Ultrathin circular polarimeter based on chiral plasmonic metasurface and monolayer MoSe2.
Two-dimensional materials are ideal platforms for intriguing physics and optoelectronic applications because of their ultrathin thicknesses and excellent properties in optics and electronics. Further studies on enhancing the interaction between light and two-dimensional materials by combining metallic nanostructures have generated broad interests in recent years, such as enhanced photoluminescence, strong coupling and functional optoelectronics. In this work, an ultrathin circular polarimeter consisting of chiral plasmonic metasurface and monolayer semiconductor is proposed to detect light with different circular polarization within a compact device. A designed chiral plasmonic metasurface with sub-wavelength thickness is integrated with monolayer MoSe2, and the circular-polarization-dependent photocurrent responses of right and left circularly polarized light for both left- and right-handed metasurfaces are experimentally demonstrated. The photoresponse circular dichroism is also obtained, which further indicates the remarkable performance of the proposed device in detecting and distinguishing circularly polarized light. This design offers a great potential to realize multifunctional measurements in an ultrathin and ultracompact two-dimensional device for future integrated optics and optoelectronic applications with circularly polarized light.


Artifact Augmentation for Learning-based Quality Control of Whole Slide Images.
The acquisition of whole slide images is prone to artifacts that can require human control and re-scanning, both in clinical workflows and in research-oriented settings. Quality control algorithms are a first step to overcome this challenge, as they limit the use of low quality images. Developing quality control systems in histopathology is not straightforward, also due to the limited availability of data related to this topic. We address the problem by proposing a tool to augment data with artifacts. The proposed method seamlessly generates and blends artifacts from an external library to a given histopathology dataset. The datasets augmented by the blended artifacts are then used to train an artifact detection network in a supervised way. We use the YOLOv5 model for the artifact detection with a slightly modified training pipeline. The proposed tool can be extended into a complete framework for the quality assessment of whole slide images.Clinical relevance- The proposed method may be useful for the initial quality screening of whole slide images. Each year, millions of whole slide images are acquired and digitized worldwide. Numerous of them contain artifacts affecting the following AI-oriented analysis. Therefore, a tool operating at the acquisition phase and improving the initial quality assessment is crucial to increase the performance of digital pathology algorithms, e.g., early cancer diagnosis.


Microcompartments for B12-dependent 1,2-propanediol degradation provide protection from DNA and cellular damage by a reactive metabolic intermediate.
Salmonella enterica grows on 1,2-propanediol (1,2-PD) in a coenzyme B(12)-dependent fashion. Prior studies showed that a bacterial microcompartment (MCP) is involved in this process and that an MCP-minus mutant undergoes a 20-h period of growth arrest during 1,2-PD degradation. It was previously proposed that growth arrest resulted from propionaldehyde toxicity, but no direct evidence was presented. Here, high-pressure liquid chromatography analyses of culture medium were used to show that the major products of aerobic 1,2-PD degradation are propionaldehyde, propionate, and 1-propanol. A MCP-minus mutant accumulated a level of propionaldehyde 10-fold higher than that of the wild type (1.6 mM compared to 15.7 mM), associating this compound with growth arrest. The addition of propionaldehyde to cultures of S. enterica caused growth arrest from 8 to 20 mM, but not at 4 mM, providing direct evidence for propionaldehyde toxicity. Studies also indicated that propionaldehyde was toxic due to the inhibition of respiratory processes, and the growth arrest ended when propionaldehyde was depleted primarily by conversion to propionate and 1-propanol and secondarily due to volatility. The Ames test was used to show that propionaldehyde is a mutagen and that mutation frequencies are increased in MCP-minus mutants during 1,2-PD degradation. We propose that a primary function of the MCPs involved in 1,2-PD degradation is the mitigation of toxicity and DNA damage by propionaldehyde.


Looking back and thinking forward: 20 years of disability and rehabilitation research.
The National Center for Medical Rehabilitation Research recently celebrated its 20th Anniversary. The celebration included a symposium highlighting advances in rehabilitation science over the past 2 decades. The anniversary also reminds us of the challenges that remain in order to strengthen the foundation of disability and rehabilitation research. These challenges have been described in 3 reports published by the Institute of Medicine (IOM) in 1991, 1997, and 2007. Three areas of concern appear across the IOM reports. These include (1) the lack of a comprehensive disability monitoring program, (2) the need for better integration and coordination of federally supported disability research, and (3) funding levels that are inconsistent with the current and projected impacts of disability on individuals, families, and communities. In this commentary we examine the lack of progress in addressing the recommendations contained in the IOM reports. We conclude that renewed efforts by consumers, clinicians, educators, researchers, administrators, and policy makers are needed to achieve the promise of rehabilitation and disability science identified 20 years ago.


Optic Disc Measures in Obstructive Sleep Apnea: A Community-based Study of Middle-aged and Older Adults.
PRéCIS:: This study found an association between thinner superotemporal retinal nerve fiber layer (RNFL) and obstructive sleep apnea (OSA). However, the lack of association of sleep apnea with other disc measures does not support a link with glaucoma. Previous findings on the link between OSA and increased glaucoma risk have been inconsistent. In a community-based study of middle-aged and older adults, we explored for differences in optic disc measures that may resemble preclinical glaucomatous changes in relation to OSA status and severity. A total of 865 participants (46 to 67 y; 45% male) underwent an at-home sleep study during which their apnea-hypopnea index (AHI) and sleep oxygen saturation level were measured. Participants were determined to have no OSA (AHI<5 events/h), mild (AHI 5 to 15), moderate (AHI 16 to 30), or severe OSA (AHI>30). At a 6-year follow-up visit, the optic discs of both eyes were imaged using spectral domain optic coherence tomography to measure the Bruch membrane opening-minimum rim widths and RNFL thicknesses. On the basis of the AHI, 411 participants (48%) had OSA, of whom 92 (11% of total sample) and 26 (3%) had moderate and severe OSA, respectively. In the multivariate analysis, participants with severe OSA had thinner RNFL superotemporally than those without OSA or with mild OSA (P<0.001 and 0.001, respectively). In addition, superotemporal RNFL was inversely associated with AHI (P=0.004) and sleep time with oxygen saturation level <90% (P=0.005). There was no association between OSA measures and Bruch membrane opening-minimum rim widths. Our findings do not provide strong evidence of a link between measures of OSA and the optic disc. However, the association between increased OSA severity and thinner superotemporal RNFL has been reported consistently in previous studies and thus warrants further evaluation.


Alterations in the proximal nephron of beige mice with the Chédiak-Higashi syndrome.
The proximal nephron of C57 beige mice with a genetic defect analagous to the Chédiak-Higashi syndrome (CHS) has been compared with that of normal C57 black mice. The concanavalin A-horseradish peroxidase (Con A-HRP) technique stained the brush border of the proximal straight tubule heavily in black mice and weakly in beige mice. In beige mice this method stained the brush border of the proximal convoluted tubules weakly and the brush border of the proximal straight tubules only negligibly. Periodic acid-Schiff staining showed no such difference between beige and black mice but revealed an increase distally in the size of the CHS inclusions in the proximal straight tubule of beige mice. Immunostaining visualized abundant lysozyme in the first portion of the proximal nephron but none in the more distal segments of beige and black mice alike. At the ultrastructural level, the proximal convoluted tubules of black mice contained two morphologic types of heterophagosomes, which apparently differed in accord with the stage of their development. Proximal straight tubules contained morphologically different heterophagic bodies. The mature stages of these heterophagosomes were greatly enlarged in CHS mice. With the periodic acid-thiocarbohydrazide-silver proteinate (PA-T-SP) method for localizing glycoprotein ultrastructurally, the microvillar brush border, apical invaginations of the plasmalemma, Golgi cisternae, and lysosomal inclusions stained selectively in the proximal nephron in both strains. The proximal straight nephron of beige mice after staining with the PA-T-SP method appeared depleted of the strongly reactive apical invaginations in some areas, particularly where large heterophagosomes bordered the apical plasmalemma. The enlarged secondary lysosomes of heterophagic origin in beige mice varied in showing both diffuse and focal PA-T-SP reactivity. Lysosomal acid phosphatase activity appeared decreased, and peroxisomes were normal in size but increased in number in the proximal nephron of beige mice.


Reduced mannose incorporation into GDP-mannose and dolichol-linked intermediates of N-glycosylation in hamster liver during vitamin A deficiency.
The molecular mechanism of reduced incorporation of radioactively labeled mannose into hamster liver glycoconjugates during the progression of vitamin A deficiency was investigated. In particular the in vivo incorporation of [2-3H]mannose into GDP-mannose, dolichyl phosphate mannose (Dol-P-Man), lipid-linked oligosaccharides, and glycopeptides of hamster liver was examined. Hamsters maintained on a vitamin A-free diet showed a reduction in the incorporation of mannose into GDP-mannose about 10 days before clinical signs of vitamin A deficiency could be observed. The decrease in [2-3H]mannose incorporated into GDP-mannose was accompanied by a reduction in label incorporated into Dol-P-Man, lipid linked oligosaccharides and glycopeptides, which became more severe with the progression of vitamin A deficiency. By the time they reached a plateau stage of growth, hamsters fed the vitamin A-free diet showed a 50% reduction in the amount of [2-3H]mannose converted to GDP-mannose, and the radioactivity associated with Dol-P-Man and glycopeptides was reduced by approximately 60% as compared to retinoic acid-supplemented controls. These results strongly indicate that the reduced incorporation of mannose into lipidic intermediates and glycoproteins observed during vitamin A deficiency is due to impaired GDP-mannose synthesis.


