and degree of dysmenorrhea, an Eysenck Personality Inventory, measuring extroversion and neuroticism, was administered. The examination results of high and low scorers on these personality scales and of those women with prolonged (greater than or equal to six days) menses were reanalyzed. Not one of these analyses revealed significant menstrual-cycle effects on examination performance. Thus, while some persons may suffer, it does not seem that menstrual cycle effects are sufficient to handicap significantly the examination performance of the majority of female students.


Self-esteem and insight as predictors of symptom change in schizophrenia: a longitudinal study.
Though it is known that symptom profiles in schizophrenia change throughout the course of the illness, it is not yet clear which psychological antecedents predict these changes. The purpose of the present study was to explore "level of insight into mental illness" and "self-esteem" as predictors of positive symptom change in schizophrenia patients. Fifty-seven schizophrenia patients completed assessments of self-esteem, insight into mental illness, positive symptoms and paranoia once every four weeks for a total of eight individual testing sessions. Hierarchical linear regression analysis revealed that changes in self-esteem predicted future changes in paranoia as well as positive symptoms more broadly; decreases in self-esteem at any given time point were associated with an increase in persecutory beliefs and other positive symptoms at the following assessment. On the other hand, decreases in insight were not significantly associated with paranoia or positive symptoms, either as a stable trait of the mental illness or as a predictor of change over time. Taken together, these results suggest that change in self-esteem, but not insight, has a significant and unique association with positive symptoms of schizophrenia, and may be a valuable target for future treatment.


Factors associated with secondhand tobacco smoke in the home: an exploratory cross-sectional study among women in Aleta Wondo, Ethiopia.
In Ethiopia, female smoking rates are currently low (1 %). However, because of male smoking rates (overall 7.7 % and up to 27 % depending on region), women and children's risk of second hand smoke (SHS) exposure is a pressing concern. In order to develop effective public health interventions that prevent the uptake and exposure to smoking, thereby averting the projected increase in tobacco-induced disease, an understanding of Ethiopian women's practices regarding tobacco is needed. The purpose of this study was to explore Ethiopian women's tobacco use and prevalence of SHS exposure, and to identify covariates associated with SHS exposure. We conducted an exploratory cross-sectional study in Southern Ethiopia between August and October 2014, and systematically sampled households in Aleta Wondo town and surrounding districts. Trained interviewers verbally administered surveys to women 18-55 years of age. Descriptive statistics and multiple logistic regression analyses were performed. None of the 353 participants reported current tobacco use and less than 1 % reported ever use, however, 11 % reported ever use of the stimulant leaf khat. Twenty-seven women (7.6 %) reported living with a tobacco user, however, twice that number (14.4 %) overall, and 22 % of urban participants reported that smoking occurred daily in their home. When controlling for other factors, living with a tobacco user (OR = 9.91, 95 % CI [3.32, 29.59]), allowing smoking in the home (OR = 5.67, 95 % CI [2.51, 12.79]), place of residence (OR = 2.74, 95 % CI [1.11, 6.74)]), and exposure to point-of-sale advertising within the last 30 days (OR = 2.87, 95 % CI [1.26, 6.54]) contributed significantly to a model predicting the likelihood of reporting daily occurrence of smoking/SHS in the home. While few women reported having ever used tobacco, one in seven women in this study reported that smoking/SHS occurred daily in their homes. Therefore SHS exposure is a potential health concern for women and children in this rural community. Findings from this study provide baseline data for monitoring tobacco control policies in Ethiopia, particularly in relation to the promotion of smoke-free homes, and could be used to inform prevention program development.


Modeling the regional spread and control of vancomycin-resistant enterococci.
Because patients can remain colonized with vancomycin-resistant enterococci (VRE) for long periods of time, VRE may spread from one health care facility to another. Using the Regional Healthcare Ecosystem Analyst, an agent-based model of patient flow among all Orange County, California, hospitals and communities, we quantified the degree and speed at which changes in VRE colonization prevalence in a hospital may affect prevalence in other Orange County hospitals. A sustained 10% increase in VRE colonization prevalence in any 1 hospital caused a 2.8% (none to 62%) average relative increase in VRE prevalence in all other hospitals. Effects took from 1.5 to >10 years to fully manifest. Larger hospitals tended to have greater affect on other hospitals. When monitoring and controlling VRE, decision makers may want to account for regional effects. Knowing a hospital's connections with other health care facilities via patient sharing can help determine which hospitals to include in a surveillance or control program.


Economic evaluation of an alternative drug to sulfadoxine-pyrimethamine as intermittent preventive treatment of malaria in pregnancy.
Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended in HIV-negative women to avert malaria, while this relies on cotrimoxazole prophylaxis (CTXp) in HIV-positive women. Alternative antimalarials are required in areas where parasite resistance to antifolate drugs is high. The cost-effectiveness of IPTp with alternative drugs is needed to inform policy. The cost-effectiveness of 2-dose IPTp-mefloquine (MQ) was compared with IPTp-SP in HIV-negative women (Benin, Gabon, Mozambique and Tanzania). In HIV-positive women the cost-effectiveness of 3-dose IPTp-MQ added to CTXp was compared with CTXp alone (Kenya, Mozambique and Tanzania). The outcomes used were maternal clinical malaria, anaemia at delivery and non-obstetric hospital admissions. The poor tolerability to MQ was included as the value of women's loss of working days. Incremental cost-effectiveness ratios (ICERs) were calculated and threshold analysis undertaken. For HIV-negative women, the ICER for IPTp-MQ versus IPTp-SP was 136.30 US$ (2012 US$) (95%CI 131.41; 141.18) per disability-adjusted life-year (DALY) averted, or 237.78 US$ (95%CI 230.99; 244.57), depending on whether estimates from Gabon were included or not. For HIV-positive women, the ICER per DALY averted for IPTp-MQ added to CTXp, versus CTXp alone was 6.96 US$ (95%CI 4.22; 9.70). In HIV-negative women, moderate shifts of variables such as malaria incidence, drug cost, and IPTp efficacy increased the ICERs above the cost-effectiveness threshold. In HIV-positive women the intervention remained cost-effective for a substantial (up to 21 times) increase in cost per tablet. Addition of IPTp with an effective antimalarial to CTXp was very cost-effective in HIV-positive women. IPTp with an efficacious antimalarial was more cost-effective than IPTp-SP in HIV-negative women. However, the poor tolerability of MQ does not favour its use as IPTp. Regardless of HIV status, prevention of malaria in pregnancy with a highly efficacious, well tolerated antimalarial would be cost-effective despite its high price. ClinicalTrials.gov NCT 00811421; Pan African Trials Registry PACTR2010020001429343 and PACTR2010020001813440.


Inconsistent susceptibility to autoimmunity in inbred LEW rats is due to genetic crossbreeding involving segregation of the arthritis-regulating gene Ncf1.
We recently identified a single-nucleotide polymorphism in the Ncf1 gene, a component of the NADPH oxidase complex, to be the cause of one of the strongest identified loci for arthritis severity in rats. This polymorphism was found to be naturally occurring in a collection of inbred rat strains as well as in wild rats. Among the inbred strains we found that different LEW substrains (LEW/Ztm and LEW/Mol), originating from different breeders, showed an allelic discrepancy in Ncf1, suggesting an impact on arthritis susceptibility between these substrains. In fact, the LEW/Mol strain was completely resistant to pristane-induced arthritis, in contrast to the LEW/Ztm strain, which was susceptible. Moreover, the LEW/Mol strain had higher production of radical oxygen species in peripheral blood leukocytes, a phenomenon most likely regulated by the polymorphisms in the Ncf1 gene. However, the phenotypic difference between LEW/Mol and LEW/Ztm is most likely a combination of several genes, of which Ncf1 is suggested to be the major regulating gene. This has also been confirmed by previous linkage analyses involving the LEW/Ztm strain which shows that a QTL on chromosome 12, most likely caused by polymorphism of Ncf1, is the major regulatory gene but that other loci are contributing. That more genes are likely to contribute was shown by a complete genome comparison of the LEW/Ztm and the LEW/Mol rat strains that uncovered an introduction of approximately 37% non-LEW genome into the LEW/Mol strain, which probably was caused by past crossbreeding. Therefore, the LEW/Mol should be regarded as a recombinant inbred strain.


