Endoscopic endonasal resection of anterior cranial base meningiomas.
The endonasal route may be feasible for the resection of anterior cranial base tumors that abut the paranasal sinuses. There are several case reports and mixed case series discussing this approach. Other than pituitary adenomas, there is a lack of literature describing the outcomes of endonasal approaches for single-tumor types such as meningiomas. In this study, we describe our current endoscopic endonasal technique and demonstrate the feasibility of using it to access anterior cranial base meningiomas from the back wall of the frontal sinus to the sella and laterally to the region of the midorbit. After this discussion, which includes key technical considerations and nuances, we address safety and efficacy by reporting the outcomes of our early experience with endoscopic endonasal resection of 35 anterior cranial base meningiomas. A total of 35 patients underwent endoscopic endonasal resection of anterior cranial base meningiomas from October 2002 to October 2005. Degree of resection by tumor location was as follows: 10 of the 12 (83%) patients with olfactory groove meningiomas planned for complete resection underwent gross total (seven of 12) or near-total (>95%) (three of 12) resection (67% of all 15 olfactory tumors); 12 of 13 patients (92%) with tuberculum meningiomas underwent gross (11 of 13) or near (>95%) (one of 13) total resection; five patients diagnosed with petroclival meningiomas had successful resection of the parasellar portion of their tumors with relief of visual symptoms (no patients underwent complete resection of their tumors via the endoscopic, endonasal approach); two giant petroclival meningiomas were debulked with 63 and 89% resection, respectively.All patients experienced resolution or improvement of visual symptoms. No patient experienced permanent worsening of vision after surgery. Only one (3%) patient without preoperative endocrine dysfunction experienced a new, permanent pituitary deficit, diabetes insipidus. One (3%) patient experienced a new neurological deficit after experiencing a hemorrhage 3 weeks after surgery. The postoperative cerebrospinal fluid leak rate was 40% (14 of 35) and varied by tumor location. All leaks were resolved without craniotomy. There were no cases of bacterial meningitis. One patient developed a superinfection of a sterile granuloma from a sinusitis 2 years after surgery. There were two cases of deep venous thrombosis and one pulmonary embolus. There were no operative or perioperative deaths. Cranial base meningiomas can be successfully managed via a purely endoscopic endonasal approach with acceptable morbidity and mortality rates. The extent of resection is guided by patient factors and symptoms, not by approach. This series had a high cerebrospinal fluid leak rate. With the evolution of new reconstruction techniques, these rates have been substantially reduced.


Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.
To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.


Alterations in endogenous circadian rhythm of core temperature in senescent Fischer 344 rats.
We assessed whether alterations in endogenous circadian rhythm of core temperature (CRT) in aging rats are associated with chronological time or with a biological marker of senescence, i.e., spontaneous rapid body weight loss. CRT was measured in male Fischer 344 (F344) rats beginning at age 689 days and then continuously until death. Young rats were also monitored. The rats were housed under constant dim red light at 24-26 degrees C, and core temperature was recorded every 10 min via biotelemetry. The CRT amplitude of the body weight-stable (presenescent) old rats was significantly less than that of young rats at all analysis periods. At the onset of spontaneous rapid weight loss (senescence), all measures of endogenous CRT differed significantly from those in the presenescent period. The suprachiasmatic nucleus (a circadian pacemaker) of the senescent rats maintained its light responsiveness as determined by an increase in c-fos expression after a brief light exposure. These data demonstrate that some characteristics of the CRT are altered slowly with chronological aging, whereas others occur rapidly with the onset of senescence.


Spatiotemporal Industrial Activity Model for Estimating the Intensity of Oil and Gas Operations in Colorado.
Oil and gas (O&G) production in the United States has increased in the last 15 years, and operations, which are trending toward large multiwell pads, release hazardous air pollutants. Health studies have relied on proximity to O&G wells as an exposure metric, typically using an inverse distance-weighting (IDW) approach. Because O&G emissions are dependent on multiple factors, a dynamic model is needed to describe the variability in air pollution emissions over space and time. We used information on Colorado O&G activities, production volumes, and air pollutant emission rates from two Colorado basins to create a spatiotemporal industrial activity model to develop an intensity-adjusted IDW well-count metric. The Spearman correlation coefficient between this metric and measured pollutant concentrations was 0.74. We applied our model to households in Greeley, Colorado, which is in the middle of the densely developed Denver-Julesburg basin. Our intensity-adjusted IDW increased the unadjusted IDW dynamic range by a factor of 19 and distinguishes high-intensity events, such as hydraulic fracturing and flowback, from lower-intensity events, such as production at single-well pads. As the frequency of multiwell pads increases, it will become increasingly important to characterize the range of intensities at O&G sites when conducting epidemiological studies.


An 18-Month-Old Child with Infantile Pompe Disease: Oral Signs.
We aim to create an information platform by contributing orodental findings of Pompe disease to literature. An 18-month-old male patient with Pompe disease was referred to our clinic due to swelling of the gums. In first dental examination, a nonfluctuant, normal gingiva colored swelling at the right anterior region of maxilla was detected. His parents were recommended to perform finger massage to the region. Six months later, 51, 52, 62, and 74 numbered teeth had erupted, there was a fusion between 51 and 52 numbered teeth, 84 numbered tooth was seen to be erupted, and a swelling at the site of this tooth, similar to previous one, was present. Finger massage was recommended for this area as well, and the swelling was found to have decreased at the follow-up, one week later. Tooth eruption problems and developmental dental abnormalities should be included in the signs for Pompe disease.