Development of a near activity visual questionnaire to assess accommodating intraocular lenses.
To develop a questionnaire that subjectively assesses near visual function in patients with 'accommodating' intraocular lenses (IOLs). A literature search of existing vision-related quality-of-life instruments identified all questions relating to near visual tasks. Questions were combined if repeated in multiple instruments. Further relevant questions were added and item interpretation confirmed through multidisciplinary consultation and focus groups. A preliminary 19-item questionnaire was presented to 22 subjects at their 4-week visit post first eye phacoemulsification with 'accommodative' IOL implantation, and again 6 and 12 weeks post-operatively. Rasch Analysis, Frequency of Endorsement, and tests of normality (skew and kurtosis) were used to reduce the instrument. Cronbach's alpha and test-retest reliability (intraclass correlation coefficient, ICC) were determined for the final questionnaire. Construct validity was obtained by Pearson's product moment correlation (PPMC) of questionnaire scores to reading acuity (RA) and to Critical Print Size (CPS) reading speed. Criterion validity was obtained by receiver operating characteristic (ROC) curve analysis and dimensionality of the questionnaire was assessed by factor analysis. Rasch Analysis eliminated nine items due to poor fit statistics. The final items have good separation (2.55), internal consistency (Cronbach's alpha=0.97) and test-retest reliability (ICC=0.66). PPMC of questionnaire scores with RA was 0.33, and with CPS reading speed was 0.08. Area under the ROC curve was 0.88 and Factor Analysis revealed one principal factor. The pilot data indicates the questionnaire to be internally consistent, reliable and a valid instrument that could be useful for assessing near visual function in patients with 'accommodating' IOLS. The questionnaire will now be expanded to include other types of presbyopic correction.


Immune evasion of the Lyme disease spirochetes.
The Lyme disease spirochetes, Borrelia burgdorferi sensu lato, have adapted very well to both surviving and persisting in the mammalian host despite a strong host antibody response. It appears that both temporal and spatial regulation of outer surface proteins have contributed to this persistence. The spirochetes are able to bind fH and FHL-1 to their surface, resulting in decreased complement activation. In addition, the organisms have taken advantage of components of tick saliva to aid in their initial immune evasion and dissemination. Studies leading to these conclusions are reviewed here.


Perception of family planning and reasons for low acceptance of NSV among married males of urban slums of Lucknow city - A community based study.
Population explosion has been India's major problem since independence. It is a major obstacle to the overall progress of the nation. Adoption of family planning methods is one of the best solutions to tackle this problem. The roots of the factors influencing family planning issues are entrenched in the socio-cultural milieu of Indian society. Uttar Pradesh is the most populated state of the country having population of 199.581 million and TFR of 3.3 (AHS 2012-2013) with high fertile trajectory. Among the family planning methods currently, male sterilization accounts for only 0.3% of all sterilizations in Uttar Pradesh (AHS 2012-2013). A strategy to promote men's involvement in effective birth control is needed to reduce the population growth. The aim of this study is: i) To access the perception of married males towards family planning. ii) To access knowledge about NSV iii) enumerate the causes for low acceptance of NSV. A cross-sectional study was carried out. Multi-stage random sampling technique was used. In the first stage, two urban slums from each Nagar-Nigam zone was selected randomly. In the second stage, from each selected slum, a sample of 24 eligible households was selected at random to achieve the desired sample size. Female sterilization technique was considered as the most effective family planning method by the male respondents. Socio-cultural barriers were the most important reason for the low acceptance of NSV. Educational status was found to be the most important predictor for these socio-cultural barriers. Measures should be taken to remove misconceptions, to increase uptake of NSV.


Exploring the efficiency of the Tilburg Frailty Indicator: a review.
Due to rapidly aging human populations, frailty has become an essential concept, as it identifies older people who have higher risk of adverse outcomes, such as disability, institutionalization, lower quality of life, and premature death. The Tilburg Frailty Indicator (TFI) is a user-friendly questionnaire based on a multidimensional approach to frailty, assessing physical, psychologic, and social aspects of human functioning. This review aims to explore the efficiency of the TFI in assessing frailty as a means to carry out research into the antecedents and consequences of frailty, and its use both in daily practice and for future intervention studies. Using a multidimensional approach to frailty, in contexts where health care professionals or researchers may have no time to interview or examine the client, we recommend employing the TFI because there is robust evidence of its reliability and validity and it is easy and quick to administer. More studies are needed to establish whether the TFI is suitable for intervention studies not only in the community, but also for specific groups such as patients in the hospital or admitted to an emergency department. We conclude that it is important to not only determine the deficits that frail older people may have, but also to assess their balancing strengths and resources. In order to be able to meet the individual needs of frail older persons, traditional and often fragmented elderly care should be developed toward a more proactive elderly care, in which frail older persons and their informal network are in charge.


Does supplemental perioperative oxygen administration reduce the incidence of wound infection in elective colorectal surgery?
An association has been proposed between perioperative administration of 80% oxygen and a lower incidence of wound infection after colorectal surgery. The present study was conducted to assess this hypothesis. Thirty-eight patients (ASA classification 1 and 2) undergoing elective colorectal cancer surgery were allocated at random to 2 groups. Group 1 consisted of 19 patients who received an admixture of 80% oxygen and 20% nitrogen during anesthesia through an orotracheal tube and during the 2 first hours in the recovery room through a tight facemask with reservoir. Group 2 consisted of 19 patients who received an admixture of 70% nitrous oxide and 30% oxygen during anesthesia, followed by administration of 30% oxygen delivered by a blender through a tight facemask with reservoir in the same manner than group 1, during the first 2 hours in the recovery room. Wound infection was evaluated daily during hospital stay and after 7 days, 2 weeks, and 1 month. The incidence of wound infection was 12.5% in group 1 and 17.6% in group 2 (p=0.53). The results of this study showed no reduction in the incidence of wound infection following elective colorectal surgery in patients receiving 80% oxygen during the perioperative period.


TCR stimulation drives cleavage and shedding of the ITIM receptor CD31.
CD31 is a transmembrane molecule endowed with T cell regulatory functions owing to the presence of 2 immunotyrosine-based inhibitory motifs. For reasons not understood, CD31 is lost by a portion of circulating T lymphocytes, which appear prone to uncontrolled activation. In this study, we show that extracellular T cell CD31 comprising Ig-like domains 1 to 5 is cleaved and shed from the surface of human T cells upon activation via their TCR. The shed CD31 can be specifically detected as a soluble, truncated protein in human plasma. CD31 shedding results in the loss of its inhibitory function because the necessary cis-homo-oligomerization of the molecule, triggered by the trans-homophilic engagement of the distal Ig-like domain 1, cannot be established by CD31(shed) cells. However, we show that a juxta-membrane extracellular sequence, comprising part of the domain 6, remains expressed at the surface of CD31(shed) T cells. We also show that the immunosuppressive CD31 peptide aa 551-574 is highly homophilic and possibly acts by homo-oligomerizing with the truncated CD31 remaining after its cleavage and shedding. This peptide is able to sustain phosphorylation of the CD31 ITIM(686) and of SHP2 and to inhibit TCR-induced T cell activation. Finally, systemic administration of the peptide in BALB/c mice efficiently suppresses Ag-induced T cell-mediated immune responses in vivo. We conclude that the loss of T cell regulation caused by CD31 shedding driven by TCR stimulation can be rescued by molecular tools able to engage the truncated juxta-membrane extracellular molecule that remains exposed at the surface of CD31(shed) cells.


Embolism of air and gas in hysteroscopic procedures: pathophysiology and implication for daily practice.
Hysteroscopic surgery has gained in popularity and has become the method of choice for diagnostic and therapeutic interventions of intrauterine pathology. Advantages consist of short operating time, rapid postoperative recovery, and low morbidity. However, there are concerns about the potential serious complications that can occur, such as venous air and gas embolism. These are rare but hazardous complications, which can occur in all surgical procedures. In hysteroscopic surgery, large uterine veins may be exposed and are, therefore, a point of entry for gas or air. A number of fatal and nonfatal cases have been described as case reports. Although awareness for air and gas embolism is raised this way, proper guidelines as to how to reduce the risk of venous gas or air embolism are lacking. The pathophysiologic difference between gas and air embolism is described herein because composition of the gases differs as does their physiologic effects. A gas embolism is likely to be derived from electrosurgical vapors whereas air embolism seems to arise from improper purging of lines or reinsertion of hysteroscopic instruments. Treatment regimens must, therefore, be designed to address the specific gases involved. Signs and symptoms of these different embolisms are described, as early detection and intervention are crucial for survival. Furthermore, we provide guidelines for operating department personnel, surgeons, and anesthesiologists to reduce the risk of venous gas or air embolism during hysteroscopic procedures. Potential complications of these procedures may be prevented this way.


Temporal coding of contrast in primary visual cortex: when, what, and why.
How do neurons in the primary visual cortex (V1) encode the contrast of a visual stimulus? In this paper, the information that V1 responses convey about the contrast of static visual stimuli is explicitly calculated. These responses often contain several easily distinguished temporal components, which will be called latency, transient, tonic, and off. Calculating the information about contrast conveyed in each component and in groups of components makes it possible to delineate aspects of the temporal structure that may be relevant for contrast encoding. The results indicate that as much or more contrast-related information is encoded into the temporal structure of spike train responses as into the firing rate and that the temporally coded information is manifested most strongly in the latency to response onset. Transient, tonic, and off responses contribute relatively little. The results also reveal that temporal coding is important for distinguishing subtle contrast differences, whereas firing rates are useful for gross discrimination. This suggests that the temporal structure of neurons' responses may extend the dynamic range for contrast encoding in the primate visual system.


Modeling the binding and function of metabotropic glutamate receptors.
A mathematical model for the binding and function of metabotropic glutamate receptors was developed, with the aim to gain new insights into the functioning of these complex receptors. These receptors are homodimers, and each subunit is composed of a ligand binding [Venus flytrap (VFT)] domain and a heptahelical domain (HD) responsible for G-protein activation. Our mechanistic model integrates all structural information available so far: the various states of the VFT dimer (open-open, closed-open, and closed-closed), as well as the fact that a single HD is active at a time. To provide the model with parameters with biological meaning, two published experimental studies were reanalyzed. The first one reports a negative cooperativity in agonist binding (J Biol Chem 279:35526-35534, 2004), whereas the other indicates a positive cooperativity in agonist-mediated response (Nat Struct Mol Biol 11:706-713, 2004). The former study allowed us to explain the mechanistic features associated with VFT recognition by agonists and antagonists integrating a negative allosteric interaction for agonist binding. The second study helped us to quantitatively describe the functional dynamics of transduction of the VFT occupation into functional response, confirming a putative positive cooperativity at the level of receptor coupling efficacy. This model will help both to better understand the functioning of these receptors and to characterize the mechanism of action of various types of allosteric modulators. Moreover, this model may be of general utility for oligomeric systems in which the ligand binding and effector domains correspond to distinct structural domains.