Teicoplanin, a new antibiotic from Actinoplanes teichomyceticus nov. sp.
Teicoplanin, a new glycopeptide antibiotic belonging to the same family as vancomycin, inhibits cell wall synthesis in Bacillus subtilis; the inhibition is accompanied by an intracellular accumulation of UDP-N-acetyl-muramyl-pentapeptide. A cell-free system from Bacillus stearothermophilus, capable of synthesizing peptidoglycan, is 50% inhibited by teicoplanin at 40 micrograms/ml and 100% inhibited at 100 micrograms/ml; suppression of peptidoglycan synthesis is accompanied by parallel accumulation of the lipid intermediate. Teicoplanin binds to cell walls and forms a complex with N,N'-diacetyl-L-lysyl-D-alanyl-D-alanine. The association constant of this complex is 2.56 X 10(6) liters mol-1, calculated by spectrophotometric titration. The mechanism of action of teicoplanin is discussed in comparison with those of other inhibitors of cell wall biosynthesis, namely, vancomycin, ristocetin, and gardimycin.


[Effect of obstructive sleep apnea hypoxia on learning memory capacity after cerebral ischemia-reperfusion in rats].
To investigate the effect of obstructive sleep apnea hypoxia on learning memory capacity in rat after ischemia. Eighty healthy male wister rats were randomly divided into: sham operation group (SO group, n=20), merely ischemia group (I/R group, n=20), and obstructive sleep apnea hypoxia for 7 days ischemia group (IH7+ I/R group, n=20), obstructive sleep apnea hypoxia for 21 days ischemia group (IH21+ I/R group, n=20). Obstructive sleep apnea hypoxia ischemia groups were respectively given obstructive sleep apnea hypoxia for 7 days and 21 days. Ischemia animals were prepared cerebral ischemia-reperfusion model by improved pulsinelli four vessels block (4-VO), the morphological changes of hippocampus nerve cells of rat brain were detected with HE, neuron pathology in hippocampal regin was observed using electron microscope, and learning memory capacity of rats were assessed by the Morris water maze test. Compared with the SO group, the I/R group demonstrated shortened escaping latency, increased frequency of crossing the platform in the water maze test, decreased survival rate of neurons, and increased apoptotic cells and ultrastructure damages(P<0.05). Compared with the I/R group, obstructive sleep apnea hypoxia ischemia groups showed shortened escaping latency, increased frequency of crossing the platform, decreased survival rate of neurons, and increased apoptotic cells and ultrastructure damages(P<0.05), especially in the IH21+ I/R group(P<0.05). Obstructive sleep apnea hypoxia can increase the damage of learning memory capacity. This damage is related to hippocampus nerve loss and ultrastructure injury from obstructive sleep apnea hypoxia.


Household Materials Selection for Homemade Cloth Face Coverings and Their Filtration Efficiency Enhancement with Triboelectric Charging.
The COVID-19 pandemic is currently causing a severe disruption and shortage in the global supply chain of necessary personal protective equipment (e.g., N95 respirators). The U.S. CDC has recommended use of household cloth by the general public to make cloth face coverings as a method of source control. We evaluated the filtration properties of natural and synthetic materials using a modified procedure for N95 respirator approval. Common fabrics of cotton, polyester, nylon, and silk had filtration efficiency of 5-25%, polypropylene spunbond had filtration efficiency 6-10%, and paper-based products had filtration efficiency of 10-20%. An advantage of polypropylene spunbond is that it can be simply triboelectrically charged to enhance the filtration efficiency (from 6 to >10%) without any increase in pressure (stable overnight and in humid environments). Using the filtration quality factor, fabric microstructure, and charging ability, we are able to provide an assessment of suggested fabric materials for homemade facial coverings.


[Abuse in healthcare - lessons learned during two decades of research].
Patients' experience of abuse in health care (AHC) is common, and may cause long-lasting suffering. In Sweden, lifetime prevalence is estimated at 20 per cent among female patients and 8 per cent among male patients, and a background of other abuse is a risk factor. Most health care staff have experience of patients who have been abused, but the topic is surrounded by silence from both patients and caregivers. Models for training staff in groups have been evaluated and a more proactive stance can be fostered. Department heads and health care authorities are responsible for providing staff with options to counteract AHC. Caregivers need training in how to carry out consultations with patients who say they have been abused in health care, and this training should be included in efforts to increase quality of care. Changes are within reach but educational efforts are urgent.


The Postoperative Pain Assessment Skills pilot trial.
BACKGROUND⁄ Pain-related misbeliefs among health care professionals (HCPs) are common and contribute to ineffective postoperative pain assessment. While standardized patients (SPs) have been effectively used to improve HCPs' assessment skills, not all centres have SP programs. The present equivalence randomized controlled pilot trial examined the efficacy of an alternative simulation method - deteriorating patient-based simulation (DPS) - versus SPs for improving HCPs' pain knowledge and assessment skills. Seventy-two HCPs were randomly assigned to a 3 h SP or DPS simulation intervention. Measures were recorded at baseline, immediate postintervention and two months postintervention. The primary outcome was HCPs' pain assessment performance as measured by the postoperative Pain Assessment Skills Tool (PAST). Secondary outcomes included HCPs knowledge of pain-related misbeliefs, and perceived satisfaction and quality of the simulation. These outcomes were measured by the Pain Beliefs Scale (PBS), the Satisfaction with Simulated Learning Scale (SSLS) and the Simulation Design Scale (SDS), respectively. Student's t tests were used to test for overall group differences in postintervention PAST, SSLS and SDS scores. One-way analysis of covariance tested for overall group differences in PBS scores. DPS and SP groups did not differ on post-test PAST, SSLS or SDS scores. Knowledge of pain-related misbeliefs was also similar between groups. These pilot data suggest that DPS is an effective simulation alternative for HCPs' education on postoperative pain assessment, with improvements in performance and knowledge comparable with SP-based simulation. An equivalence trial to examine the effectiveness of deteriorating patient-based simulation versus standardized patients is warranted.


The chemokine and scavenger receptor CXCL16/SR-PSOX is expressed in human vascular smooth muscle cells and is induced by interferon gamma.
Atherosclerosis is an inflammatory disease that is characterised by the involvement of chemokines that are important for the recruitment of leukocytes and scavenger receptors that mediate foam cell formation. Several cytokines are involved in the regulation of chemokines and scavenger receptors in atherosclerosis. CXCL16 is a chemokine and scavenger receptor and found in macrophages in human atherosclerotic lesions. Using double-labelled immunohistochemistry, we identified that smooth muscle cells in human lesions express CXCL16. We then analysed the effects of IFN-gamma, TNF-alpha, IL-12, IL-15, IL-18, and LPS on CXCL16 expression in cultured aortic smooth muscle cells. IFN-gamma was the most potent CXCL16 inducer and increased mRNA, soluble form, membrane form, and total cellular levels of CXCL16. The IFN-gamma induction of CXCL16 was also associated with increased uptake of oxLDL into these cells. Taken together, smooth muscle cells express CXCL16 in atherosclerotic lesions, which may play a role in the attraction of T cells to atherosclerotic lesions and contribute to the cellular internalisation of modified LDL.


Bacterial strategies along nutrient and time gradients, revealed by metagenomic analysis of laboratory microcosms.
There is considerable interest in the functional basis of ecological strategies amongst bacteria. We used laboratory microcosms based on culturing of elutant from soil to study the effects of varying initial nutrient concentration, and time succession, on the community metagenome. We found a distinct set of nutrient-related or time-related changes in the functional metagenome. For example, a high nutrient (copiotrophic) strategy was associated with greater abundance of genes related to cell division and cell cycle, while a low nutrient (oligotrophic) strategy had greater abundance of genes related to carbohydrate metabolism and virulence, disease and defense. We also found time-related changes in the functional metagenome, revealing a distinct 'r'-related strategy with greater abundance of genes related to regulation and cell signaling, and a 'K' strategy rich in motility and chemotaxis-related genes. These different gene-based strategies may help to explain how so many bacterial OTUs coexist in nature, and the functional principles dominating natural communities. In terms of diversity, both the OTU richness and the richness of species assignment of functional genes showed linear correlations with functional gene richness, supporting the hypothesis that greater taxonomic diversity is associated with greater functional diversity, with possible implications for ecosystem stability.