Modeling high-resolution broadband discourse in complex adaptive systems.
Numerous researchers and practitioners have turned to complexity science to better understand human systems. Simulation can be used to observe how the microlevel actions of many human agents create emergent structures and novel behavior in complex adaptive systems. In such simulations, communication between human agents is often modeled simply as message passing, where a message or text may transfer data, trigger action, or inform context. Human communication involves more than the transmission of texts and messages, however. Such a perspective is likely to limit the effectiveness and insight that we can gain from simulations, and complexity science itself. In this paper, we propose a model of how close analysis of discursive processes between individuals (high-resolution), which occur simultaneously across a human system (broadband), dynamically evolve. We propose six different processes that describe how evolutionary variation can occur in texts-recontextualization, pruning, chunking, merging, appropriation, and mutation. These process models can facilitate the simulation of high-resolution, broadband discourse processes, and can aid in the analysis of data from such processes. Examples are used to illustrate each process. We make the tentative suggestion that discourse may evolve to the "edge of chaos." We conclude with a discussion concerning how high-resolution, broadband discourse data could actually be collected.


Microstructural Organization of Distributed White Matter Associated With Fine Motor Control in US Service Members With Mild Traumatic Brain Injury.
Mild traumatic brain injury (mTBI) is the most common form of brain injury. While most individuals recover from mTBI, roughly 20% experience persistent symptoms, potentially including reduced fine motor control. We investigate relationships between regional white matter organization and subcortical volumes associated with performance on the Grooved Pegboard (GPB) test in a large cohort of military Service Members and Veterans (SM&Vs) with and without a history of mTBI(s). Participants were enrolled in the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium. SM&Vs with a history of mTBI(s) (n = 847) and without mTBI (n = 190) underwent magnetic resonance imaging and the GPB test. We first examined between-group differences in GPB completion time. We then investigated associations between GPB performance and regional structural imaging measures (tractwise diffusivity, subcortical volumes, and cortical thickness) in SM&Vs with a history of mTBI(s). Lastly, we explored whether mTBI history moderated associations between imaging measures and GPB performance. SM&Vs with mTBI(s) performed worse than those without mTBI(s) on the non-dominant hand GPB test at a trend level (p < 0.1). Higher fractional anisotropy (FA) of tracts including the posterior corona radiata, superior longitudinal fasciculus, and uncinate fasciculus were associated with better GPB performance in the dominant hand in SM&Vs with mTBI(s). These findings support that the organization of several white matter bundles are associated with fine motor performance in SM&Vs. We did not observe that mTBI history moderated associations between regional FA and GPB test completion time, suggesting that chronic mTBI may not significantly influence fine motor control.


Potential Role of Bioactive Proteins and Peptides Derived from Legumes towards Metabolic Syndrome.
Legumes have been widely consumed and used to isolate bioactive compounds, mainly proteins. The aim of this study was to review the beneficial actions of different legumes proteins and peptides updating the main findings that correlate legumes consumption and the effects on non-transmissible chronic diseases, specifically metabolic syndrome. An exhaustive revision of five relevant bioactivities (antioxidant, anti-inflammatory, antihypertensive, hypocholesterolemic -all of them linked to metabolic syndrome- and antitumoral) of proteins and peptides from legumes focused on isolation and purification, enzymatic hydrolysis and in vitro gastrointestinal digestion was carried out. The promising potential of bioactive hydrolysates and peptides from pulses has been demonstrated by in vitro tests. However, only a few studies validated these biological activities using animal models. No clinical trials have been carried out yet; so further research is required to elucidate their effective health implications.


Assessing teacher education and professional development needs for the implementation of integrated approaches to STEM education.
Given the growing interest in, and relevance of, integrated approaches to STEM (science, technology, engineering, and mathematics) education, there is an urgent desire to understand the challenges and obstacles to developing and implementing integrated STEM curricula and instruction. In this article, we present phase 1 of a two-phase needs assessment study to identify challenges and needs of promoting integrated approaches in STEM education. Utilizing a key informant approach, 22 K-12 teachers and four administrators selected as potential leaders in STEM education in an unidentified state on the East Coast of the USA were interviewed. Participants were asked to identify challenges and perceived supports to conduct integrated STEM education. Questions were open-ended in order to inform a larger, state-wide questionnaire study in phase 2 to be reported subsequently and were qualitatively coded. Several distinctive themes were identified as described by teacher participants when discussing challenges and obstacles of implementing integrated STEM education, as well as supports that would be most helpful in overcoming them. Participants also provided specific suggestions for teacher education needed to support integrated STEM education. Preliminary findings suggest that many teachers are interested in integrated approaches to STEM, but do not believe they are well prepared to implement them. Teachers and administrators also suggest that adequate preparation in integrated STEM would entail a considerable rethinking and redesigning of pre-service courses and in-service workshops. Findings provide a starting point for better understanding teacher needs in integrated STEM and a springboard for further study.


Transition-state analogue gamma-secretase inhibitors stabilize a 900 kDa presenilin/nicastrin complex.
Gamma-secretase mediates the final step, which generates Alzheimer's disease Abeta amyloid protein, by cleaving the transmembrane domain of the amyloid-beta protein precursor. Four gene products, presenilin, nicastrin, APH-1, and PEN-2, are required for gamma-secretase activity that is contained within a high molecular mass complex. To further characterize gamma-secretase, we probed membranes from human neuroblastoma SH-SY5Y cells with gamma-secretase inhibitor biotin derivatives of L-685,458, pepstatin A, and the difluoro alcohol 1-Bt. These inhibitor derivatives bound and precipitated PS1 fragments from membrane CHAPSO extracts. Analysis of PS1 complexes by blue native gel electrophoresis and western blotting indicated that the CHAPSO extracts contained complexes of approximately 900, 500, and 400 kDa. With this technique, derivatives of the three inhibitors were detected only in association with the 900 kDa species. Size-exclusion chromatography showed that 13% of PS1 immunoreactivity extracted with CHAPSO was comprised within a >or=900 kDa species with the remaining eluting in fractions of 669-250 kDa but that most enzymatic activity was associated with the 900 kDa fractions. After treatment with L-685,458 inhibitor, 49% PS1 immunoreactivity was eluted in the 900 kDa fraction, supporting evidence that the inhibitor stabilized this complex. Subcellular fractionation of SH-SY5Y cells indicated that the 900 kDa complex was formed as PS1 and NCT matured through the secretory pathway and that enzymatic activity correlated with complex maturation. From these observations, we propose a model for the structure of active gamma-secretase that would consist of dimerization of 400-500 kDa subunits and be consistent with the apparent molecular mass of the complex.