Environmental determinants of Opisthorchis viverrini prevalence in northeast Thailand.
Opisthorchis viverrini infection is an important, human, parasitic disease along the middle and lower Mekong River of Southeast Asia. Despite vast efforts in epidemiological research, the wide geographical variation in O. viverrini prevalence remains unexplained. To investigate the potential influence of village location, prevalence data recorded during the year 2009 for 90 villages in northeast Thailand were analysed by a geographical information systems approach based on a digital elevation model for altitude determination. Land use compositions of village surroundings were derived from images produced by the Thematic Mapper of the Landsat satellite and landscape metrics were applied to quantify spatial patterns. Pearson's correlation coefficients were used to evaluate the associations between the environmental factors and O. viverrini prevalence. In spite of no statistical difference (P = 0.117), higher-ground villages generally had a lower level of opisthorchiasis than those situated lower down, while a significant negative correlation was detected between O. viverrini prevalence and the composition of farmland with low water content (P = 0.028), indicating the potential influence of agricultural lands with drought-tolerant crops. Strengthening this hypothesis, a significant positive association with O. viverrini prevalence was found for the combined land use classes of water and of farmland with high water content (P = 0.032), indicating that the dominance of a large land use patch capable of providing suitable habitats for the intermediate hosts might contribute to the disease. This study highlights the influence of landscapes on the epidemiology of O. viverrini infection and emphasises the need to incorporate land use planning into control strategies.


Evidence that two ATP-dependent (Lon) proteases in Borrelia burgdorferi serve different functions.
The canonical ATP-dependent protease Lon participates in an assortment of biological processes in bacteria, including the catalysis of damaged or senescent proteins and short-lived regulatory proteins. Borrelia spirochetes are unusual in that they code for two putative ATP-dependent Lon homologs, Lon-1 and Lon-2. Borrelia burgdorferi, the etiologic agent of Lyme disease, is transmitted through the blood feeding of Ixodes ticks. Previous work in our laboratory reported that B. burgdorferi lon-1 is upregulated transcriptionally by exposure to blood in vitro, while lon-2 is not. Because blood induction of Lon-1 may be of importance in the regulation of virulence factors critical for spirochete transmission, the clarification of functional roles for these two proteases in B. burgdorferi was the object of this study. On the chromosome, lon-2 is immediately downstream of ATP-dependent proteases clpP and clpX, an arrangement identical to that of lon of Escherichia coli. Phylogenetic analysis revealed that Lon-1 and Lon-2 cluster separately due to differences in the NH(2)-terminal substrate binding domains that may reflect differences in substrate specificity. Recombinant Lon-1 manifested properties of an ATP-dependent chaperone-protease in vitro but did not complement an E. coli Lon mutant, while Lon-2 corrected two characteristic Lon-mutant phenotypes. We conclude that B. burgdorferi Lons -1 and -2 have distinct functional roles. Lon-2 functions in a manner consistent with canonical Lon, engaged in cellular homeostasis. Lon-1, by virtue of its blood induction, and as a unique feature of the Borreliae, may be important in host adaptation from the arthropod to a warm-blooded host.


A study of the proliferating activity in lens epithelium and the identification of tissue-type stem cells.
Using a newly established fixation method and immunohistochemical methods, we precisely described the regions of cells stained with various antibodies relating to cell proliferation; this method enabled us to make cellular-level diagrams of the epithelium in which the position of every lens epithelial cell (LEC) was determined in reference to the cell located at the top of the bow area. The proliferating activity of LECs of 4-week-old (4W) mice was examined either by labeling with 5-bromodeoxyuridine (BrdU) in vivo or by measuring the amount of mRNA prepared from LECs, which had been separated into the posterior part, containing the germinative zone, and the anterior part and then cultured. The epithelial region stained with antibody for proliferating cell nuclear antigen (PCNA) and cyclin D1 remained relatively constant during the study period, although the positive region was reduced a little from embryonic day 18 (E18) to 12W. This region at 4W overlapped well with the DNA synthesizing region. Therefore, we reasoned that this region would correspond to the germinative zone of the adult mouse. Considering together with results of the reactivation pattern of genes, we considered that the location of tissue-type stem cells in lens epithelium (LE) as immediately anterior to the germinative zone.


Neuronal Effects of Listening to Entrainment Music Versus Preferred Music in Patients With Chronic Cancer Pain as Measured via EEG and LORETA Imaging.
Previous studies examining EEG and LORETA in patients with chronic pain discovered an overactivation of high theta (6-9 Hz) and low beta (12-16 Hz) power in central regions. MEG studies with healthy subjects correlating evoked nociception ratings and source localization described delta and gamma changes according to two music interventions. Using similar music conditions with chronic pain patients, we examined EEG in response to two different music interventions for pain. To study this process in-depth we conducted a mixed-methods case study approach, based on three clinical cases. Effectiveness of personalized music therapy improvisations (entrainment music - EM) versus preferred music on chronic pain was examined with 16 participants. Three patients were randomly selected for follow-up EEG sessions three months post-intervention, where they listened to recordings of the music from the interventions provided during the research. To test the difference of EM versus preferred music, recordings were presented in a block design: silence, their own composed EM (depicting both "pain" and "healing"), preferred (commercially available) music, and a non-participant's EM as a control. Participants rated their pain before and after the EEG on a 1-10 scale. We conducted a detailed single case analysis to compare all conditions, as well as a group comparison of entrainment-healing condition versus preferred music condition. Power spectrum and according LORETA distributions focused on expected changes in delta, theta, beta, and gamma frequencies, particularly in sensory-motor and central regions. Intentional moment-by-moment attention on the sounds/music rather than on pain and decreased awareness of pain was experienced from one participant. Corresponding EEG analysis showed accompanying power changes in sensory-motor regions and LORETA projection pointed to insula-related changes during entrainment-pain music. LORETA also indicated involvement of visual-spatial, motor, and language/music improvisation processing in response to his personalized EM which may reflect active recollection of creating the EM. Group-wide analysis showed common brain responses to personalized entrainment-healing music in theta and low beta range in right pre- and post-central gyrus. We observed somatosensory changes consistent with processing pain during entrainment-healing music that were not seen during preferred music. These results may depict top-down neural processes associated with active coping for pain.


The role of α-synuclein in neurodegenerative diseases: from molecular pathways in disease to therapeutic approaches.
Parkinson disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease (AD). The formation of the cytoplasmic inclusions named "Lewy bodies" in the brain, considered to be a marker for neuronal degeneration in PD and dementia with Lewy bodies. However, Lewy bodies (LBs) are also observed in approximately 60 percent of both sporadic and familial cases with AD. LBs consist of fibrils mainly formed by post-translational modified α-synuclein (α-syn) protein. The modifications can be truncation, phosphorylation, nitration and mono-, di-, or tri-ubiquitination. Development of disease seems to be linked to events that increase the concentration of α-syn or cause its chemical modification, either of which can accelerate α-syn aggregation. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or modified forms of α-syn. As the aggregation of α-syn in the brain has been strongly implicated as a critical step in the development of several neurodegenerative diseases, the current search for disease-modifying drugs is focused on modification of the process of α-syn deposition in the brain. Recently researchers have screened and designed various molecules that are selectively focused on inhibiting or preventing α-syn aggregation and toxicity. Another strategy that has emerged is to target α-syn expression as a potential therapy for neurodegenerative diseases associated with LBs.


Child advocacy training: curriculum outcomes and resident satisfaction.
Many health problems affecting children today are based in the community and cannot be easily addressed in the office setting. Child advocacy is an effective approach for pediatricians to take. To describe pediatric residents' choices of advocacy topics and interventions. Cross-sectional observational study. Residents from 3 pediatric training programs participated in the Child Advocacy Curriculum, which featured standardized workshops and the development of individual advocacy projects. To evaluate the curriculum, project descriptions and material products were analyzed to determine individual advocacy topics, topic themes, and targets of project interventions. Differences among programs were assessed. Residents also completed an anonymous questionnaire assessing their experience with the Child Advocacy Curriculum. Residents demonstrated a wide range of interests in selecting advocacy topics: 99 residents chose 38 different topics. The most common topic was obesity (13 residents) followed by health care access (9), teen pregnancy prevention (6), and oral health (5). Themes included health promotion and disease prevention, injury prevention, health care access, children with special health care needs, child development, at-risk populations, and the impact of media on child health. The project interventions targeted the local community most frequently (37%), followed by resident education (27%), hospital systems (21%), and public and health policy (15%). The vast majority of participating residents reported a positive experience with the Child Advocacy Curriculum. The wide range of topics and settings in which residents developed projects illustrates residents' extensive interests and ingenuity in applying needed advocacy solutions to complex child health issues.