Comparison of 68Ga-FAPI PET/CT and 18FDG PET/CT Modalities in Gastrointestinal System Malignancies with Peritoneal Involvement.
In this study, we aimed to investigate the utilization of 68Ga-FAPI PET/CT in comparison to 18FDG PET/CT to evaluate the peritoneal involvement of the gastrointestinal malignancies alongside primary lesions and other metastatic foci. A total of 37 patients with various gastrointestinal malignancies with accompanying peritoneal involvement who underwent 68Ga-FAPI PET/CT and 18FDG PET/CT imaging between September 2020 and June 2021 were included in this retrospective study. SUVmax values of 68Ga-FAPI and 18FDG were compared according to lesion locations. Also, the lesion localization ability of both imaging was compared in patient basis. Of the 37 patients with peritoneal involvement (23 males and 14 females; median age, 62.8 ± 12.7 years), 35.1% (n = 13) had colorectal cancer, 37.8% (n = 14) gastric cancer, and 27.0% (n = 10) pancreaticobiliary cancer. While 45.9% of them were operated, the remaining did not have surgery. The mean time interval between two studies was 3.2 days (range: 2-6 days). The mean SUVmax value of peritoneal metastases (p < 0.001) was significantly higher with 68Ga-FAPI PET/CT compared to that with 18FDG PET/CT, as in primary lesions (p < 0.001), lymph node metastases (p = 0.006), liver metastases (p = 0.002), and bone metastases (p = 0.018). A total of 185 lesions was detected in the initial assessment with 18FDG PET/CT. Of the total lesions detected with 18FDG PET/CT, 5 of them were evaluated as benign lesions with 68Ga-FAPI PET/CT also in accordance with the reference standard. In addition to 180 lesions detected with 18FDG PET/CT, a total of 37 additional malignant lesions, 12 of which were peritoneal metastases, were detected with 68Ga-FAPI PET/CT. 68Ga-FAPI PET/CT was determined to be superior to 18FDG PET/CT in terms of detection of peritoneal involvement with high image quality as well as primary tumor and other metastatic foci. Consequently, 68Ga-FAPI PET/CT can be used as a complementary imaging modality especially for inconclusive 18FDG findings due to the lack of accuracy of 18FDG PET/CT in some of the metastatic regions, especially in the liver.


Exchanges across land-water-scape boundaries in urban systems: strategies for reducing nitrate pollution.
Conservation in urban areas typically focuses on biodiversity and large green spaces. However, opportunities exist throughout urban areas to enhance ecological functions. An important function of urban landscapes is retaining nitrogen thereby reducing nitrate pollution to streams and coastal waters. Control of nonpoint nitrate pollution in urban areas was originally based on the documented importance of riparian zones in agricultural and forested ecosystems. The watershed and boundary frameworks have been used to guide stream research and a riparian conservation strategy to reduce nitrate pollution in urban streams. But is stream restoration and riparian-zone conservation enough? Data from the Baltimore Ecosystem Study and other urban stream research indicate that urban riparian zones do not necessarily prevent nitrate from entering, nor remove nitrate from, streams. Based on this insight, policy makers in Baltimore extended the conservation strategy throughout larger watersheds, attempting to restore functions that no longer took place in riparian boundaries. Two urban revitalization projects are presented as examples aimed at reducing nitrate pollution to stormwater, streams, and the Chesapeake Bay. An adaptive cycle of ecological urban design synthesizes the insights from the watershed and boundary frameworks, from new data, and from the conservation concerns of agencies and local communities. This urban example of conservation based on ameliorating nitrate water pollution extends the initial watershed-boundary approach along three dimensions: 1) from riparian to urban land-water-scapes; 2) from discrete engineering solutions to ecological design approaches; and 3) from structural solutions to inclusion of individual, household, and institutional behavior.


Skin burns from monochloroacetic acid leak in a chemical plant: a case report.
The patient, a 45-year-old male chemical factory worker, was burned by monochloroacetic acid discharged from a ruptured pipe. The patient was merely flushed with water and did not leave the workplace immediately. As a result, he suffered local burn symptoms, which gradually worsened. Two and a half hours after the accident, he developed symptoms of systemic poisoning, such as lethargy and dyspnoea. After a thorough debridement of the wound surface and subsequent skin grafting combined with early glucocorticoid therapy and haemofiltration, a satisfactory result was achieved, and the patient eventually recovered. With the widespread use of monochloroacetic acid in China, incidents of poisoning with this chemical are becoming increasingly common, with more than 100 cases reported in the past ten years in China alone.


Melanocytic tumors with intraepidermal melanophages: a report of five cases with review of 231 archived cutaneous melanocytic tumors.
Dermal melanophages are frequently encountered in both benign melanocytic nevi and malignant melanoma. In contrast, intraepidermal melanophages (IEM) are under-recognized in melanocytic lesions and their biologic significance is not understood. Herein, we report the clinical and histopathologic features of five melanocytic lesions featuring IEM encountered prospectively in our dermatopathology practice at the University of Chicago. Two hundred and thirty-one (231) archived skin primary melanocytic proliferations were also investigated retrospectively in a de-identified, archival teaching set collection. Nineteen of 231 of the archived cases were positive for IEM. Among the total 24 IEM-positive cases (5 prospective and 19 archived cases), 13 were categorized as Spitz nevi (p < 0.0001) and 3 as atypical Spitz tumors (p = 0.0152). Fourteen of 24 cases with IEM also exhibited intracorneal melanocytes (p < 0.0001). IEM are evidently not rare, especially in spitzoid melanocytic neoplasms. IEM in our series were significantly correlated with intracorneal melanocytosis, possibly indicating an association between IEM and suprabasal melanocytosis and/or transepidermal elimination of melanocytes.


Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure.
Somatic mutations causing clonal expansion of hematopoietic cells (clonal hematopoiesis of indeterminate potential [CHIP]) are increased with age and associated with atherosclerosis and inflammation. Age and inflammation are the major risk factors for heart failure, yet the association of CHIP with heart failure in humans is unknown. To assess the potential prognostic significance of CHIP in patients with chronic heart failure (CHF) owing to ischemic origin. We analyzed bone marrow-derived mononuclear cells from 200 patients with CHF by deep targeted amplicon sequencing to detect the presence of CHIP and associated such with long-term prognosis in patients with CHF at University Hospital Frankfurt, Frankfurt, Germany. Data were analyzed between October 2017 and April 2018. Median age of the patients was 65 years. Forty-seven mutations with a variant allele fraction (VAF) of at least 0.02 were found in 38 of 200 patients with CHF (18.5%). The somatic mutations most commonly occurred in the genes DNMT3A (14 patients), TET2 (9 patients), KDM6A (4 patients), and BCOR (3 patients). Patients with CHIP were older and more frequently had a history of hypertension. During a median follow-up of 4.4 years, a total of 53 patients died, and 23 patients required hospitalization for heart failure. There was a significantly worse long-term clinical outcome for patients with either DNMT3A or TET2 mutations compared with non-CHIP carriers. By multivariable Cox proportional regression analysis, the presence of somatic mutations within TET2 or DNMT3A (HR, 2.1; 95% CI, 1.1-4.0; P = .02, for death combined with heart failure hospitalization) and age (HR, 1.04; 95% CI, 1.01-1.07 per year; P = .005) but not a history of hypertension remained independently associated with adverse outcome. Importantly, there was a significant dose-response association between VAF and clinical outcome. Our data suggest that somatic mutations in hematopoietic cells, specifically in the most commonly mutated CHIP driver genes TET2 and DNMT3A, may be significantly associated with the progression and poor prognosis of CHF. Future studies will have to validate our findings in larger cohorts and address whether targeting specific inflammatory pathways may be valuable for precision medicine in patients with CHF carrying specific mutations encoding for CHIP.