The formation and structure of Olympic gels.
Different methods for creating Olympic gels are analyzed using computer simulations. First ideal reference samples are obtained from freely interpenetrating semi-dilute solutions and melts of cyclic polymers. The distribution of pairwise concatenations per cyclic molecule is given by a Poisson-distribution and can be used to describe the elastic structure of the gels. Several batches of linear chains decorated with different selectively binding groups at their ends are mixed in the "DNA Origami" technique and network formation is realized. While the formation of cyclic molecules follows mean field predictions below overlap of the precursor molecules, an enhanced ring formation above overlap is found that is not explained by mean field arguments. The "progressive construction" method allows to create Olympic gels with a single reaction step from a concentrated mixture of large compressed rings with a low weight fraction of short chains that are below overlap concentration. This method, however, is limited by the difficulty to obtain a sufficiently high degree of polymerization of the large rings.


[Influence of storage period and grading standards on quality of Prunella vulgaris].
To investigate the influence of storage period and grading standards on the quality of Prunella vulgaris in order to provide a theoretical basis for standardized cultivation. The spices of P. vulgaris in different storage period (including current year, first-year and second-year) were collected from Lujiang base in Anhui Province. The samples were randomized, with the methods of morphologic characteristics and commercial size on P. vulgaris, the samples were graded into three grades; according to the methods from the Pharmacopoeia of the People's Republic of China, water-soluble extracts, ethanol-soluble extracts, total ash and acid insoluble ash were measured, respectively, utilizing the UV spectrophotometry to detection the contents of total flavonoids and polysaccharides, the levels of ursolic acid, oleanolic acid and rosmarinic acid were adopted by HPLC. The total ash and acid insoluble ash of P. vulgaris showed significantly increase during prolonged storage; however, the content of water-soluble extracts, ethanol-soluble, total flavonoids, polysaccharides, ursolic acid, oleanolic acid,rosmarinic acid showed significantly decrease during prolonged storage. The spica of P. vulgaris exhibited no rules differences between the quality and grading standards, The second-degree belongs to high content of total flavonoids; the high content of polysaccharides was first-degree; the total ash and acid insoluble ash of spicas exhibited gradually decreased from first-degree to third-grade, and the content of water-soluble extracts, ethanol-soluble extracts,ursolic acid,oleanolic acid, rosmarinic acid showed gradually increased from first-degree to third-grade. The current year was a suitable storage time of spicas from P. vulgaris could be selected; and the main bioactive components highest level of P. vulgaris spicas was third-degree, second-grade next, first-degree minimum.


PhotoTag: Photoactivatable Fluorophores for Protein Labeling.
We report experimental studies on the development of photoactivatable fluorophores for rapid, light-induced synthesis of protein conjugates. Proof-of-concept studies demonstrated that electronic excitation of photoactivatable BODIPY-ArN3 (1) in the presence of different proteins leads to efficient labeling in less than 10 min. After synthesis and isolation of the fluorescently tagged protein, photochemical conversion yields using human serum albumin and onartuzumab were 47 ± 7% and 42 ± 5%, respectively.


Acetone precipitation--an improved procedure for the isolation of soybean agglutinin.
Isolation of soybean agglutinin (SBA) by the salt fractionation involves excessive amounts of (NH4)2SO4. We have found that SBA could be fractionally precipitated from an aqueous extract by adding acetone (40% final concentration). It is stable under these conditions for minimum 2 h at 5 degrees C and 25 degrees C. Incorporating these results, an improved procedure for the isolation of SBA has been developed. The SBA isolated by this method is obtained in better yield, has 6000 HU/mg protein and is identical to that isolated by the (NH4)2SO4 method as ascertained by chromatographic and electrophoretic comparisons and hapten inhibition assays.


Adrenocortical suppression in the dog given a single intramuscular dose of prednisone or triamcinolone acetonide.
Adrenocortical function was assessed in dogs given a single intramuscular dose of either prednisone or triamcinolone acetonide (TCA; or saline solution to controls) to determine the duration of adrenocortical suppression caused by 2 commonly used glucocorticoids. The glucocorticoids were administered at recommended therapeutic doses; therefore, dogs given prednisone received a greater amount of glucocorticoid activity than did in dogs given TCA. Basal and ACTH-stimulated plasma cortisol concentrations, as determined by radioimmunoassay, were obtained once a week. Total intravascular eosinophil concentration and skin responses to intradermally injected histamine phosphate were quantitated. Dogs given TCA showed suppressed basal and ACTH-stimulated plasma cortisol concentrations 1 week after injection; the latter change persisted 2 weeks after injection. Adrenocortical function in 1 of 4 dogs given TCA remained suppressed for 4 weeks. In contrast, prednisone did not significantly alter adrenocortical function. Although intravascular eosinophil concentrations did not vary among groups, skin responses to intradermally injected histamine phosphate were reduced 6 days after prednisone and TCA were given.


Fever prevalence and management among three rural communities in the North West Zone, Somalia.
Between March and August 2008 we undertook 2 cross-sectional surveys among 1375 residents of 3 randomly selected villages in the district of Gebiley in the North-West Zone, Somalia. We investigated for the presence of malaria infection and the period prevalence of self-reported fever 14 days prior to both surveys. All blood samples examined were negative for both species of Plasmodium. The period prevalence of 14-day fevers was 4.8% in March and 0.6% in August; the majority of fevers (84.4%) were associated with other symptoms including cough, running nose and sore throat; 48/64 cases had resolved by the day of interview (mean duration 5.4 days). Only 18 (37.5%) fever cases were managed at a formal health care facility: 7 within 24 hours and 10 within 24-72 hours of onset. None of the fevers were investigated for malaria; they were treated with antibiotics, antipyretics and vitamins.