Immunosuppressive regimens based on Cyclophospamide or Calcineurin inhibitors: Comparison of their effect in the long term outcome of Primary Membranous Nephropathy.
Management of the Primary Membranous Nephropathy (PMN) usually involves administration of immunosuppressives. Cyclophosphamide (Cyclo) and Calcineurin Inhibitors (CNIs) are both widely used but only limited data exist to compare their efficacy in long term follow-up. The aim of the present study was to estimate and compare long term effects of Cyclo and CNIs in patients with PMN. Clinical data, histologic findings and long term outcome were retrospectively studied. The response to treatment and rate of relapse was compared between patients treated with CNIs or Cyclo based immunosuppressive regimens. Twenty three centers participated in the study, with 752 PMN patients (Mean age 53.4(14-87) yrs, M/F 467/285), followed for 10.1±5.7 years. All patients were initially treated with Renin Angiotensin Aldosterone System inhibitors (RAASi) for at least 6 months. Based on their response and tolerance to initial treatment, patients were divided into 3 groups, group I with spontaneous remission, who had no further treatment, group II, continued on RAASi only, and group III on RAASi+immunosuppression. Immunosuppressive regimes were mainly based on CNIs or Cyclo. Frequent relapses and failure to treatment were more common between patients who had started on CNIs (n = 381) compared to those initially treated with Cyclo (n = 110), relapse rate: 25.2% vs. 6.4%, p<0.0001, and no response rate: 22.5% vs. 13.6%, p = 0.04, respectively. Long term follow up showed that administration of Cyclo in PMN is followed by better preservation of renal function, increased response rate and less frequent relapses, compared to CNIs.


Three-dimensional surgical navigation model with TilePro display during robot-assisted radical prostatectomy.
Abstract To facilitate robotic nerve-sparing radical prostatectomy, we developed a novel three-dimensional (3D) surgical navigation model that is displayed on the TilePro function of the da Vinci® surgeon console. Based on 3D transrectal ultrasonography (TRUS)-guided prostate biopsies, we reconstructed a 3D model of the TRUS-visible, histologically confirmed "index" cancer lesion in 10 consecutive patients. Five key anatomic structures (prostate, image-visible biopsy-proven "index" cancer lesion, neurovascular bundles, urethra, and recorded biopsy trajectories) were image-fused and displayed onto the TilePro function of the robotic console. The 3D model facilitated careful surgical dissection in the vicinity of the biopsy-proven index lesion. Geographic location of the index lesion on the final histology report correlated with the software-created 3D model. Negative surgical margins were achieved in 90%, except for one case with extensive extra-prostate extension. At postoperative 3 months, prostate-specific antigen levels were undetectable (<0.03 ng/mL) in all cases. The initial experience of the navigation model is presented.


[Bacterial meningitis: pathophysiology and therapy 1991].
The new concepts of pathogenesis and pathophysiology of purulent meningitis are discussed and evaluated in logical sequence. Possible therapeutic down-modulation of the initial burst of inflammatory responses, especially with steroids (dexamethasone), is critically analyzed. Prompt and adequate antibiotic therapy remains the essential measure in the management of patients with bacterial meningitis. The individual aspects of antimicrobial therapy are described and specific recommendations are made.


Outward-rectifying K+ channel activities regulate cell elongation and cell division of tobacco BY-2 cells.
Potassium ions (K+) are required for plant growth and development, including cell division and cell elongation/expansion, which are mediated by the K+ transport system. In this study, we investigated the role of K+ in cell division using tobacco BY-2 protoplast cultures. Gene expression analysis revealed induction of the Shaker-like outward K+ channel gene, NTORK1, under cell-division conditions, whereas the inward K+ channel genes NKT1 and NtKC1 were induced under both cell-elongation and cell-division conditions. Repression of NTORK1 gene expression by expression of its antisense construct repressed cell division but accelerated cell elongation even under conditions promoting cell division. A decrease in the K+ content of cells and cellular osmotic pressure in dividing cells suggested that an increase in cell osmotic pressure by K+ uptake is not required for cell division. In contrast, K+ depletion, which reduced cell-division activity, decreased cytoplasmic pH as monitored using a fluorescent pH indicator, SNARF-1. Application of K+ or the cytoplasmic alkalizing reagent (NH(4))(2)SO(4) increased cytoplasmic pH and suppressed the reduction in cell-division activity. These results suggest that the K+ taken up into cells is used to regulate cytoplasmic pH during cell division.


Regulation of polyphenols accumulation by combined overexpression/silencing key enzymes of phenylpropanoid pathway.
There is a growing interest in the metabolic engineering of plant with increased desirable polyphenols such as chlorogenic acid (CGA) and rutin. In this study, the effects of overexpression of both phenylalanine ammonia lyase (AtPAL2), the first enzyme of the phenylpropanoid pathway, and hydroxycinnamoyl-CoA quinate:hydroxycinnamoyl transferase (NtHQT), the last enzyme of CGA biosynthesis, and the overexpression of AtPAL2 together with silencing of NtHQT were investigated in tobacco. Transgenic tobacco plants overexpressing AtPAL2 showed two and five times increases of CGA and rutin levels than the wild-type (WT) plants, respectively. Overexpression of NtHQT further increases the accumulation of CGA in the AtPAL2 plants to about three times than that of the WT level, while silencing of NtHQT in AtPAL2 plants results in about 12 times increase in rutin level than that of the WT plants. Simultaneous overexpression of phenylalanine ammonia lyase (PAL) and overexpression/silencing HQT could be used for the production of functional food with increased polyphenols.


pH-dependent changes of nitric oxide, peroxynitrite, and reactive oxygen species in hepatocellular damage.
Low arterial blood pH and sustained nitric oxide (NO) production are critical parameters in inflammatory events such as sepsis, and appropriate treatment is still under debate. Because the stability of nitrogen and oxygen intermediates is dependent on the surrounding pH, we investigated whether the relationship among NO, peroxynitrite (ONOO-), and reactive oxygen species production also depends on the pH value, particularly with respect to their effects on hepatocellular damage. Our studies demonstrate that the extracellular pH influences NO and hydroxyl radical (OH) production in hepatocytes. Acidification (pH 7.0) of the medium revealed a significant increase (P < 0.05) of OH-like radicals, enhanced hepatocellular damage, and a sharp drop in cellular glutathione (GSH) content compared with levels measured at physiological or alkaline pH conditions. Furthermore, inhibition of NO synthesis at all pH conditions resulted in decreased NO production and cellular GSH levels but a simultaneous increase of OH-like radicals and hepatocellular damage with a maximum seen at pH 7.0. Our results suggest that hepatocellular damage is in part regulated by the surrounding pH and that inhibition of NO synthesis at acidic conditions (e.g., in sepsis) leads to increased reactive oxygen-mediated cell injury.


Complete genome sequence of the cystic fibrosis pathogen Achromobacter xylosoxidans NH44784-1996 complies with important pathogenic phenotypes.
Achromobacter xylosoxidans is an environmental opportunistic pathogen, which infects an increasing number of immunocompromised patients. In this study we combined genomic analysis of a clinical isolated A. xylosoxidans strain with phenotypic investigations of its important pathogenic features. We present a complete assembly of the genome of A. xylosoxidans NH44784-1996, an isolate from a cystic fibrosis patient obtained in 1996. The genome of A. xylosoxidans NH44784-1996 contains approximately 7 million base pairs with 6390 potential protein-coding sequences. We identified several features that render it an opportunistic human pathogen, We found genes involved in anaerobic growth and the pgaABCD operon encoding the biofilm adhesin poly-β-1,6-N-acetyl-D-glucosamin. Furthermore, the genome contains a range of antibiotic resistance genes coding efflux pump systems and antibiotic modifying enzymes. In vitro studies of A. xylosoxidans NH44784-1996 confirmed the genomic evidence for its ability to form biofilms, anaerobic growth via denitrification, and resistance to a broad range of antibiotics. Our investigation enables further studies of the functionality of important identified genes contributing to the pathogenicity of A. xylosoxidans and thereby improves our understanding and ability to treat this emerging pathogen.


A Phenomenographic Approach to Understanding the Expertise of Perioperative Nurses.
Understanding the ways that perioperative nurses view the acquisition of expertise may provide foundational information for perioperative nurse educators. Our study aimed to evaluate specific types of expertise exhibited by experienced perioperative nurses and identify how nurses perceived these areas of expertise. We interviewed 20 perioperative nurses working in a university hospital in Korea. We extracted six themes regarding perioperative nursing expertise: sticking to principles, using available resources in complex situations, paying close attention to details, seeing the whole picture, prioritizing actions according to patients' conditions, and organizing a team to maximize efficiency. These findings may help perioperative educators develop practical educational strategies for novice perioperative nurses by providing a common language regarding the areas of expertise exhibited by experienced perioperative nurses.


Latent asymmetric intraocular pressure as a predictor of visual field defects.
To investigate the association of latent asymmetric intraocular pressure (IOP) (IOP asymmetry between fellow eyes when patients were in the supine position but not when sitting) with visual field (VF) defects in patients with open-angle glaucoma. Fifty-three patients with open-angle glaucoma, who were receiving the same topical medication in both eyes, were enrolled and were housed in a sleep laboratory for 24 hours. Intraocular pressures were measured when the patients with open-angle glaucoma were in the supine position or were sitting. A group of patients with latent asymmetric IOP was identified. Intraocular pressure asymmetry, monocular diurnal IOP fluctuation, and VF indexes were compared between the groups with and without latent asymmetric IOP. Among the study population, 16 patients had latent asymmetric IOP. Compared with fellow eyes, their hypertensive eyes demonstrated greater IOP fluctuations in the sitting and supine positions and had more aggressive VF defects. In addition, the eyes in patients having latent symmetric IOP showed significantly greater diurnal IOP fluctuations in the sitting and supine positions and more severe VF defects compared with the eyes in patients having symmetric sitting and supine position IOPs. Patients with latent asymmetric IOP are at increased risk of VF deterioration. Latent asymmetric IOP may be a predictor of glaucomatous VF defects. Further investigation in a larger, more diverse group of patients is needed to assess the diagnostic implications of latent asymmetric IOP relative to glaucoma therapy.