Perceptual learning in the developing auditory cortex.
A hallmark of the developing auditory cortex is the heightened plasticity in the critical period, during which acoustic inputs can indelibly alter cortical function. However, not all sounds in the natural acoustic environment are ethologically relevant. How does the auditory system resolve relevant sounds from the acoustic environment in such an early developmental stage when most associative learning mechanisms are not yet fully functional? What can the auditory system learn from one of the most important classes of sounds, animal vocalizations? How does naturalistic acoustic experience shape cortical sound representation and perception? To answer these questions, we need to consider an unusual strategy, statistical learning, where what the system needs to learn is embedded in the sensory input. Here, I will review recent findings on how certain statistical structures of natural animal vocalizations shape auditory cortical acoustic representations, and how cortical plasticity may underlie learned categorical sound perception. These results will be discussed in the context of human speech perception.


On some Cuban species of the genus Longior Travassos & Kloss, 1958 (Oxyurida, Hystrignathidae), with description of a new species.
Longior zayasi Coy, García & Alvarez, 1993 is established as incertae sedis because the males (declared as the holotype) are inconsistent with the generic diagnosis, particularly in relation to the morphology of the head and tail. Thus, the females of Longior zayasi species (which agree with the generic diagnosis) are renamed and re-described as Longior longior Morffe & García sp. n. We also described males found in the sample and considered as conspecific with the new species. A comparative table with the measurements of the most of the records of Longior longior is given. The male of Longior similis Morffe, García & Ventosa, 2009 is described from the type locality of the species and compared with the known males of the genus. A key to the females of the Cuban Longior is given.


Determinants of Iliac Blade Orientation in Anthropoid Primates.
Orientation of the iliac blades is a key feature that appears to distinguish extant apes from monkeys. Iliac morphology is hypothesized to reflect variation in thoracic shape that, in turn, reflects adaptations for shoulder and forearm function in anthropoids. Iliac orientation is traditionally measured relative to the acetabulum, whereas functional explanations pertain to its orientation relative to the cardinal anatomical planes. We investigated iliac orientation relative to a median plane using digital models of hipbones registered to landmark data from articulated pelves. We fit planes to the iliac surfaces, midline, and acetabulum, and investigated linear metrics that characterize geometric relationships of the iliac margins. Our results demonstrate that extant hominoid ilia are not rotated into a coronal plane from a more sagittal position in basal apes and monkeys but that the apparent rotation is the result of geometric changes within the ilia. The whole ilium and its gluteal surface are more coronally oriented in apes, but apes and monkeys do not differ in orientation of the iliac fossa. The angular differences in the whole blade and gluteal surface primarily reflect a narrower iliac tuberosity set closer to the midline in extant apes, reflecting a decrease in erector spinae muscle mass associated with stiffening of the lumbar spine. Mediolateral breadth across the ventral dorsal iliac spines is only slightly greater in extant apes than in monkeys. These results demonstrate that spinal musculature and mobility have a more significant effect on pelvic morphology than does shoulder orientation, as had been previously hypothesized. Anat Rec, 300:810-827, 2017. © 2017 Wiley Periodicals, Inc.


Controversies over the use of GnRH agonists for reduction of chemotherapy-induced gonadotoxicity.
The increase in cancer incidence in younger people and the significant improvement in long and permanent remission have brought concern about their reproductive future and quality of life. Up to two-thirds of adult female patients undergoing chemotherapy for malignancies eventually develop premature ovarian failure. This condition is related to many complaints including vasomotor symptoms, osteoporosis, increased risk of cardiovascular diseases, sexual dysfunction, and infertility. Therefore, protection against iatrogenic infertility and loss of endocrine ovarian function caused by chemotherapy is currently of high priority. Several options have been used for preserving ovarian function. Established methods include cryopreservation of embryos and/or ova, and ovarian transposition, while others such as ovarian tissue preservation are new, yet promising treatments for fertility preservation. The administration of gonadotropin releasing hormone (GnRH) agonistic analogs (GnRH-a) is still considered experimental. However, the recent evidence is strong to recommend the use of GnRH-a co-treatment during chemotherapy in young women with cancer to protect ovarian function, with promising results regarding fertility preservation. As the use of GnRH-a is non-invasive, highly available and without impact on cancer treatment outcomes, it should be offered to all young female cancer patients to preserve their ovarian function.


Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction.
The purpose of this study was to comprehensively examine cardiovascular reserve function with exercise in patients with heart failure and preserved ejection fraction (HFpEF). Optimal exercise performance requires an integrated physiologic response, with coordinated increases in heart rate, contractility, lusitropy, arterial vasodilation, endothelial function, and venous return. Cardiac and vascular responses are coupled, and abnormalities in several components may interact to promote exertional intolerance in HFpEF. Subjects with HFpEF (n = 21), hypertension without heart failure (n = 19), and no cardiovascular disease (control, n = 10) were studied before and during exercise with characterization of cardiovascular reserve function by Doppler echocardiography, peripheral arterial tonometry, and gas exchange. Exercise capacity and tolerance were reduced in HFpEF compared with hypertensive subjects and controls, with lower VO(2) and cardiac index at peak, and more severe dyspnea and fatigue at matched low-level workloads. Endothelial function was impaired in HFpEF and in hypertensive subjects as compared with controls. However, blunted exercise-induced increases in chronotropy, contractility, and vasodilation were unique to HFpEF and resulted in impaired dynamic ventricular-arterial coupling responses during exercise. Exercise capacity and symptoms of exertional intolerance were correlated with abnormalities in each component of cardiovascular reserve function, and HFpEF subjects were more likely to display multiple abnormalities in reserve. HFpEF is characterized by depressed reserve capacity involving multiple domains of cardiovascular function, which contribute in an integrated fashion to produce exercise limitation. Appreciation of the global nature of reserve dysfunction in HFpEF will better inform optimal design for future diagnostic and therapeutic strategies.


A new method for determining the optimal CT threshold for extracting the upper airway.
The purpose of this study was to evaluate the optimal upper threshold levels of a number of individuals and determine the most suitable upper threshold. A phantom model and ten patients were used in this study. The phantom was made of acrylic resin and urethane resin and had nine pillar-shaped air spaces. The subjects were ten female patients with jaw deformities who were not affected by respiratory disease. The optimal threshold levels were determined using the "calculation of CT value disparities" (CCTD) technique, which we devised. In other words, the mean CT values along two lines (air space and soft tissue) were calculated and the optimal threshold level was determined as the level that produced the maximum difference between the CT values measured inside and outside of the air-space border. The optimal upper threshold levels of the nine phantom holes calculated using the CCTD technique in the front-on standing position and side-on standing position were -434 HU and -456 HU, respectively. The optimal upper threshold level of the ten patients calculated using the CCTD technique was -472 HU. The true threshold level of each patient was defined as the optimal threshold level calculated using the CCTD technique. The mean threshold level was defined as -472 HU. The absolute differences between the volume measurements obtained with these two measures were considered. Therefore, the no error values were -460 HU and -470 HU. We consider that the most suitable upper threshold level for extracting the airway is from -460 HU to -470 HU.


Comparison of the structure and expression pattern for a low molecular weight heat-shock protein cDNA clone from Nicotiana tabacum.
We isolated a cDNA clone, named TLHS-1, for a low molecular weight heat-shock protein (LMW HSP) from tobacco. The nucleotide sequence determination of the clone identified an open reading frame for 159 amino acids. To the upstream of the open reading frame, a sequence of 124 nucleotides was determined. To the 3' downstream of the open reading frame, 212 nucleotides were identified which carried a poly(A) tail. A comparison of the open reading frame of TLHS-1 with the previously reported class I LMW HSPs showed a high identity which classified the TLHS-1 as a class I LMW HSP cDNA clone. Reexamination of the amino acid sequences for LMW HSPs including the TLHS-1 argued for the necessity to redraw the consensus region. Six consensus regions were proposed instead of the two consensus regions suggested previously. A RNA blot hybridization for TLHS-1 showed the typical expression pattern of a heat-shock inducible gene from 3 common tobacco cultivars. The genomic DNA blot hybridization for the TLHS-1 gene from the 3 tobacco cultivars showed identical patterns. These results implied that the expression control and structure of the TLHS-1 gene have been well conserved in the tobacco cultivars which are not bred for high temperature stress resistance.