Developing a method and deriving an uncertainty budget for the internal calibration of dosemeters for radiographic equipment.
Any institution wishing to perform an internal cross calibration of its diagnostic dosemeters should first quantify the uncertainty associated with this to demonstrate that it remains appropriate for the measurements being undertaken.An uncertainty budget for internal cross calibration that covers a range of locally used dosemeters has been derived using the methodology of the International Atomic Energy Agency. The specific internal cross calibration protocol requirements necessary for this uncertainty budget to be valid are discussed.The final quantified uncertainty is 5.31%; this is dominated by the 5% uncertainty associated with the calibration of the reference instrument. The next largest contributions are from differences in temperature and pressure and dosemeter energy dependence.It has been demonstrated that with careful adherence to a well designed internal cross calibration protocol, dosemeters can be calibrated in-house against a calibrated reference dosemeter with very little increase in the associated calibration uncertainty.


Evaluation of systemic antifungal agents in X-irradiated mice.
The effect of X irradiation on the survival time of animals experimentally infected with pathogenic fungi was studied, and the activity of antifungal agents in pre-irradiated hosts was evaluated. A 24-hr preinfection dose of X irradiation decreased the survival time of mice infected with Cryptococcus neoformans and Histoplasma capsulatum to a greater extent than Candida albicans or Blastomyces dermatitidis infections. Exposure to 400 r caused a significant reduction in the variation (S(2)) survival time of C. albicans or H. capsulatum mouse infections. A single 100-mg/kg dose of 5-fluorocytosine or amphotericin B administered within 24 hr postinfection significantly extended the survival time of mice infected with C. albicans. Delayed treatment with amphotericin B was effective against C. neoformans infections. Four 50-mg/kg doses of 5-fluorocytosine were more effective than a single 200-mg/kg dose against C. neoformans infections. A single dose of amphotericin B provided significant protection when administered 48 hr postinfection against B. dermatitidis in preirradiated mice. A single dose of saramycetin 48 hr postinfection was highly effective against H. capsulatum mouse infections. A 100-mg/kg dose of amphotericin B was only effective against this fungal pathogen when administered within 8 hr postinfection. In vivo activity of the antifungal agents studied was detected within 8 to 14 days. The relative in vivo activity of several antifungal agents indicated the importance of considering their individual pharmacological properties for optimum effectiveness. The experimental model used in this study should be useful for the detection and for the preclinical evaluation of new antifungal agents.


Sensorimotor Functional Connectivity: A Neurophysiological Factor Related to BCI Performance.
Brain-Computer Interfaces (BCIs) are systems that allow users to control devices using brain activity alone. However, the ability of participants to command BCIs varies from subject to subject. About 20% of potential users of sensorimotor BCIs do not gain reliable control of the system. The inefficiency to decode user's intentions requires the identification of neurophysiological factors determining "good" and "poor" BCI performers. One of the important neurophysiological aspects in BCI research is that the neuronal oscillations, used to control these systems, show a rich repertoire of spatial sensorimotor interactions. Considering this, we hypothesized that neuronal connectivity in sensorimotor areas would define BCI performance. Analyses for this study were performed on a large dataset of 80 inexperienced participants. They took part in a calibration and an online feedback session recorded on the same day. Undirected functional connectivity was computed over sensorimotor areas by means of the imaginary part of coherency. The results show that post- as well as pre-stimulus connectivity in the calibration recording is significantly correlated to online feedback performance in μ and feedback frequency bands. Importantly, the significance of the correlation between connectivity and BCI feedback accuracy was not due to the signal-to-noise ratio of the oscillations in the corresponding post and pre-stimulus intervals. Thus, this study demonstrates that BCI performance is not only dependent on the amplitude of sensorimotor oscillations as shown previously, but that it also relates to sensorimotor connectivity measured during the preceding training session. The presence of such connectivity between motor and somatosensory systems is likely to facilitate motor imagery, which in turn is associated with the generation of a more pronounced modulation of sensorimotor oscillations (manifested in ERD/ERS) required for the adequate BCI performance. We also discuss strategies for the up-regulation of such connectivity in order to enhance BCI performance.


A skeptical look at viral immune evasion.
In the past several years, many viral gene products have been found to encode proteins which interfere with immune defense mechanisms. Whether these interactions between virus and immune system components are actually evasion mechanisms used during viral infections in their natural hosts remains to be proven. In vitro studies do, however, reveal several tactics which may aid viral replication and dissemination by interfering with components of both the innate and adaptive immune systems. In this manuscript, we discuss the more intensively studied of these putative in vitro evasion tactics and ponder their relevance in in vivo situations.


β-Glucosidases.
β-Glucosidases (18.104.22.168) are found in all domains of living organisms, where they play essential roles in the removal of nonreducing terminal glucosyl residues from saccharides and glycosides. β-Glucosidases function in glycolipid and exogenous glycoside metabolism in animals, defense, cell wall lignification, cell wall β-glucan turnover, phytohormone activation, and release of aromatic compounds in plants, and biomass conversion in microorganisms. These functions lead to many agricultural and industrial applications. β-Glucosidases have been classified into glycoside hydrolase (GH) families GH1, GH3, GH5, GH9, and GH30, based on their amino acid sequences, while other β-glucosidases remain to be classified. The GH1, GH5, and GH30 β-glucosidases fall in GH Clan A, which consists of proteins with (β/α)(8)-barrel structures. In contrast, the active site of GH3 enzymes comprises two domains, while GH9 enzymes have (α/α)(6) barrel structures. The mechanism by which GH1 enzymes recognize and hydrolyze substrates with different specificities remains an area of intense study.


Vanillin formation from ferulic acid in Vanilla planifolia is catalysed by a single enzyme.
Vanillin is a popular and valuable flavour compound. It is the key constituent of the natural vanilla flavour obtained from cured vanilla pods. Here we show that a single hydratase/lyase type enzyme designated vanillin synthase (VpVAN) catalyses direct conversion of ferulic acid and its glucoside into vanillin and its glucoside, respectively. The enzyme shows high sequence similarity to cysteine proteinases and is specific to the substitution pattern at the aromatic ring and does not metabolize caffeic acid and p-coumaric acid as demonstrated by coupled transcription/translation assays. VpVAN localizes to the inner part of the vanilla pod and high transcript levels are found in single cells located a few cell layers from the inner epidermis. Transient expression of VpVAN in tobacco and stable expression in barley in combination with the action of endogenous alcohol dehydrogenases and UDP-glucosyltransferases result in vanillyl alcohol glucoside formation from endogenous ferulic acid. A gene encoding an enzyme showing 71% sequence identity to VpVAN was identified in another vanillin-producing plant species Glechoma hederacea and was also shown to be a vanillin synthase as demonstrated by transient expression in tobacco.