Cohort study of hospitalists' procedural skills: baseline competence and durability after simulation-based training.
Hospitalists are expected to be competent in performing bedside procedures, which are associated with significant morbidity and mortality. A national decline in procedures performed by hospitalists has prompted questions about their procedural competency. Additionally, though simulation-based mastery learning (SBML) has been shown to be effective among trainees whether this approach has enduring benefits for independent practitioners who already have experience is unknown. We aimed to assess the baseline procedural skill of hospitalists already credentialed to perform procedures. We hypothesised that simulation-based training of hospitalists would result in durable skill gains after several months. Prospective cohort study with pretraining and post-training measurements. Single, large, urban academic medical centre in the USA. Twenty-two out of 38 eligible participants defined as hospitalists working on teaching services where they would supervise trainees performing procedures. One-on-one, 60 min SBML of lumbar puncture (LP) and abdominal paracentesis (AP). Our primary outcome was the percentage of hospitalists obtaining minimum passing scores (MPS) on LP and AP checklists; our secondary outcomes were average checklist scores and self-reported confidence. At baseline, only 16% hospitalists met or exceeded the MPS for LP and 32% for AP. Immediately after SBML, 100% of hospitalists reached this threshold. Reassessment an average of 7 months later revealed that only 40% of hospitalists achieved the MPS. Confidence increased initially after training but declined over time. Hospitalists may be performing invasive bedside procedures without demonstration of adequate skill. A single evidence-based training intervention was insufficient to sustain skills for the majority of hospitalists over a short period of time. More stringent practices for certifying hospitalists who perform risky procedures are warranted, as well as mechanisms to support skill maintenance, such as periodic simulation-based training and assessment.


Motion sickness: comparison of metoclopramide and diphenhydramine to placebo.
This is an evaluation of the efficacy of metoclopramide (MTCP) or diphenhydramine (DPH) to relieve symptoms of motion sickness in patients being transported via ambulance in a mountainous setting. This is a prospective, randomized, double-blinded, placebo-controlled study of patients transported by ambulance in the Sierra Nevada mountains of Fresno County. Consenting patients who met the inclusion criteria were asked to rate their motion sickness every five minutes using a visual analog scale (VAS) during transport. If motion sickness occurred, they were randomized to receive MTCP (20 mg IV), DPH (50 mg IV), or placebo (normal saline), and remaining symptoms were recorded every five minutes. If signs and symptoms of motion sickness persisted after 15 minutes, a rescue dose of MTCP was offered. Twenty-six patients were enrolled in the study. Twenty-two (84.6%) developed motion sickness and were randomized to MTCP, DPH, or placebo. Eight patients received MTCP, seven received DPH, and seven received placebo. The MTCP group showed a statistically significant decrease in the mean VAS score at 15 minutes compared to the DPH and placebo groups. There was no significant difference in the decrease in VAS score between the placebo and the DPH group. Twelve out of 22 patients requested a rescue dose of MTCP after 15 minutes. At 25 minutes, there was no significant difference in the VAS score between the three groups. During ambulance transport in a mountainous setting, the administration of MTCP is superior to both DPH and placebo in the treatment of motion sickness. Diphenhydramine is not superior to placebo.


Can unconditional cash transfers raise long-term living standards? Evidence from Zambia.
In Africa, state-sponsored cash transfer programs now reach nearly 50 million people. Do these programs raise long-term living standards? We examine this question using experimental data from two unconditional cash transfer programs implemented by the Zambian Government. We find far-reaching effects of the programs both on food security and consumption as well as on a range of productive outcomes. After three years, household spending is on average 67 percent larger than the value of the transfer received, implying a sizeable multiplier effect, which works through increased non-farm activity and agricultural production.


Xpert MTB/RIF - why the lack of morbidity and mortality impact in intervention trials?
Compared with smear microscopy, the Xpert MTB/RIF assay (Xpert), with superior accuracy and capacity to diagnose rifampicin resistance, has advanced TB diagnostic capability. However, recent trials of Xpert impact have not demonstrated reductions in patient morbidity and mortality. We conducted a narrative review of Xpert impact trials to summarize which patient-relevant outcomes Xpert has improved and explore reasons for no observed morbidity or mortality reductions. We searched PubMed, Google Scholar, Cochrane Library and Embase and identified eight trials meeting inclusion criteria: three individually randomized, three cluster-randomized, and two pre-post trials. In six trials Xpert increased diagnostic yield of bacteriologically-confirmed TB from sputa and in four trials Xpert shortened time to TB treatment. However, all-cause mortality was similar between arms in all six trials reporting this outcome, and the only trial to assess Xpert impact on morbidity reported no impact. Trial characteristics that might explain lack of observed impact on morbidity and mortality include: higher rates of empiric TB treatment in microscopy compared with Xpert arms, enrollment of study populations not comprised exclusively of populations most likely to benefit from Xpert, and health system weaknesses. So far as equipoise exists, future trials that address past limitations are needed to inform Xpert use in resource-limited settings.


Microbial syntrophy: interaction for the common good.
Classical definitions of syntrophy focus on a process, performed through metabolic interaction between dependent microbial partners, such as the degradation of complex organic compounds under anoxic conditions. However, examples from past and current scientific discoveries suggest that a new, simple but wider definition is necessary to cover all aspects of microbial syntrophy. We suggest the term 'obligately mutualistic metabolism', which still focuses on microbial metabolic cooperation but also includes an ecological aspect: the benefit for both partners. By the combined metabolic activity of microorganisms, endergonic reactions can become exergonic through the efficient removal of products and therefore enable a microbial community to survive with minimal energy resources. Here, we explain the principles of classical and non-classical syntrophy and illustrate the concepts with various examples. We present biochemical fundamentals that allow microorganism to survive under a range of environmental conditions and to drive important biogeochemical processes. Novel technologies have contributed to the understanding of syntrophic relationships in cultured and uncultured systems. Recent research highlights that obligately mutualistic metabolism is not limited to certain metabolic pathways nor to certain environments or microorganisms. This beneficial microbial interaction is not restricted to the transfer of reducing agents such as hydrogen or formate, but can also involve the exchange of organic, sulfurous- and nitrogenous compounds or the removal of toxic compounds.


Addressing gaps in AMR awareness in the public: an evidence-based policy brief to guide school curriculum review in Uganda.
The government of Uganda, through its Ministry of Health, previously adopted curriculum review as a mechanism to respond to public health threats such as HIV/AIDS and include content in primary and secondary schools. This approach contributes to raising public awareness, a key strategy recommended by the World Health Organization to support the global response to the threat of antimicrobial resistance (AMR). This policy brief, developed for policymakers related to school curricula, aims to advocate for and support integration of AMR content in Uganda's primary and secondary level school curricula. The policy brief supports efforts by the multisectoral National AMR Subcommittee to create awareness on this issue as part of its role in facilitating the operationalization of Uganda's National Action Plan on AMR.


The ScpC protease of Streptococcus pyogenes affects the outcome of sepsis in a murine model.
The ScpC protease of Streptococcus pyogenes degrades interleukin-8 (IL-8), a chemokine that mediates neutrophil transmigration and activation. The ability to degrade IL-8 differs dramatically among clinical isolates of S. pyogenes. Bacteria expressing ScpC overcome immune clearance by preventing the recruitment of neutrophils in soft tissue infection of mice. To study the role of ScpC in streptococcal sepsis, we generated an ScpC mutant that did not degrade IL-8 and thus failed to prevent the recruitment of immune cells as well as to cause disease after soft tissue infection. In a murine model of sepsis, challenge with the ScpC mutant resulted in more severe systemic disease with higher bacteremia levels and mortality than did challenge with the wild-type strain. As expected, the blood level of KC, the murine IL-8 homologue, increased in mice infected with the ScpC mutant. However, the elevated KC levels did not influence neutrophil numbers in blood, as it did in soft tissue, indicating that additional factors contributed to neutrophil transmigration in blood. In addition, the absence of ScpC increased tumor necrosis factor, IL-6, and C5a levels in blood, which contributed to disease severity. Thus, the ScpC mutant triggers high neutrophil infiltration but not lethal outcome after soft tissue infection, whereas intravenous infection leads to highly aggressive systemic disease.


The new aneurysm clip system for particularly complex aneurysm surgery: technical note.
Currently, there is an ongoing debate regarding the best treatment option for ruptured aneurysms. The International Subarachnoid Aneurysm Trial study suggests that an endovascular procedure is the best treatment. In some complex cases, or in patients with an additional large intracerebral hemorrhage, aneurysms require further microsurgical clipping. We introduce a new clip system to improve clipping procedures in especially complex aneurysms. The inverted opening mechanism of the clip in combination with the special clip applier provides the surgeon with a good overview in the operating field. The new design also enables a wider opening of the clip jaws in contrast to all other well-known titanium aneurysm clips. This should provide a better and safer application and decrease the danger of premature rupture. From January 2006 to July 2008, 55 aneurysms were clipped in 45 patients. The most common aneurysm location was the anterior communicating artery (20 patients) followed by the M1 segment of the middle cerebral artery (16 patients). Four patients had 2, one had 3, and one had 5 aneurysms. Two clipping procedures were performed for an arteriovenous malformation-associated aneurysm. All aneurysms were clipped without any technical complication. The use of the new clip system, especially in complex aneurysm surgery, has potential benefits because of the better surgical vision during clip application and the wider opening of the clip jaws. It is easy to handle and compatible with magnetic resonance imaging.


Cranial shape varies along an elevation gradient in Gambel's white-footed mouse (Peromyscus maniculatus gambelii) in the Grinnell Resurvey Yosemite transect.
Environmental variation over a species's range creates differing pressures to which organisms must adjust in order to survive. Taxa can respond to these pressures at population and individual levels, leading to localized phenotypic differentiation. Assessing the spatial distribution of phenotypic variation can illuminate how dramatically varying environmental factors shape phenotypes and may forecast a taxon's ability to adapt should conditions change. We characterized morphological variation along a transect sampled in the Grinnell Resurvey project to determine whether Gambel's white-footed mouse (Peromyscus maniculatus gambelii), a generalist taxon inhabiting the full elevational range of habitats in Yosemite National Park and surrounding areas, has responded morphologically to variation in its environment. We quantified variation in modern P. m. gambelii cranial shape using 2D generalized Procrustes analysis and Euclidean distance matrix-based geometric morphometrics. We performed multivariate regression of shape coordinates on elevation to test for environmental influences on shape within the principal geographic dimension of change along the transect. We observe a statistically significant correlation with shape on elevation for occlusal and lateral views of the cranium, explaining a small percentage of the overall variation in shape. Modern P. m. gambelii crania show a pattern of flexion in which the angle of the cranial base decreases at higher elevations. Results of EDMA parallel these findings, but highlight additional areas of the cranium that vary with elevation. Collectively, the patterns of variation detected suggest a biological response to the environment that warrants further study. This work lays the foundation for comparison with morphological data from historical specimens, which can address evolutionary scenarios generated from our findings, and for investigation of other taxa included in the resurvey project.