Hodgkin lymphoma: Focus on evolving treatment paradigms.
Hodgkin lymphoma (HL) is a highly curable B-cell malignancy of germinal center origin. Biologically it is a hematologic malignancy that is highly dependent on the immune microenvironment and utilizes immune escape through upregulation of the programmed-death ligands on the neoplastic cells. Despite being highly curable, consensus is lacking nationally and internationally about the optimal approach to management, particularly in limited-stage disease. The addition of brentuximab vedotin and checkpoint inhibitors for the management of HL has led to a rapidly changing treatment landscape. Further studies should be done to include these novel agents at all stages of disease to determine improvements in frontline cure rates and long-term toxicity.


An Integrated Workflow Assisted by In Silico Predictions To Expand the List of Priority Polycyclic Aromatic Compounds.
The limited information in existing mass spectral libraries hinders an accurate understanding of the composition, behavior, and toxicity of organic pollutants. In this study, a total of 350 polycyclic aromatic compounds (PACs) in 9 categories were successfully identified in fine particulate matter by gas chromatography high resolution mass spectrometry. Using mass spectra and retention indexes predicted by in silico tools as complementary information, the scope of chemical identification was efficiently expanded by 27%. In addition, quantitative structure-activity relationship models provided toxicity data for over 70% of PACs, facilitating a comprehensive health risk assessment. On the basis of extensive identification, the cumulative noncarcinogenic risk of PACs warranted attention. Meanwhile, the carcinogenic risk of 53 individual analogues was noteworthy. These findings suggest that there is a pressing need for an updated list of priority PACs for routine monitoring and toxicological research since legacy polycyclic aromatic hydrocarbons (PAHs) contributed modestly to the overall abundance (18%) and carcinogenic risk (8%). A toxicological priority index approach was applied for relative chemical ranking considering the environmental occurrence, fate, toxicity, and analytical availability. A list of 39 priority analogues was compiled, which predominantly consisted of high-molecular-weight PAHs and alkyl derivatives. These priority PACs further enhanced source interpretation, and the highest carcinogenic risk was attributed to coal combustion.


Distributed solute and water reabsorption in a central core model of the renal medulla.
In this model study we investigate the dependence of urine concentrating capability on the spatial distribution of solute and water reabsorption from Henle's loops. Within the context of model assumptions, urine concentrating capability is increased by exponential decline in loop population as a function of medullary depth and by solute efflux localized near loop bends, in accordance with earlier, but less comprehensive, studies. Further, we find that water-impermeable prebend enlargements of the descending limb may release urine concentrating capacity that would otherwise be needed to concentrate the fluid flowing in the prebend enlargements. Calculations reported here suggest that without some distributed features, even vigorous net active transport of solute from the ascending limbs of the inner medulla would not be sufficient to explain the large concentration gradients generated by some mammals. We consider the significance of distributed reabsorption for the operation of the concentrating mechanisms of the mammalian inner medulla, the mammalian outer medulla, and the avian medullary cone.


Improving behaviour in self-testing (IBIS): Study on frequency of use, consequences, information needs and use, and quality of currently available consumer information (protocol).
Self-tests are available to consumers for more than 25 conditions, ranging from infectious diseases to cardiovascular risk factors. Self-tests are defined as in-vitro tests on body materials such as blood, urine, faeces, or saliva that are initiated by consumers to diagnose a particular disorder or risk factor without involving a medical professional. In 2006, 16% of a sample of Dutch Internet users had ever used at least one self-test and 17% intended to use a self-test in the future. The objectives of this study are to determine (1) the frequency of self-test use, (2) the consumers' reasons for using or not using a self-test, (3) the information that is used by self-testers in the different self-test stages and the consumers' interpretation of the quality of this information, (4) the consumers' response to self-test results in terms of their confidence in the result, reassurance by the test result, and follow-up behaviour, (5) the information consumers report to need in the decision making process of using or not using a self-test, and in further management on the basis of the self-test result, and (6) the quality of the currently available consumer information on a selected set of self-tests. Mixed methods study with (1) a cross-sectional study consisting of a two-phase Internet-questionnaire, (2) semi-structured interviews with self-testers and consumers who intend to use a self-test, and (3) the assessment of the quality of consumer information of self-tests. The Health Belief Model and the Theory of Planned Behaviour will serve as the theoretical basis for the questionnaires and the interview topic guides. The self-testing area is still in a state of flux and therefore it is expected that self-test use will increase in the future. To the best of our knowledge, this is the first study which combines quantitative and qualitative research to identify consumers' information needs and use concerning self-testing, and the consumers' actual follow-up behaviour based on the self-test result, and simultaneously investigates the quality of the currently available consumer information. The results of this study will be used as an input in developing consumer information on self-testing.


Hemojuvelin N-terminal mutants reach the plasma membrane but do not activate the hepcidin response.
Hemojuvelin is a glycosylphosphatidylinositol-anchored protein, expressed in liver, skeletal muscle and heart. As a co-receptor of bone morphogenetic protein, membrane hemojuvelin positively modulates the iron regulator hepcidin. Mutations of the gene encoding for hemojuvelin cause juvenile hemochromatosis, characterized by hepcidin deficiency and severe iron overload. We have previously shown that several hemojuvelin variants do not efficiently reach the plasma membrane, whereas a few N-terminal mutants localize to the plasma membrane. We studied hemojuvelin mutants of N-terminus (C80R, S85P, G99V, DeltaRGD) and GDPH-consensus site for autoproteolysis (A168D, F170S, D172E) transiently expressed in HeLa cells, using electron microscopy, morphometric analysis and binding assays at different time points. Hepcidin activation by wild-type and mutant forms of hemojuvelin was assessed in Hep3B cells transfected with a hepcidin-promoter luciferase-reporter construct. S85P, G99V and DeltaRGD were localized to plasma membrane 36 hours after transfection, but less efficiently exported than the wild-type protein at earlier (24-30 hours) times. Morphometric analysis clearly documented delayed export and endoplasmic reticulum retention of G99V. C80R was exported without delay. GDPH variants were partially retained in the endoplasmic reticulum and Golgi apparatus, but showed impaired plasma membrane localization. In the hepcidin promoter assay only wild type hemojuvelin was able to activate hepcidin. The delayed export and retention in the endoplasmic reticulum of some N-terminal mutants could contribute to the pathogenesis of juvenile hemochromatosis, reducing a prompt response of bone morphogenetic protein. However, independently of their plasma membrane export, all hemojuvelin mutants tested showed no or minimal hepcidin activation.


The Effect of Ingredient Item Depiction on the Packaging Frontal View on Pre- and Post-Consumption Product Evaluations.
The current research focused on the (in)congruity between pictorial (ingredient item depiction) and textual (ingredient list) information on food packaging, namely, an apple-mango juice. Specifically, the influence of these information sources on expected and perceived flavor intensities, mismatched perceptions, perceived deception, and intention to purchase was studied by taking into account the possible moderating role of consumers' thinking style. Three studies were performed, the first and third at a Dutch University by means of surveys and sensory tests, and the second via an online survey. The results showed that, overall, most consumers did not perceive the incongruity between pictorial and textual information as mismatching. However, a perceived mismatch from packaging, whether originated by the design manipulations or not, did increase perceived deception and lowered willingness to purchase. This effect was robust for both mismatches, among packaging elements (pre-consumption) and from expected and perceived flavor ratios (post-consumption), but was more substantial for the post-consumption mismatch. Although the moderating effect of cognitive processing style regarding expected and perceived flavor ratios from pictorial and textual (ingredient list) information was not confirmed, the results indicated that the effect of salient textual information is substantial, independent of a particular processing style or label usage.