[Correlations between brain SPECT and neuropsychology assessments in mild and moderate stages of Alzheimer's disease].
Thirty-four patients with a probable Alzheimer's Disease (AD) (mild AD = 16; moderate AD = 18) and 12 matched controls were evaluated using semiquantitative SPECT-99mTc-HMPAO and neuropsychological tests (CERAD). Both temporal hypoperfusion (p < 0.01) and memory tests (p < 0.001) made it possible to differentiate the controls from mild AD patients. In these patients, significant correlations (p < 0.05) were also found between: 1) delayed recall test/temporal hypoperfusion, 2) learning memory test/temporoparietal and frontal hypoperfusion and 3) visual constructive praxis/posterior temporal hypoperfusion. In contrast to mild AD, moderate AD patients showed higher temporal (p < 0.01) parietal and frontal (p < 0.05) hypoperfusion along with worsening of praxis (p < 0.001) and memory tests (p < 0.05). SPECT imaging and neuropsychology evaluation can distinguish controls from AD patients with mild an moderate grades of dementia, showing a strong correlation from the early stages of AD.


MicroRNA miR-125b controls melanoma progression by direct regulation of c-Jun protein expression.
A fundamental event in the development and progression of malignant melanoma is the deregulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of tumor progression in melanoma and thus the most important member of the AP-1 transcription factor family for this disease. Interestingly, we revealed that c-Jun expression was regulated on the post-transcriptional level and therefore speculated that miRNAs could be involved in c-Jun regulation. We determined seed sequences for miR-125b and miR-527 in the coding region of c-Jun mRNA that hints at the direct involvement of miRNA-dependent regulation on the protein level. We found that the expression of miR-125b was significantly reduced in malignant melanoma cell lines and tissue samples compared with melanocytes, whereas miR-527 remained unchanged. In further functional experiments, treatment of melanoma cells with pre-miR-125b resulted in strong suppression of cellular proliferation and migration, supporting the role of miR-125b in melanoma. In addition, transfection of pre-miR-125b led to strong downregulation of c-Jun protein but not mRNA expression in melanoma cells. Luciferase assays using reporter plasmids containing the miR-125b seed sequence in the luciferase coding region confirmed the direct interaction with miR-125b. Furthermore, immunoprecipitation of Ago-2 revealed that c-Jun mRNA accumulated in the RNA-induced silencing complex after pre-miR-125b transfection in melanoma cells. In summary, we identified an important role for miR-125b in malignant melanoma. Moreover, we demonstrated post-transcriptional regulation of c-Jun by this miRNA and showed that c-Jun is a main mediator of the effects of miR-125b on melanoma cells.


Increased in vitro tetraploidy in dermal monolayer cultures derived from normals.
Increased in vitro tetraploidy has been considered an in vitro expression of some cancer-prone genes in dermal monolayer cultures. (Danes BS, Alm T, Scand J Gastroenterol 16, 421-427, 1981; Danes BS, Cancer 48, 1596-1601, 1981). Its occurrence was determined in cultures established from skin biopsies from 112 normals (university students and personnel) whose family cancer histories were known to ascertain its relevance to cancer occurrence based on pedigree data. Of the 40 who gave no family cancer history, one showed increased in vitro tetraploidy (1% of the total studied; 2.5% of those without a family cancer history). Of the 72 with one or more first- or second-degree relatives with a family cancer history, 14 showed this alteration (12.5% of the total studied; 19% of those with a family cancer history). Increased in vitro tetraploidy was found in some normals from families with lung, breast, genital system, and gastrointestinal tract cancers. It may prove ultimately to be relevant to include such in vitro information in medical surveillance and cancer management programs.


Signature proteins for the major clades of Cyanobacteria.
The phylogeny and taxonomy of cyanobacteria is currently poorly understood due to paucity of reliable markers for identification and circumscription of its major clades. A combination of phylogenomic and protein signature based approaches was used to characterize the major clades of cyanobacteria. Phylogenetic trees were constructed for 44 cyanobacteria based on 44 conserved proteins. In parallel, Blastp searches were carried out on each ORF in the genomes of Synechococcus WH8102, Synechocystis PCC6803, Nostoc PCC7120, Synechococcus JA-3-3Ab, Prochlorococcus MIT9215 and Prochlor. marinus subsp. marinus CCMP1375 to identify proteins that are specific for various main clades of cyanobacteria. These studies have identified 39 proteins that are specific for all (or most) cyanobacteria and large numbers of proteins for other cyanobacterial clades. The identified signature proteins include: (i) 14 proteins for a deep branching clade (Clade A) of Gloebacter violaceus and two diazotrophic Synechococcus strains (JA-3-3Ab and JA2-3-B'a); (ii) 5 proteins that are present in all other cyanobacteria except those from Clade A; (iii) 60 proteins that are specific for a clade (Clade C) consisting of various marine unicellular cyanobacteria (viz. Synechococcus and Prochlorococcus); (iv) 14 and 19 signature proteins that are specific for the Clade C Synechococcus and Prochlorococcus strains, respectively; (v) 67 proteins that are specific for the Low B/A ecotype Prochlorococcus strains, containing lower ratio of chl b/a2 and adapted to growth at high light intensities; (vi) 65 and 8 proteins that are specific for the Nostocales and Chroococcales orders, respectively; and (vii) 22 and 9 proteins that are uniquely shared by various Nostocales and Oscillatoriales orders, or by these two orders and the Chroococcales, respectively. We also describe 3 conserved indels in flavoprotein, heme oxygenase and protochlorophyllide oxidoreductase proteins that are specific for either Clade C cyanobacteria or for various subclades of Prochlorococcus. Many other conserved indels for cyanobacterial clades have been described recently. These signature proteins and indels provide novel means for circumscription of various cyanobacterial clades in clear molecular terms. Their functional studies should lead to discovery of novel properties that are unique to these groups of cyanobacteria.