Dry electrolyte-balanced heparinized syringes evaluated for determining ionized calcium and other electrolytes in whole blood.
By analyzing whole blood containing no anticoagulants (uncoagulated whole blood) immediately after collection, we evaluated the relative changes in the concentrations of ionized calcium and other electrolytes in whole blood collected in dry heparinized syringes and in serum prepared from blood collected in evacuated blood-collection tubes. Using these dry heparinized syringes, we collected and analyzed whole blood that contained either 33 or 13 int. units of lithium heparin or 40 int. units of electrolyte-balanced heparin per milliliter of blood. We evaluated the effects both of these heparins at different concentrations of ionized calcium and of the incomplete filling of the syringes. We conclude that: (a) when analyzed within 2-3 min after collection, uncoagulated whole blood provides ionized calcium results unaffected by anticoagulants or cellular metabolism; (b) the preparation of serum unpredictably changes ionized calcium; (c) the use of dry electrolyte-balanced heparin virtually eliminates the interference in ionized calcium concentrations between 0.9 and 1.6 mmol/L; and (d) incomplete filling of electrolyte-balanced heparinized syringes produces no effect in syringes two-thirds full (60 int. units/mL heparin concentration) and a small effect in syringes one-third full (120 int. units/mL heparin).


Phantom Menace: Dengue and Yellow Fever in Asia.
This article explores the entangled histories of dengue and yellow fever. It traces how historical conflations of these diseases deepened at the start of the twentieth century in the context of rising fears that yellow fever might spread to Asia. Advances in biomedicine, I suggest, reinforced notions of their kinship and generated competing theories that dengue either foreshadowed yellow fever in Asia or inoculated the region against it. This history in which the language and science of dengue and yellow fever shadowed one another offers a nonlinear narrative of scientific progress. Furthermore, as the so-called neglected tropical diseases resurge in the present, it elucidates how disease threats are read against one another. Thus, the article offers a historical context to ongoing discussions on disease emergence and pandemic preparedness.


International symposium on levamisole in rheumatoid arthritis. A review of short and longterm effects on articular manifestations.
Reports of 28 authors with a total of nearly 1,000 enrolled patients have been reviewed regarding changes in clinical manifestations of disease in rheumatoid arthritis during short term and long term administration of levamisole. Global clinical improvement was observed in 60% of patients after three months and in 75% of patients after six months of drug treatment. There was no significant difference in response whether the drug was given in a continuous daily or intermittent weekly fashion. The longest observation times extend to 3 1/2 years. An optimal effect is usually reached between six and 12 months of treatment, after which time no further improvement is observed. After cessation of drug administration, the rate of deterioration varies with the length of previous exposure.


Evidence to suggest morphological and physiological alterations of lacrimal gland acini with ageing.
This study investigates changes in the morphology and physiology of lacrimal gland acinar cells with age. Changes in microstructural appearance of the acinar cells, the type and distribution of the different acini in glands and the secretory granules within the acini were examined in glands from animals of 3-5, 9, 12, 20, 24 and 28 month old rats. Differences in the secretory capacity of the acinar cells were also examined in animals of each age-group, with the exception of 28 months. The typical acini of young glands (3-5 months) were of the serous type. This was also true of 9 month glands, although there was a significant reduction in their overall distribution compared to young glands. The acini in the 12 month glands were predominantly of the seromucous type and appeared to be at the expense of the serous acini which were further significantly reduced compared to 3-5 and 9 month glands. This remained the prevalent acini type in 20 month glands, however by 24 months there was a significant increase in the occurrence of mucous acini and this time appeared to be at the expense of the seromucous acini which were significantly reduced in glands of this age-group. The predominant acinar cell in 28 month glands, like 24 month glands, was of the mucous variety. Qualitative EM studies revealed a progressive change in the secretory products of the lacrimal gland acini, strongly correlating to changes in acinar cell type. Typical acini of both 3-5 and 9 month glands contained numerous protein secretory granules. The seromucous acini also of these age groups contained both protein and mucous secretory granules, with the protein secretory granules in higher abundance. By 12 months the typical seromucous acini was packed with both protein and mucous secretory granules of equal proportions. However, by 20 months the predominant seromucous acini contained fewer protein secretory granules and elevated occurrence of mucous secretory granules. By 24 and 28 months the acini contained even fewer protein secretory granules and the typical acinar cell was of the mucous type containing exclusively mucous secretory granules. The secretory capacity of the acini was also altered with age. Maximum protein output in response to cholinergic stimulation resulted in an initial significant increase with ageing from 3-5 months to 9 and 12 months followed by a later significant age-dependent reduction in output. However, maximal peroxidase release from acinar cells of 3-5 and 9 month glands was the same. This was followed by a significant age-dependent reduction in peroxidase release. Furthermore, the concentrations required to evoke these responses differed with age. These results present evidence to suggest that acinar cells of the lacrimal gland undergo progressive alterations with age. The type of acini changing initially from serous to seromucous acini (intermediate phase) followed by a gradual transformation of the seromucous acini to mucous acini. This in turn changes the properties of the acini from protein producing and secreting acini to mucous producing and secreting acini. The results also suggest a reduction in the ability of the acini to synthesise proteins with age and altered responsiveness to cholinergic stimulation to secrete proteins. These findings may help in explaining the occurrence of altered protein/tear secretion with ageing.


Hypertension in the elderly.
Hypertension is predictive of a wide variety of subsequent adverse events in elderly patients, at least up to the age of 80 years. Treatment can reduce these adverse outcomes, although the benefits in the very elderly remain somewhat unclear. In the very elderly, there appears to be a reduction in cardiovascular events, but this reduction is perhaps at the expense of an increase in overall mortality. Target BPs in the elderly remain controversial. Among patients who have not had previous stroke or significant cardiovascular or renal disease, the benefits of reducing the SBP below 159 mm Hg are well documented. There is some evidence to suggest, however, that if doing so increases the day-night difference in BP by more than 20% or is associated with a decline in DBP below 65 mm Hg, then the benefits of treatment may be attenuated or lost. In addition, there is some suggestion that reducing SBP consistently below 135 mm Hg may accelerate cognitive decline. There appears to be a role for sodium restriction in those who can comply without otherwise compromising nutrient intake. Likewise, exercise may be beneficial and have benefits beyond simply lowering BP. Weight loss in those who are overweight may also help in lowering the BP. For most patients, low-dose thiazides such as hydrochlorothiazide are likely to be the appropriate first-line therapy (even in patients who have diabetes) unless they exacerbate or precipitate urinary incontinence or gout or complicate concomitant drug therapy (eg, lithium treatment of bipolar disorder). In very elderly patients, the apparent beneficial effects on strokes, major cardiovascular events, and heart failure rates may justify treating despite lack of benefit on overall mortality.


Learning about the equal sign: does comparing with inequality symbols help?
This study investigated whether instruction that involves comparing the equal sign with other relational symbols is more effective at imparting a relational interpretation of the equal sign than instruction about the equal sign alone. Third- and fourth-grade students in a comparing symbols group learned about the greater than, less than, and equal signs and had the opportunity to compare the inequality symbols with the equal sign. Students in an equal sign group learned about the equal sign only. A third group of students served as a control group. Three aspects of students' knowledge were assessed before and after the lesson: (a) conceptual understanding of the equal sign, (b) equation encoding, and (c) problem solving. Students in the comparing symbols group showed greater gains in conceptual understanding from pretest to posttest than students in the other two groups, and students in the comparing symbols group also scored higher on a posttest that assessed knowledge about inequality symbols and inequality problem solving. Thus, they learned about three symbols in the same amount of time as other students learned about the equal sign alone or not at all. Therefore, an instructional approach involving comparison can be an effective tool for learning about concepts in mathematics.


Detecting genes in new and old mouse models for epilepsy: a prospectus through the magnifying glass.
Various spontaneous mutants and natural strain variants for either generalized tonic-clonic seizures, or non-convulsive absence seizures have been described in mice and rats over the years. Convulsive seizure models are usually ascertained by mere visual observation, while finding the less noticeable seizures of absence models often requires proactive screening of existing mutants with other phenotypes. To date, molecular cloning technologies has elucidated the primary basis of most of the known single locus epilepsy mutants. Together with the 20 or so mouse knockouts with seizure-related phenotypes described to date, the frequency at which the mutants appear and diversity of the proteins involved would suggest that 1000 or more genes can be mutated to give rise to influence epilepsy phenotypes. As many of these genes will cluster into molecular, cellular and developmental pathways, their identification may be very important for better understanding epileptic mechanisms. With this perspective, the approaches taken towards positional cloning of mouse epilepsy mutations is illustrated by comparing and contrasting the different stages of gene identification in three different models with which this author has been fortunate enough to be intimately involved: slow-wave epilepsy (common gene symbol: swe, Chr 4); tottering (tg, Chr 8); and stargazer (stg, Chr 15). The comparatively sobering outlook for positional cloning of the more common genetically 'complex' epilepsies will also be discussed, as will more efficient new strategies for model screening and identifying the remaining 985 (or so) genes.