Nontargeted Analysis Reveals a Broad Range of Bioactive Pollutants in Drinking Water by Estrogen Receptor Affinity-Mass Spectrometry.
Exposure to environmental endocrine-disrupting chemicals (EDCs) can cause extensive health issues. However, specific EDCs remain elusive. This work aimed at performing nontargeted identification of estrogen receptor α (ERα)-active compounds using an ERα protein affinity assay combined with high-resolution mass spectrometry in the source and drinking water sampled from major rivers in China. Fifty-one potential ERα-active compounds across 13 categories were identified. For the first time, diisodecyl phenyl phosphate was found to have antiestrogenic activity, and three chemicals (galaxolidone, bensulfuron methyl, and UV234) were plausible ERα ligands. Among the 51 identified compounds, 12 were detected in the aquatic environment for the first time, and the concentration of N-phenyl-2-naphthylamine, a widely used antioxidant in rubber products, was up to 1469 and 1190 ng/L in source and drinking water, respectively. This study demonstrated the widespread presence of known and unknown ERα estrogenic and antiestrogenic pollutants in the major rivers that serve as key sources of drinking water in China and the low removal efficiency of these chemicals in drinking water treatment plants.


Noncardiovascular deaths are more common than cardiovascular deaths in patients with cardiovascular disease or cardiovascular risk factors and impaired glucose tolerance: Insights from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.
Patients with impaired glucose tolerance have an elevated risk of cardiovascular (CV) death; however, the causes and risk factors associated with non-CV deaths are poorly understood. The NAVIGATOR trial enrolled 9,306 participants with impaired glucose tolerance and CV disease or at high CV risk, with a median follow-up of 6.4years. Using this population, we identified (1) the proportion of deaths attributed to CV, non-CV, and unknown causes, and (2) the risk factors associated with non-CV death. During the NAVIGATOR trial follow-up, 622 patients died. Investigators reported 244 (39.2%) CV deaths, 313 (50.3%) non-CV deaths, and 65 (10.5%) deaths of unknown cause. Myocardial infarction was the leading cause of investigator-reported death (57/622 [9.2%]). Among non-CV deaths, the most commonly identified cause related to malignancy (177/313 [56.5%]). Using adjudicated causes of death, Cox proportional hazard models identified 3 independent prognostic markers that increased the risk of non-CV death: history of non-melanoma skin cancer (hazard ratio 2.67 [95% CI 1.65-4.33]; P<.0001), white blood cell count (1 unit >5000/mm3; 1.10 [1.02-1.18]; P=.011), and serum potassium levels (per 1mmol/L above any value; 1.67 [1.302.15]; P<.0001). Despite the high baseline CV risk among patients in the NAVIGATOR trial, the most common cause of death was non-CV. The high burden of non-CV death in this population has potential implications for future CV event-driven trials.


Self-blood pressure monitoring in an urban, ethnically diverse population: a randomized clinical trial utilizing the electronic health record.
Hypertension is a leading risk factor for cardiovascular disease. Although control rates have improved over time, racial/ethnic disparities in hypertension control persist. Self-blood pressure monitoring, by itself, has been shown to be an effective tool in predominantly white populations, but less studied in minority, urban communities. These types of minimally intensive approaches are important to test in all populations, especially those experiencing related health disparities, for broad implementation with limited resources. The New York City Health Department in partnership with community clinic networks implemented a randomized clinical trial (n=900, 450 per arm) to investigate the effectiveness of self-blood pressure monitoring in medically underserved and largely black and Hispanic participants. Intervention participants received a home blood pressure monitor and training on use, whereas control participants received usual care. After 9 months, systolic blood pressure decreased (intervention, 14.7 mm Hg; control, 14.1 mm Hg; P=0.70). Similar results were observed when incorporating longitudinal data and calculating a mean slope over time. Control was achieved in 38.9% of intervention and 39.1% of control participants at the end of follow-up; the time-to-event experience of achieving blood pressure control in the intervention versus control groups were not different from each other (logrank P value =0.91). Self-blood pressure monitoring was not shown to improve control over usual care in this largely minority, urban population. The patient population in this study, which included a high proportion of Hispanics and uninsured persons, is understudied. Results indicate these groups may have additional meaningful barriers to achieving blood pressure control beyond access to the monitor itself. http://clinicaltrials.gov. Unique Identifier: NCT01123577.


Illuminating Child Mortality: Discovering Why Children Die.
Current understanding of the causes of under-5 childhood deaths in low- and middle-income countries relies heavily on country-level vital registration data and verbal autopsies. Reliable data on specific causes of deaths are crucial to target interventions more effectively and achieve rapid reductions in under-5 mortality. The Child Health and Mortality Prevention Surveillance (CHAMPS) network aims to systematically describe causes of child death and stillbirth in low- and middle-income countries using minimally invasive tissue sampling. The articles in this supplement introduce the set of foundational epidemiologic, demographic surveillance, social behavioral science, and laboratory methods. Undergirding the CHAMPS surveillance system designed to determine causes of child mortality.


UV regulates the expression of phenylpropanoid biosynthesis genes in cucumber (Cucumis sativus L.) in an organ and spectrum dependent manner.
Expression of cucumber (Cucumis sativus) genes encoding the phenylpropanoid and flavonoid biosynthetic enzymes phenylalanine ammonia lyase (PAL), cinnamic acid 4-hydroxylase (C4H), and chalcone synthase (CHS), was studied under control light conditions (photosynthetically active radiation, PAR) in root, stem, and leaf. Furthermore, the expression was quantified in leaves illuminated with PAR and supplemental ultraviolet-A (315-400 nm) or ultraviolet-B (280-315 nm) radiation. The expression patterns of all twelve CsPAL, three CsC4H, and three CsCHS genes were established. Among the genes regulated by UV two general expression patterns emerge. One pattern applies to genes primarily regulated by enriched UV-A illumination (pattern 1). Another pattern (pattern 2) was found for the genes regulated by enriched UV-B. Three of the pattern 2 genes (CsPAL4, CsPAL10, and CsCHS2) displayed a particular sub-pattern (pattern 2b) with transcription enriched by at least 30-fold. In contrast to the other genes studied, the promoters of the genes regulated according to pattern 2b contained a combination of a number of cis-acting regulatory elements (MREs, ACEs, and G-boxes) that may be of importance for the particularly high enhancement of expression under UV-B-containing light. The regulation of phenylpropanoid and flavonoid biosynthesis genes in cucumber resembles that of a number of other plants. However, cucumber, due to its greater size, is an attractive species for combining more detailed studies of the morphology, physiological parameters and fine regulation of spatial and temporal expression of key genes. This, in turn, can facilitate the quantitative investigation of the relationships among different promoter motifs, the expression levels of each of these three genes, and metabolite accumulation profiles.


[A critical analysis of medical specialities and strategies for their integration into the Unified National Health System in Brazil]
The implementation of medical specialization in Brasil has been relatively free of constraints. There has thus been a progressive fragmentation of medical work. The so-called root specialities are losing both their strength and clinical problem-solving capacity. Two operational concepts are proposed for achieving better administration of medical responsibilities and the role of medical professionals: 1) field of competence and 2) core competence. General goals are suggested for reforming specialized training and integration of specialists into the Unified National Health System.


Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL.
IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastrointestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th-cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity against A20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes.


Global emission inventories for C4-C14 perfluoroalkyl carboxylic acid (PFCA) homologues from 1951 to 2030, part II: the remaining pieces of the puzzle.
We identify eleven emission sources of perfluoroalkyl carboxylic acids (PFCAs) that have not been discussed in the past. These sources can be divided into three groups: [i] PFCAs released as ingredients or impurities, e.g., historical and current use of perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA) and their derivatives; [ii] PFCAs formed as degradation products, e.g., atmospheric degradation of some hydrofluorocarbons (HFCs) and hydrofluoroethers (HFEs); and [iii] sources from which PFCAs are released as both impurities and degradation products, e.g., historical and current use of perfluorobutane sulfonyl fluoride (PBSF)- and perfluorohexane sulfonyl fluoride (PHxSF)-based products. Available information confirms that these sources were active in the past or are still active today, but due to a lack of information, it is not yet possible to quantify emissions from these sources. However, our review of the available information on these sources shows that some of the sources may have been significant in the past (e.g., the historical use of PFBA-, PFHxA-, PBSF- and PHxSF-based products), whereas others can be significant in the long-term (e.g., (bio)degradation of various side-chain fluorinated polymers where PFCA precursors are chemically bound to the backbone). In addition, we summarize critical knowledge and data gaps regarding these sources as a basis for future research.