[A case of myasthenia gravis with invasive thymoma associated with diffuse panbronchiolitis, alopecia, dysgeusia, cholangitis and myositis].
A 43-year-old man was admitted to our hospital because of diplopia, ptosis, and dysphagia that had begun three years previously. He was diagnosed with myasthenia gravis (MG) and invasive thymoma and treated with corticosteroid, thymectomy, and radiation therapy. Ten years after the thymectomy, computed tomography (CT) showed metastasis of the thymoma in the left lower lobe of the lung. Two years after this recurrence, when the patient was 55, respiratory symptoms such as wheezing, persistent cough, and dyspnea appeared. Chronic sinusitis, diffuse centrilobular opacities on CT, and positivity for HLA-B54 led to a diagnosis of diffuse panbronchiolitis (DPB). Despite treatment with clarithromycin, the respiratory symptoms worsened. The patient developed alopecia and body hair loss at the age of 56 followed by dysgeusia, cholangitis, and myositis with positivity for anti-Kv1.4 antibodies. Although treatment with an increased dose of corticosteroid improved hair loss, dysgeusia, cholangitis, and myositis, he died of progression of DPB and serious respiratory infection at the age of 58. In this case, various autoimmune disorders occurred together with MG as complications of thymoma. Although alopecia, dysgeusia, and myositis are already known as complications of MG associated with thymoma, cholangitis is not well-recognized since there have been few reports suggesting a causal relationship between cholangitis and thymoma. Furthermore, DPB caused by immunodeficiency and respiratory tract hypersensitivity associated with thymoma and HLA-B54, respectively, is the distinctive feature of our case. Neurologists should be aware that various organs can be damaged directly and indirectly by abnormal T cells from thymoma in patients with MG.


Pharmacokinetic Study of Sirolimus-Eluting BioResorbable Vascular Scaffold System for Treatment of De Novo Native Coronary Lesions: A Sub-Study of MeRes-1 Trial.
MeRes100™ (Meril Life Sciences Pvt. Ltd., Vapi, India) is a novel sirolimus-eluting bioresorbable vascular scaffold (BRS). The purpose of this sub-study of MeRes-1 trial is to evaluate the systemic release of sirolimus from MeRes100 BRS implanted for the treatment of de novo native coronary artery lesions. The MeRes-1 is a prospective, multicenter, first-in-human trial of sirolimus-eluting MeRes100 BRS. The pharmacokinetic sub-study was conducted at two Indian sites in 10 patients who were implanted with the MeRes100 BRS loaded with sirolimus at a dose of 1.25 µg/mm2. Venous blood samples were collected at pre-dose and 12-time points after implantation of the scaffold. Sirolimus concentration was successively analyzed using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry method. A total of 12 scaffolds were implanted in 10 patients. Non-compartmental analysis demonstrated time to reach peak concentration of sirolimus between 0.5 h to 3 h after scaffold implantation. The peak concentration (Cmax) was deduced to be 7.47 ± 2.61 ng/mL, AUC was 436.45 ± 171.24 h·ng/mL, and the t½ was observed at 98.59 ± 33.58 h. The clearance was 0.66 ± 0.16 L/h and lower limit of quantification was detectable at 14.1 days. The MeRes-1 pharmacokinetic sub-study confirmed that MeRes100 BRS is safe and tolerable at limited systemic exposure of sirolimus.


Effect of ventromedial and dorsomedial hypothalamic lesions on circadian corticosterone rhythms.
Weanling rats received bilateral electrolytic lesions in the dorsomedial (DMH) or ventromedial (VMH) hypothalamic areas destroying primarily the dorsomedial (DMN) or ventromedial (VMN) hypothalamic nuclei. Sham-operated rats served as controls. Lesions in the VMN and DMN, both of which have previously been shown to disrupt normal diurnal feeding rhythms, were also observed to disrupt normal plasma corticosterone rhythms in the present study. The a.m. values of plasma corticosterone in the DMN-lesioned rats were higher than the sham-operated controls. In the p.m., the values of both VMN- and DMN-lesioned rats were lower than those of the controls but unchanged in comparison to their own a.m. concentrations. This disruption of the normal diurnal plasma corticosterone rhythm persisted for at least 9 post-operative weeks.


Atrial pacing and thallium 201 scintigraphy: combined use for diagnosis of coronary artery disease.
To evaluate the presence of coronary artery disease (CAD), atrial pacing and thallium 201 scintigraphy were performed in 36 patients with stable angina pectoris who were unable to perform an adequate exercise stress test. All patients underwent cardiac catheterization. Nine patients had previously undergone coronary artery bypass surgery. Significant CAD (one or more lesions greater than or equal to 50%) was present in 33 patients. Atrial pacing produced ischemic ST segment depression (greater than or equal to 1 mm) in 18 (55%) patients with CAD, and angina in 20 patients (61%). As the number of vessels with CAD increased, there was no significant change in the sensitivities of pacing-induced angina or ST segment depression for detecting CAD. In the 3 patients without CAD, ST segment depression occurred in 1 patient and angina in none. Thallium 201 scintigraphy demonstrated perfusion defects in 27 (82%) patients with CAD, with fixed defects seen in 13 studies (39%) and reversible defects in 15 (45%). In the 3 patients without CAD, no perfusion defects were seen. The thallium 201 scan successfully predicted the presence of CAD in patients with single-vessel disease but usually underestimated the number of vessels involved in patients with multivessel disease. Combined sensitivity of pacing-induced ST segment depression and an abnormal thallium 201 scan finding for detecting CAD was 91%. The authors conclude that combined atrial pacing and thallium 201 scintigraphy is a useful test for detecting CAD in patients unable to perform an adequate exercise stress test.