Ultrastable Natural Ester-Based Nanofluids for High Voltage Insulation Applications.
Nanofluids for high voltage insulation systems have emerged as a potential substitute for liquid dielectrics in industrial applications. Nevertheless, the sedimentation of nanoparticles has been so far a serious barrier for their wide and effective exploitation. The present work reports on the development and in-depth characterization of colloidally ultrastable natural ester oil insulation systems containing iron oxide nanocrystals which lift the problem of sedimentation and phase separation. Compared to state-of-the-art systems, the final product is endowed with increased dielectric strength, faster thermal response, lower dielectric losses (decreased dissipation factor: tan δ), and very high endurance during discharge stressing. The developed nanofluid was studied and compared with a similar system containing commercial iron oxide nanoparticles, the latter demonstrating extensive sedimentation. Herein, the dielectric properties of the nanofluids are analyzed at various concentrations by means of breakdown voltage and dissipation factor measurements. The characterization techniques unequivocally demonstrate the high performance reliability of the reported nanofluid, which constitutes a significant breakthrough in the field of high voltage insulation technologies.


An artificial intelligence-based EEG algorithm for detection of epileptiform EEG discharges: Validation against the diagnostic gold standard.
To validate an artificial intelligence-based computer algorithm for detection of epileptiform EEG discharges (EDs) and subsequent identification of patients with epilepsy. We developed an algorithm for automatic detection of EDs, based on a novel deep learning method that requires a low amount of labeled EEG data for training. Detected EDs are automatically grouped into clusters, consisting of the same type of EDs, for rapid visual inspection. We validated the algorithm on an independent dataset of 100 patients with sharp transients in their EEG recordings (54 with epilepsy and 46 with non-epileptic paroxysmal events). The diagnostic gold standard was derived from the video-EEG recordings of the patients' habitual events. The algorithm had a sensitivity of 89% for identifying EEGs with EDs recorded from patients with epilepsy, a specificity of 70%, and an overall accuracy of 80%. Automated detection of EDs using an artificial intelligence-based computer algorithm had a high sensitivity. Human (expert) supervision is still necessary for confirming the clusters of detected EDs and for describing clinical correlations. Further studies on different patient populations will be needed to confirm our results. The automated algorithm we describe here is a useful tool, assisting neurophysiologist in rapid assessment of EEG recordings.


Age-Dependent Disparities in the Prevalence of Single and Clustering Cardiovascular Risk Factors: A Cross-Sectional Cohort Study in Middle-Aged and Older Adults.
Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide; with age acknowledged as an independent cardiovascular risk factor (CRF) in adults. Appreciating the association between age and classic CRFs is believed to boost all potential benefits of prevention. Assessment of the prevalence of single and clustered CRFs and their association with age. The survey involved 4735 people (33.6% men) who were PONS project attendees aged 45-64. The study protocol comprised the Health Status Questionnaire, general medical examination, anthropometric measurements, and blood and urine sampling. The prevalence of single and clustered CRFs (hypertension, dyslipidemia, diabetes mellitus, and obesity) in the incrementally split age groups was calculated. The incidence rate of CRFs, against their absence, was determined by Poisson regression models with robust standard errors. The prevalence of CRFs was established in 90% of the respondents. Except dyslipidemia and ≥1 CRFs, prevalence of risk factors increased with age, although this trend was the weakest in men. In the total group, and in women, prevalence of dyslipidemia and ≥1 CRFs was unrelated to age, whereas in men, it was on the rise in the younger age groups. The incidence rate of CRFs was strongly related to age, and, with the exception of dyslipidemia, was higher in the older age groups. Cardiovascular risk factors are common in the adult population, while their prevalence and clustering are more prevalent in seniors. Apart from dyslipidemia, the risk of CRFs is appreciably age-related, and higher in seniors.


A model for direct and quantitative assessment of pancreatic hormone secretion.
The usual parameters for the assessment of pancreatic endocrine function are oral or intravenous tolerance tests with various kinds of stimuli, generally glucose. Such tests provide information as to the pancreatic endocrine capacity in an indirect fashion, and the actual hormone output cannot be readily determined. The results are presented of a model in dogs with which the hormone producing capacity of the left lobe of the pancreas can be quantitatively assessed directly. The complete and undiluted venous blood from the left pancreatic lobe is sampled by cannulation of the splenic and the portal vein, under general anaesthesia. Removal of the right lobe is obligatory. With this model pancreatic blood flow, hormone secretion, and oxygen consumption can be studied after different sorts of stimuli. Moreover there is opportunity to determine the effect of various manipulations of the pancreas on its hormone secreting capacity directly.


[Effect of the physiological conditions on alpha-amylase and glucoamylase formation by a selected strain of Aspergillus oryzae].
The production of alpha-amylase and glucoamylase by a selected strain of Aspergillus oryzae was investigated using different carbon and nitrogen sources. The best and most economic fermentation medium for the production of the both amylases in submerged cultures had the following composition (in %): defatted rice brain, 8; corn steep liquor, 3; MgSO4 X 7H2O, 0.1; KH2PO4, 0.1; CaCl2, 0.1. The optimum pH was 5.0. The optimal conditions for biosynthesis of the amylases were as follows: cultivation at 28 degrees C for 96 h using the 0.5% mycelial suspension as an inoculum.


Filtering closed curves.
A closed curve in the plane can be described in several ways. We show that a simple representation in terms of radius of curvature versus normal direction has certain advantages. In particular, convolutional filtering of the extended circular image leads to a closed curve. Similar filtering operations applied to some other representations of the curve do not guarantee that the result corresponds to a closed curve. In one case, where a closed curve is produced, it is smaller than the original. A description of a curve can be based on a sequence of smoothed versions of the curve. This is one reason why smoothing of closed curves is of interest.


Visualizing Dynamic Data with Maps.
Maps offer a familiar way to present geographic data (continents, countries), and additional information (topography, geology), can be displayed with the help of contours and heat-map overlays. In this paper, we consider visualizing large-scale dynamic relational data by taking advantage of the geographic map metaphor. We describe a map-based visualization system which uses animation to convey dynamics in large data sets, and which aims to preserve the viewer's mental map while also offering readable views at all times. Our system is fully functional and has been used to visualize user traffic on the Internet radio station last.fm, as well as TV-viewing patterns from an IPTV service. All map images in this paper are available in high-resolution at [1] as are several movies illustrating the dynamic visualization.


Seroprevalence of six different viruses among pregnant women and blood donors in rural and urban Burkina Faso: A comparative analysis.
A seroprevalence study was carried out of six different human pathogenic viruses, namely human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-cell leukemia virus (HTLV), human herpesvirus type 8 (HHV-8), and dengue virus among pregnant women and blood donors from rural (Nouna) and urban (Ouagadougou) Burkina Faso, West Africa. A total of 683 samples from blood donors (n = 191) and pregnant women (n = 492) were collected from both sites and screened for the different virus infection markers resulting in the following prevalence values for Nouna or Ouagadougou, respectively: HIV 3.6/4.6, anti-HBV core (anti-HBc) 69.6/76.4, HBV surface antigen (HBsAg)14.3/17.3, HCV 2.2/1.5, HTLV 1.4/0.5, HHV-8 11.5/13.5, dengue virus 26.3/36.5. Individuals aged > or =25 years were more likely to be infected with HIV than those below 24 years (P < 0.05). Infection with HIV increased the likelihood of co-infection with other viruses, such as HHV-8, HBV and HTLV. Co-infection studies involving five viruses (HBV-HBsAg, HHV-8, HIV, HCV, and HTLV) showed that 4.8% (33/683) of the studied population were dually infected, with HBsAg+ HHV-8 (13/33), HBsAg+HIV (8/33) and HIV+HHV-8 (8/33) being the most common co-infections. Of the population studied 0.6% (4/683) was triply infected, the most common infection being with HBV+HIV+HHV-8 (3/4). There was no difference in the prevalence of HIV, anti-HBc, HBsAg, HCV, HTLV, and HHV-8 either among blood donors or pregnant women in urban or rural setting, while dengue virus prevalence was relatively lower in rural (26.3%) than in urban (36.5%) Burkina Faso.


Engineering and Modulating Functional Cyanobacterial CO2-Fixing Organelles.
Bacterial microcompartments (BMCs) are proteinaceous organelles widespread among bacterial phyla and provide a means for compartmentalizing specific metabolic pathways. They sequester catalytic enzymes from the cytoplasm, using an icosahedral proteinaceous shell with selective permeability to metabolic molecules and substrates, to enhance metabolic efficiency. Carboxysomes were the first BMCs discovered and their unprecedented capacity of CO2 fixation allows cyanobacteria to make a significant contribution to global carbon fixation. There is an increasing interest in utilizing synthetic biology to construct synthetic carboxysomes in new hosts, i.e., higher plants, to enhance carbon fixation and productivity. Here, we report the construction of a synthetic operon of the β-carboxysome from the cyanobacterium Synechococcus elongatus PCC7942 to generate functional β-carboxysome-like structures in Escherichia coli. The protein expression, structure, assembly, and activity of synthetic β-carboxysomes were characterized in depth using confocal, electron and atomic force microscopy, proteomics, immunoblot analysis, and enzymatic assays. Furthermore, we examined the in vivo interchangeability of β-carboxysome building blocks with other BMC components. To our knowledge, this is the first production of functional β-carboxysome-like structures in heterologous organisms. It provides important information for the engineering of fully functional carboxysomes and CO2-fixing modules in higher plants. The study strengthens our synthetic biology toolbox for generating BMC-based organelles with tunable activities and new scaffolding biomaterials for metabolic improvement and molecule delivery.


Gene polymorphism of MTHFR rs1801133 and susceptibility to childhood leukemia in Chinese population.
The purpose of this study is to investigate the genotype and allele distribution of MTHFR rs1801133 in the Chinese population, and to analyze the relationship between gene polymorphism of MTHFR rs1801133 and risk of childhood leukemia. Blood samples and clinical data of childhood leukemia cases (n=1132) and age-matched healthy controls (n=1053) were collected. Genotypes and allele distribution of MTHFR rs1801133 were detected by PCR-RFLP. Logistic regression model was generated to analyze the relation between MTHFR rs1801133 and susceptibility to childhood leukemia and the chemotherapy response. Age, sex, BMI and family history of tumor were comparable between childhood leukemia cases and healthy controls. Genotypes and allele distribution of MTHFR rs1801133 were remarkably correlated to the risk of childhood leukemia. Genotype risk of MTHFR rs1801133 was parallel to the susceptibility to childhood leukemia. Specifically, compared with people carrying AA allele of MTHFR rs1801133, higher risk of childhood leukemia may occur in people carrying AG+GG allele of MTHFR rs1801133 with a younger age (<15 years) or complete remission from chemotherapy. MTHFR rs1801133 gene polymorphism has a significant correlation with childhood leukemia. It is an important genetic susceptibility gene of childhood leukemia. The reliability of the results requires to be further validated by the high-quality research involving a large sample size in multi-center hospitals.