Long-term outcomes of the octogenarian donor liver recipient: The era of the new centurion.
Studies have suggested transplantation using older donor livers results in similar short-term outcomes as younger donor livers; however, little data exist on long-term patient/graft outcomes of the octogenarian liver recipient. Retrospective data were collected from 2 centers, (Valencia, Spain and Rochester, MN, USA) of all recipients of octogenarian donor liver allografts from 2000 to 2011 with follow-up to 2016. The aim was to compare long-term patient/graft survival as well as metabolic outcomes of the recipient with the octogenarian liver vs younger than 60 years donor. 78 recipients of older liver allografts were compared to 78 matched controls. No difference in 10-year patient mortality was demonstrated (P = 0.074). Octogenarian livers were associated with 3-fold higher likelihood of graft failure (P = 0.002) but no increase in the risk of post-LT cardiovascular disease (P = 0.60), hypertension (P = 0.33), vascular complications (P = 0.53), or malignancy (P = 0.14). In multivariate analysis, elder livers remained a significant factor associated with rejection (P = 0.034) with a trend not reaching statistical significance for graft failure (P = 0.052). For appropriately selected recipients, receiving an octogenarian liver does not clearly influence patient survival but does impact early graft survival with a notable increase in early posttransplant rejection rates and re-transplantation. Over 1.5 decades, older allografts have not adversely affected metabolic outcomes.


Who will be the faculty of the future? Results of a 5-year study growing educators using an immersive third postgraduate year (PGY-3) faculty development mini-fellowship.
Residency education requires large numbers of skilled teaching faculty. Potential faculty can often be identified during residency training. Employ a 4-week immersive faculty development mini-fellowship to enhance the teaching skills of selected PGY-3 residents and study outcomes over 5 years. PGY-3 residents were competitively selected and completed the 4-week curriculum to increase skills in precepting, small group teaching, large group teaching, learner feedback/assessment, academic career development, and research. Fifteen residents completed the mini-fellowship over the 5-year study period. The curriculum was rated highly by the residents with mean ratings of curriculum components ranging from 4.5 to 4.9 on a 5-point scale. Eight residents (53%) were selected for faculty positions compared to a usual selection rate of 11%. Compared to new faculty without mini-fellowship completion, program directors rated the residents completing the mini-fellowship as better prepared to perform learner feedback (4.1 vs. 3.0, p ≤ 0.01) and to understand the conduct of research (3.6 vs. 2.5 p ≤ 0.01). This study demonstrates short-term success at growing faculty with enhanced teaching skills during residency. While long-term retention in academic medicine cannot be predicted, this program represents one method to mitigate shortages of qualified junior residency faculty.


Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer.
Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown. In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety. A total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P = 0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures. In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.).


Associations of Physical Activity and Exercise with Health-related Outcomes in Patients with Melanoma During and After Treatment: A Systematic Review.
Although exercise medicine is recommended to counter treatment-related side-effects and improve health-related outcomes of patients affected by different cancers, no specific recommendations exist for patients with melanoma. As a result, we systematically examined the current evidence regarding the effects of physical activity and exercise on objectively-measured and patient-reported outcomes among patients with melanoma. Searches were conducted in PubMed, CINAHL, EMBASE, SPORTDiscus, and Web of Science databases. This review included published data involving physical activity or exercise and objectively-measured or patient-reported outcomes of patients with cutaneous melanoma. The quality of included studies was assessed using the McMaster University Critical Appraisal Tool for Quantitative Studies. Six studies including 882 patients with melanoma were included. Studies presented heterogeneity of design with 2 cross-sectional surveys, 2 retrospective analyses, and 2 non-randomized intervention trials. No statistically significant change in quality of life, fatigue, physical function, cardiorespiratory fitness, body composition, psychological distress, cognitive function, or treatment-related side-effects were attributable to physical activity or exercise. Importantly, physical activity or exercise during melanoma treatment or into survivorship did not adversely impact patients/survivors. In summary, physical activity or exercise did not adversely impact quality of life, objectively-measured or patient-reported outcomes in patients with melanoma. In addition, there is a paucity of quality studies examining the effects of physical activity or exercise on patients with melanoma throughout the cancer care continuum.


Surface components of Bacteroides fragilis involved in adhesion and haemagglutination.
The ability of 19 strains of Bacteroides fragilis to adhere to buccal epithelial cells (BEC) and to the human intestinal cell line HT-29 Clone 19A, and to agglutinate rabbit erythrocytes was compared. Adhesion to BEC was poor compared with that to the cell line. Adhesion to the latter was high for 21% of the strains, moderate for 37% and poor for 42%. Only 53% of the strains agglutinated rabbit red blood cells and only strain A459 did so strongly. Haemagglutination and adhesion of B. fragilis strain A459 were inhibited by sodium periodate, but not by proteases, heat or carbohydrates. These properties were not affected by protease which removed surface appendages. Periodate treatment did not remove the fimbriae or ruthenium red-staining layer, although the capsule was lost. This suggests that carbohydrate residues on the cell surface, possibly forming part of the capsule, are involved in adhesion and haemagglutination by this strain.


Do orthopaedic shoes improve local dynamic stability of gait? An observational study in patients with chronic foot and ankle injuries.
Complex foot and ankle fractures, such as calcaneum fractures or Lisfranc dislocations, are often associated with a poor outcome, especially in terms of gait capacity. Indeed, degenerative changes often lead to chronic pain and chronic functional limitations. Prescription footwear represents an important therapeutic tool during the rehabilitation process. Local Dynamic Stability (LDS) is the ability of locomotor system to maintain continuous walking by accommodating small perturbations that occur naturally during walking. Because it reflects the degree of control over the gait, LDS has been advocated as a relevant indicator for evaluating different conditions and pathologies. The aim of this study was to analyze changes in LDS induced by orthopaedic shoes in patients with persistent foot and ankle injuries. We hypothesised that footwear adaptation might help patients to improve gait control, which could lead to higher LDS: Twenty-five middle-aged inpatients (5 females, 20 males) participated in the study. They were treated for chronic post-traumatic disabilities following ankle and/or foot fractures in a Swiss rehabilitation clinic. During their stay, included inpatients received orthopaedic shoes with custom-made orthoses (insoles). They performed two 30s walking trials with standard shoes and two 30s trials with orthopaedic shoes. A triaxial motion sensor recorded 3D accelerations at the lower back level. LDS was assessed by computing divergence exponents in the acceleration signals (maximal Lyapunov exponents). Pain was evaluated with Visual Analogue Scale (VAS). LDS and pain differences between the trials with standard shoes and the trials with orthopaedic shoes were assessed. Orthopaedic shoes significantly improved LDS in the three axes (medio-lateral: 10% relative change, paired t-test p < 0.001; vertical: 9%, p = 0.03; antero-posterior: 7%, p = 0.04). A significant decrease in pain level (VAS score -29%) was observed. Footwear adaptation led to pain relief and to improved foot & ankle proprioception. It is likely that that enhancement allows patients to better control foot placement. As a result, higher dynamic stability has been observed. LDS seems therefore a valuable index that could be used in early evaluation of footwear outcome in clinical settings.


Binding affinity of the methyl ester of AK-toxin I to membrane fractions from Japanese pear leaves.
The binding site of AK-toxin, a host-specific toxin against Japanese pear, was searched for in the membrane fractions of the pear leaves, using 3H-labeled AK-toxin I methyl ester. Binding activity, which was displaceable by the unlabeled ligand, was observed for microsomal fraction from a toxin-susceptible cultivar, Nijisseiki. However, the binding was also observed for those from toxin-resistant cultivars, Kosui and Hosui. Detection of the specific binding failed for the plasma membrane fraction which was prepared from microsomal fraction of the toxin-susceptible cultivar by aqueous two-phase separation, and the hitherto presumed model of the AK-toxin receptor in the plasma membrane could not be verified.