In vitro methylation of the BsuRI (5'-GGCC-3') sites in the E2a region of adenovirus type 2 DNA does not affect expression in Xenopus laevis oocytes.
The early region 2a (E2a) of adenovirus type 2 (Ad2) DNA codes for a 72,000-dalton DNA-binding protein and is expressed in the Ad2-transformed hamster cell line HE1 but not in cell lines HE2 and HE3 (H. Esche, J. Virol. 41:1076-1082, 1982; K. Johansson et al., J. Virol. 27:628-639, 1978). An inverse correlation between DNA methylation at the 5'-CCGG-3' sites of the E2a region and of gene expression in these cell lines has been observed (L. Vardimon et al., Nucleic Acids Res. 8:2461-2473, 1980). When the cloned E2a region of Ad2 DNA is methylated in vitro at the 5'-CCGG-3' sites, the gene is not transcribed after being injected into the nuclei of Xenopus laevis oocytes, whereas unmethylated DNA is expressed (L. Vardimon et al., Eur. J. Cell Biol. 25:13-15, 1981; L. Vardimon et al., Proc. Natl. Acad. Sci. U.S.A. 79:1073-1077, 1982). These data demonstrate that DNA methylation is directly involved in the shut-off of transcription. In the present communication we investigated in detail the control region of the gene for the DNA-binding protein in Ad2-transformed cell lines and showed that the first late control region (map coordinate 72 on the viral DNA) of the E2a region is present in its entirety in cell lines HE1, HE2, and HE3. The HaeIII sites (5'-GGCC-3') in the E2a region in all three cell lines were not methylated. When the DNA methyltransferase BsuRI was used, all 5'-GGCC-3' sites in the cloned E2a region of Ad2 DNA were methylated in vitro. It was shown that methylation of these sites did not inhibit the expression of this viral gene in X. laevis oocytes. Thus, for methylation to affect gene expression in the E2a region it has to occur at specific sites (e.g., 5'-CCGG-3') which may be different for other genes.


Understanding and Treating Niemann-Pick Type C Disease: Models Matter.
Biomedical research aims to understand the molecular mechanisms causing human diseases and to develop curative therapies. So far, these goals have been achieved for a small fraction of diseases, limiting factors being the availability, validity, and use of experimental models. Niemann-Pick type C (NPC) is a prime example for a disease that lacks a curative therapy despite substantial breakthroughs. This rare, fatal, and autosomal-recessive disorder is caused by defects in NPC1 or NPC2. These ubiquitously expressed proteins help cholesterol exit from the endosomal-lysosomal system. The dysfunction of either causes an aberrant accumulation of lipids with patients presenting a large range of disease onset, neurovisceral symptoms, and life span. Here, we note general aspects of experimental models, we describe the line-up used for NPC-related research and therapy development, and we provide an outlook on future topics.


Do different case-mix measures affect assessments of provider efficiency? Lessons from the Department of Veterans Affairs.
Although case-mix adjustment is critical for provider profiling, little is known regarding whether different case-mix measures affect assessments of provider efficiency. We examine whether two case-mix measures, Adjusted Clinical Groups (ACGs) and Diagnostic Cost Groups (DCGs), result in different assessments of efficiency across service networks within the Department of Veterans Affairs (VA). Three profiling indicators examine variation in resource use. Although results from the ACGs and DCGs generally agree on which networks have greater or lesser efficiency than average, assessments of individual network efficiency vary depending upon the case-mix measure used. This suggests that caution should be used so that providers are not misclassified based on reported efficiency.


Distinct metabolic profile of primary focal segmental glomerulosclerosis revealed by NMR-based metabolomics.
Primary focal segmental glomerulosclerosis (FSGS) is pathological entity which is characterized by idiopathic steroid-resistant nephrotic syndrome (SRNS) and progression to end-stage renal disease (ESRD) in the majority of affected individuals. Currently, there is no practical noninvasive technique to predict different pathological types of glomerulopathies. In this study, the role of urinary metabolomics in the diagnosis and pathogenesis of FSGS was investigated. NMR-based metabolomics was applied for the urinary metabolic profile in the patients with FSGS (n = 25), membranous nephropathy (MN, n = 24), minimal change disease (MCD, n = 14) and IgA nephropathy (IgAN, n = 26), and healthy controls (CON, n = 35). The acquired data were analyzed using principal component analysis (PCA) followed by orthogonal projections to latent structure discriminant analysis (OPLS-DA). Model validity was verified using permutation tests. FSGS patients were clearly distinguished from healthy controls and other three types of glomerulopathies with good sensitivity and specificity based on their global urinary metabolic profiles. In FSGS patients, urinary levels of glucose, dimethylamine and trimethylamine increased compared with healthy controls, while pyruvate, valine, hippurate, isoleucine, phenylacetylglycine, citrate, tyrosine, 3-methylhistidine and β-hydroxyisovalerate decreased. Additionally, FSGS patients had lower urine N-methylnicotinamide levels compared with other glomerulopathies. NMR-based metabonomic approach is amenable for the noninvasive diagnosis and differential diagnosis of FSGS as well as other glomerulopathies, and it could indicate the possible mechanisms of primary FSGS.


Visual evoked potentials and dietary long chain polyunsaturated fatty acids in preterm infants.
The influence of dietary long chain polyunsaturated fatty acid (LCP) supply, and especially of docosahexaenoic acid (DHA), on evoked potential maturation, was studied in 58 healthy preterm infants using flash visual evoked potentials (VEPs), flash electroretinography (ERG), and brainstem acoustic evoked potentials (BAEPs) at 52 weeks of postconceptional age. At the same time, the fatty acid composition of red blood cell membranes was examined. The infants were fed on breast milk (n = 12), a preterm formula supplemented with LCP (PF-LCP) (n = 21), or a traditional preterm formula (PF) (n = 25). In the breast milk and PF-LCP groups the morphology and latencies of the waves that reflect the visual projecting system were similar; in the PF group the morphology was quite different and the wave latencies were significantly longer. This could mean that the maturation pattern of VEPs in preterm infants who did not receive LCP was slower. Moreover, a higher level of erythrocyte LCP, especially DHA, was found in breast milk and PF-LCP groups compared with the PF group. ERG and BAEP recordings were the same in all three groups. These results suggest that a well balanced LCP supplement in preterm formulas can positively influence the maturation of visual evoked potentials in preterm infants when breast milk is not available.