Rapid prototyping of temporal bone for surgical training and medical education.
The skills of ear surgery are best developed by dissecting a temporal bone. However, only a limited number of trainees can be afforded this opportunity because of the scarcity of available bones. The aim of this study was to investigate the validity of a prototype temporal bone model for surgical training and education. A simulated 3D model of a human temporal bone was made using a selective laser sintering method. The powder layers were laser-fused based on detailed CT data and accumulated to create a 3D structure. Conventional surgical instruments were used to dissect the model under a microscope. The model was as hard as real bone and surface structures were accurately reproduced. The model could be shaved using a surgical drill, burr and suction irrigator in the same way as a real bone. The malleus and incus were reproduced. The semicircular canals and the oval and round window niches were identified. Cavity structures, such as the semicircular canal, vestibule, antrum and air cells, were filled with powder which had to be removed using a pick and suction irrigator during dissection. A magnified model was useful for educating medical students. This prototype 3D model made using selective laser sintering serves as a good educational tool for middle ear surgery.


Genome-Wide Association Study Identifies Pharmacogenomic Variants Associated With Metformin Glycemic Response in African American Patients With Type 2 Diabetes.
Metformin is the most common treatment for type 2 diabetes (T2D). However, there have been no pharmacogenomic studies for T2D in which a population of color was used in the discovery analysis. This study sought to identify genomic variants associated with metformin response in African American patients with diabetes. Patients in the discovery set were adult, African American participants from the Diabetes Multi-omic Investigation of Drug Response (DIAMOND), a cohort study of patients with T2D from a health system serving southeast Michigan. DIAMOND participants had genome-wide genotype data and longitudinal electronic records of laboratory results and medication fills. The genome-wide discovery analysis identified polymorphisms correlated to changes in glycated hemoglobin (HbA1c) levels among individuals on metformin monotherapy. Lead associations were assessed for replication in an independent cohort of African American participants from Kaiser Permanente Northern California (KPNC) and in European American participants from DIAMOND. The discovery set consisted of 447 African American participants, whereas the replication sets included 353 African American KPNC participants and 466 European American DIAMOND participants. The primary analysis identified a variant, rs143276236, in the gene ARFGEF3, which met the threshold for genome-wide significance, replicated in KPNC African Americans, and was still significant in the meta-analysis (P = 1.17 × 10-9). None of the significant discovery variants replicated in European Americans DIAMOND participants. We identified a novel and biologically plausible genetic variant associated with a change in HbA1c levels among African American patients on metformin monotherapy. These results highlight the importance of diversity in pharmacogenomic studies.


Diagnostic sensitivity of motor nerve conduction studies in ulnar neuropathy at the elbow.
Seventy-six patients with ulnar neuropathy at the elbow were divided into 3 classes (Grades I, II, and III) according to their clinical features and the maximal motor nerve conduction velocity (MCV), and the amplitude ratios at the across-elbow segment were retrospectively analyzed. To determine the criteria for abnormality, a control study was conducted on 150 healthy volunteers ranging in age from 20 to 89 years (6 age groups). The normal value for MCV could be set for two age groups: those under 60 and those over 60 years old. The 95% confidence limit was 54m/s for the former and 50m/s for the latter. There was no statistically significant difference in the amplitude ratio among the age groups. The confidence limit was set uniformly at 0.82 (above elbow/below elbow). An abnormality in either MCV or the amplitude ratio was found in 66.7% of Grade I (recent and mild symptoms), 89.7% of Grade II (persistent symptoms), and 100% of Grade III cases (marked intrinsic muscle atrophy). Evaluation using the combination of MCV and the amplitude ratio, considering the age-related normal value, appeared to be useful in establishing a differential diagnosis of ulnar neuropathy at the elbow.


A novel functional electrical stimulation-control system for restoring motor function of post-stroke hemiplegic patients.
Hemiparesis is one of the most common consequences of stroke. Advanced rehabilitation techniques are essential for restoring motor function in hemiplegic patients. Functional electrical stimulation applied to the affected limb based on myoelectric signal from the unaffected limb is a promising therapy for hemiplegia. In this study, we developed a prototype system for evaluating this novel functional electrical stimulation-control strategy. Based on surface electromyography and a vector machine model, a self-administered, multi-movement, force-modulation functional electrical stimulation-prototype system for hemiplegia was implemented. This paper discusses the hardware design, the algorithm of the system, and key points of the self-oscillation-prone system. The experimental results demonstrate the feasibility of the prototype system for further clinical trials, which is being conducted to evaluate the efficacy of the proposed rehabilitation technique.


A novel synthetic 1,3-phenyl bis-thiourea compound targets microtubule polymerization to cause cancer cell death.
Microtubules are essential cytoskeletal components with a central role in mitosis and have been particularly useful as a cancer chemotherapy target. We synthesized a small molecule derivative of a symmetrical 1,3-phenyl bis-thiourea, (1,1'-[1,3-phenylene]bis[3-(3,5-dimethylphenyl)thiourea], named "41J"), and identified a potent effect of the compound on cancer cell survival. 41J is cytotoxic to multiple cancer cell lines at nanomolar concentrations. Cell death occurred by apoptosis and was preceded by mitotic arrest in prometaphase. Prometaphase arrest induced by 41J treatment was accompanied by dissociation of cyclin B1 levels from the apparent mitotic stage and by major spindle abnormalities. Polymerization of purified tubulin in vitro was directly inhibited by 41J, suggesting that the compound works by directly interfering with microtubule function. Compound 41J arrested the growth of glioblastoma multiforme xenografts in nude mice at doses that were well-tolerated, demonstrating a relatively specific antitumor effect. Importantly, 41J overcame drug resistance due to β-tubulin mutation and P-glycoprotein overexpression. Compound 41J may serve as a useful new lead compound for anticancer therapy development.


Association of apolipoprotein E epsilon2 with white matter disease but not with microbleeds.
Apolipoprotein E (apoE) alleles (epsilon2 and epsilon4) are associated with cerebral amyloid angiopathy, in which white matter disease and microbleeds are prominent features. The role of apoE in patients with microbleeds or white matter disease but no evidence of cerebral amyloid angiopathy has not been elucidated. We studied apoE alleles in relation to white matter disease and microbleeds in patients with transient ischemic attack or ischemic stroke. We obtained brain MRI scans and apoE genotypes in 334 transient ischemic attack or ischemic stroke patients. Microbleeds were scored on a gradient echo MRI and white matter disease was examined on fluid attenuated inversion recovery MRI using a semiquantitative rating scale. Patients with moderate to severe white matter disease more frequently carried apoE epsilon2 alleles (25.2% versus 11.3%, P=0.001), but not apoE epsilon4 (26.6% in apoE epsilon4 carriers versus 25.9%; P=0.98). Adjustment for traditional risk factors did not modify this relationship (odds ratio, 2.9; 95% confidence interval, 1.5 to 5.3). There was no association between the presence of microbleeds and the apoE epsilon4 or apoE epsilon2 alleles. ApoE alleles do not exert a major influence on the development of microbleeds, but apoE epsilon2 may be associated with development of moderate to severe white matter disease in transient ischemic attack and stroke patients.


Visualization of centrioles and basal bodies by fluorescent staining with nonimmune rabbit sera.
Several sera from nonimmunized rabbits have been found which stain centrioles and basal bodies by indirect immunofluorescence in a wide variety of cell types. So far, approximately 10% of the rabbit sera that we have examined gave strong positive staining of centrioles and basal bodies. Cytoplasmic networks, mitotic spindles, and ciliary axonemes, however, remain unstained. This specific fluorescent staining of centrioles and basal bodies could not be abolished by absorption of sera with purified brain tubulin. This technique is superior to previous methods for the visualization of basal bodies and centrioles at the light microscopic level and should be useful for rapid and convenient detection of these organelles in large populations of cells.


Ranacyclins, a new family of short cyclic antimicrobial peptides: biological function, mode of action, and parameters involved in target specificity.
We report on two new cyclic 17-residue peptides that we named ranacyclins E and T, the first isolated from Rana esculenta frog skin secretions and the second discovered by screening a cDNA library from Rana temporaria. Ranacyclins have a loop region that is homologous with that of an 18-mer peptide, pLR, isolated from the skin of the Northern Leopard frog, Rana pipiens, with no reported antimicrobial activity. Here we show that ranacyclins and pLR have antimicrobial and antifungal activity. However, despite the high structural similarity, they differ in their spectrum of activity. The data reveal that ranacyclins and pLR have several properties that differentiate them from most known antimicrobial peptides. These include the following: (i) they adopt a significant portion of random coil structure in the membrane as revealed by ATR-FTIR and CD spectroscopy (50% for ranacyclin T and 70% for both ranacyclin E and pLR); (ii) they bind similarly to both zwitterionic and negatively charged membranes as revealed by using tryptophan fluorescence and surface plasmon resonance (SPR; BIAcore biosensor); (iii) they insert into the hydrophobic core of the membrane and presumably form transmembrane pores without damage to the bacterial wall, as revealed by SPR, ATR-FTIR, and transmission electron microscopy (TEM); and (iv) despite being highly and equally active in permeating bacterial spheroplasts and negatively charged membranes, they differ significantly in their potencies against target cells. Furthermore, a significant fraction of a given secondary structure is not prerequisite for membrane permeation and antimicrobial activity. However, increasing the fraction of a secondary structure and reducing peptide assembly in the membrane make it easier for the peptide to diffuse through the cell wall, which is different for each microorganism, into the cytoplasmic membrane.