Technical advantages of an ultrasonic bone curette in spinal surgery.
The authors discuss the safety and efficacy of an ultrasonic bone curette in various spinal surgeries and report its advantages in clinical application. Between April 2002 and September 2003, 76 patients with various spinal diseases (29 cervical, five thoracic, 40 lumbosacral, and two foramen magnum regions) were treated microsurgically by using a Sonopet ultrasonic bone curette with longitudinal and torsional tips and lightweight handpieces. The operations were performed successfully and the device was easy to handle. There were no instrument-related complications or -induced damage to any structure even when removing osseous spurs or ossified lesions near the dura mater, nerves, and vessels. The ultrasonic curette is a useful instrument for procedures performed near the dura mater or other neural tissue without excessive heat production or mechanical injury. This device is recommended for various spinal surgeries in addition to high-speed drills or other tools.


Non-invasive imaging of human embryonic stem cells.
Human embryonic stem cells (hESCs) hold tremendous therapeutic potential in a variety of diseases. Over the last decade, non-invasive imaging techniques have proven to be of great value in tracking transplanted hESCs. This review article will briefly summarize the various techniques used for non-invasive imaging of hESCs, which include magnetic resonance imaging (MRI), bioluminescence imaging (BLI), fluorescence, single-photon emission computed tomography (SPECT), positron emission tomography (PET), and multimodality approaches. Although the focus of this review article is primarily on hESCs, the labeling/tracking strategies described here can be readily applied to other (stem) cell types as well. Non-invasive imaging can provide convenient means to monitor hESC survival, proliferation, function, as well as overgrowth (such as teratoma formation), which could not be readily investigated previously. The requirement for hESC tracking techniques depends on the clinical scenario and each imaging technique will have its own niche in preclinical/clinical research. Continued evolvement of non-invasive imaging techniques will undoubtedly contribute to significant advances in understanding stem cell biology and mechanisms of action.


Endothelial cells expressing low levels of CD143 (ACE) exhibit enhanced sprouting and potency in relieving tissue ischemia.
The sprouting of endothelial cells from pre-existing blood vessels represents a critical event in the angiogenesis cascade. However, only a fraction of cultured or transplanted endothelial cells form new vessels. Moreover, it is unclear whether this results from a stochastic process or instead relates to certain endothelial cells having a greater angiogenic potential. This study investigated whether there exists a sub-population of cultured endothelial cells with enhanced angiogenic potency in vitro and in vivo. First, endothelial cells that participated in sprouting, and non-sprouting cells, were separately isolated from a 3D fibrin gel sprouting assay. Interestingly, the sprouting cells, when placed back into the same assay, displayed a sevenfold increase in the number of sprouts, as compared to control cells. Angiotensin-converting enzyme (CD143) was significantly down regulated on sprouting cells, as compared to regular endothelial cells. A subset of endothelial cells with low CD143 expression was then prospectively isolated from an endothelial cell culture. Finally, these cells were found to have greater potency in alleviating local ischemia, and restoring regional blood perfusion when transplanted into ischemic hindlimbs, as compared to unsorted endothelial cells. In summary, this study indicates that low expression of CD143 can be used as a biomarker to identify an endothelial cell sub-population that is more capable to drive neovascularization.


The Availability of Slow and Fast Calories in the Dutch Diet: The Current Situation and Opportunities for Interventions.
Choosing foods that require more time to consume and have a low energy density might constitute an effective strategy to control energy intake, because of their satiating capacity. The current study assessed the eating rate of Dutch food, and investigated the associations between eating rate and other food properties. We also explored the opportunities for a diet with a low energy intake rate (kJ/min). Laboratory data on the eating rate of 240 foods-representing the whole Dutch diet-was obtained. The results show a wide variation in both eating rate (from 2 g/min for rice waffle to 641 g/min for apple juice) and energy intake rate (from 0 kJ/min (0 kcal/min) for water to 1766 kJ/min (422 kcal/min) for chocolate milk). Eating rate was lower when foods were more solid. Moreover, eating rate was positively associated with water content and inversely with energy density. Energy intake rate differed substantially between and within food groups, demonstrating that the available foods provide opportunities for selecting alternatives with a lower energy intake rate. These findings offer guidance when selecting foods to reduce energy intake.


Reproductive toxicity, mutagenicity and antigenicity of pamiteplase (genetical recombination).
Pamiteplase (genetical recombination), YM866, is a novel recombinant modified human tissue-type plasminogen activator developed by Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan. An intended route of administration in the clinical use of this drug is intravenous administration. We conducted an intravenous fertility and general reproduction studies of this drug in male and female rats and teratology study of this drug in rabbits at the dose levels of 0 (vehicle control), 0.1, 0.3 or 1 mg/kg/day. In the rat, no treatment-related abnormalities were observed up to the maximum dose in parental animals and their offspring. In the teratology study in rabbits, prolonged coagulation time at the injection site was observed at 0.3 mg/kg or more. One death and one abortion occurred at 1 mg/kg on days 22 and 23 of pregnancy, respectively. No toxic effects on the litters were observed up to the maximum dose. Results of evaluation of the mutagenicity of YM866 and its ability to induce chromosome aberrations using the L5178Y TK+/- mouse lymphoma assay, human lymphocyte chromosome aberration assay and the micronucleus assay in mice were negative. Evaluation of the immunogenicity of YM866 by repeated intravenous injection in chimpanzees elicited no confirmed antibody titers.


Our 11-Year Experience With Percutaneous Tibial Nerve Stimulation in Men and Women for the Treatment of Interstitial Cystitis/Bladder Pain Syndrome.
To evaluate the effect of percutaneous tibial nerve stimulation (PTNS) in interstitial cystitis/bladder pain syndrome (IC/BPS). Retrospective chart review was completed for patients with at least 10 weekly treatments of PTNS from January 2010 to October 2021. PTNS success was defined as conversion to PTNS maintenance therapy following 12weeks of PTNS induction therapy. Data were analyzed using GraphPad. Over the 11-year study period, 27 out of 34 patients (mean age 52.9 ± 16.8years; 25 females, 9 males) completed 12weeks of PTNS induction therapy, and 48.1% (13/27) successfully converted to PTNS maintenance therapy. Following 12weeks of PTNS induction therapy, significant improvements were noted in the urgency severity scale (range 0-4: 2.9 ± 1.2 before vs 1.1 ± 1.1 after PTNS, P = .001) and nocturnal urinary frequency (number of voids: 3.3 ± 1.9 before vs 2.2 ± 1.6 after PTNS, P = .041); and nonsignificant improvements were noted in daytime void frequency (hours: 1.5 ± 0.7 before vs 2.0 ± 0.9 after PTNS, P = .090) and the pain domain of the interstitial cystitis symptoms index (question 4, range 0-4: 2.5 ± 1.4 before vs 1.3 ± 1.8 after PTNS, P = .082). Our sample size is among the largest sample of PTNS in IC/BPS from a single center. While PTNS achieved nonsignificant improvements in pain and daytime void frequency, significant improvements were observed in urinary urgency and nocturia. PTNS appears to be a plausible option in the multimodal approach to managing IC/BPS.


Biosynthesis of nonribosomal peptides1.
Bacteria and fungi use large multifunctional enzymes, the so-called nonribosomal peptide synthetases (NRPSs), to produce peptides of broad structural and biological activity. Biochemical studies have contributed substantially to the understanding of the key principles of these modular enzymes that can draw on a much larger number of catalytic tools for the incorporation of unusual features compared with the ribosomal system. Several crystal structures of NRPS-domains have yielded deep insight into the catalytic mechanisms involved and have led to a better prediction of the products assembled and to the construction of hybrid enzymes. In addition to the structure-function relationship of the core- and tailoring-domains of NRPSs, which is the main focus of this review, different biosynthetic strategies and essential enzymes for posttranslational modification and editing are discussed.