An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice.
Lipopolysaccharide endotoxin is the only known bacterial product which, when subcutaneously infused into mice in its purified form, can induce obesity and insulin resistance via an inflammation-mediated pathway. Here we show that one endotoxin-producing bacterium isolated from a morbidly obese human's gut induced obesity and insulin resistance in germfree mice. The endotoxin-producing Enterobacter decreased in relative abundance from 35% of the volunteer's gut bacteria to non-detectable, during which time the volunteer lost 51.4 kg of 174.8 kg initial weight and recovered from hyperglycemia and hypertension after 23 weeks on a diet of whole grains, traditional Chinese medicinal foods and prebiotics. A decreased abundance of endotoxin biosynthetic genes in the gut of the volunteer was correlated with a decreased circulating endotoxin load and alleviated inflammation. Mono-association of germfree C57BL/6J mice with strain Enterobacter cloacae B29 isolated from the volunteer's gut induced fully developed obesity and insulin resistance on a high-fat diet but not on normal chow diet, whereas the germfree control mice on a high-fat diet did not exhibit the same disease phenotypes. The Enterobacter-induced obese mice showed increased serum endotoxin load and aggravated inflammatory conditions. The obesity-inducing capacity of this human-derived endotoxin producer in gnotobiotic mice suggests that it may causatively contribute to the development of obesity in its human host.


Where are the breaks in translation from theory to clinical practice (and back) in addressing depression? An empirical graph-theoretic approach.
Research in depression has progressed rapidly over the past four decades. Yet depression rates are not subsiding and treatment success is not improving. We examine the extent to which the gap between science and practice is associated with the level of integration in how depression is considered in research and stakeholder-relevant documents. We used a network-science perspective to analyze similar uses of depression relevant terms in the Google News corpus (approximately 1 billion words) and the Web of Science database (120 000 documents). These analyses yielded consistent pictures of insular modules associated with: (1) patient/providers, (2) academics, and (3) industry. Within academia insular modules associated with psychology, general medical, and psychiatry/neuroscience/biology were also detected. These analyses suggest that the domain of depression is fragmented, and that advancements of relevance to one stakeholder group (academics, industry, or patients) may not translate to the others. We consider potential causes and associated responses to this fragmentation that could help to unify and advance translation from research on depression to the clinic, largely involving harmonizing employed language, bridging conceptual domains, and increasing communication across stakeholder groups.


qnrB, another plasmid-mediated gene for quinolone resistance.
A novel plasmid-mediated quinolone resistance gene, qnrB, has been discovered in a plasmid encoding the CTX-M-15 beta-lactamase from a Klebsiella pneumoniae strain isolated in South India. It has less than 40% amino acid identity with the original qnr (now qnrA) gene or with the recently described qnrS but, like them, codes for a protein belonging to the pentapeptide repeat family. Strains with qnrB demonstrated low-level resistance to all quinolones tested. The gene has been cloned in an expression vector attaching a polyhistidine tag, which facilitated purification to >or=95% homogeneity. As little as 5 pM of QnrB-His6 protected purified DNA gyrase against inhibition by 2 microg/ml (6 microM) ciprofloxacin. With a PCR assay qnrB has been detected in Citrobacter koseri, Enterobacter cloacae, and Escherichia coli isolates from the United States, linked to SHV-12 beta-lactamase and coding for a product differing in five amino acids from the Indian (now QnrB1) variety. The qnrB gene has been found near Orf1005 in some, but not all, plasmids and in association with open reading frames matching known chromosomal genes, suggesting that it too was acquired by plasmids from an as-yet-unknown bacterial source.


High-throughput flow cytometry for drug discovery.
High-throughput flow cytometry exploits a novel many-samples/one-file approach to dramatically speed data acquisition, limit aspirated sample volume to as little as 2 μl/well and produce multisample data sets that facilitate automated analysis of samples in groups as well as individually. It has been successfully applied to both cell- and microsphere-based bioassays in 96- and 384-well formats, to screen tens-of-thousands of compounds and identify novel bioactive structures. High-content multiparametric analysis capabilities have been exploited for assay multiplexing, allowing the assessment of biologic selectivity and specificity to be an integral component of primary screens. These and other advances in the last decade have contributed to the application of flow cytometry as a uniquely powerful tool for probing biologic and chemical diversity and complex systems biology.


CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs.
Emerging resistance to first-line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required to protect existing drugs and enhance treatment efficacy. We report that the piperazine-containing compound ACT-451840 exhibits single-digit nanomolar inhibition of the Plasmodium falciparum asexual blood stages and transmissible gametocyte forms. Genome sequence analyses of in vitro-derived ACT-451840-resistant parasites revealed single nucleotide polymorphisms in pfmdr1, which encodes a digestive vacuole membrane-bound ATP-binding cassette transporter known to alter P. falciparum susceptibility to multiple first-line antimalarials. CRISPR-Cas9 based gene editing confirmed that PfMDR1 point mutations mediated ACT-451840 resistance. Resistant parasites demonstrated increased susceptibility to the clinical drugs lumefantrine, mefloquine, quinine and amodiaquine. Stage V gametocytes harboring Cas9-introduced pfmdr1 mutations also acquired ACT-451840 resistance. These findings reveal that PfMDR1 mutations can impart resistance to compounds active against asexual blood stages and mature gametocytes. Exploiting PfMDR1 resistance mechanisms provides new opportunities for developing disease-relieving and transmission-blocking antimalarials.


Antibacterial and cytotoxic activities of the Syzygium polyanthum leaf extract from Malaysia.
The increasing prevalence of drug resistance eventually leads scientist to discover new drugs that could solve the problem. Since ancient immemorial times, medicinal plants generally known as herbs were widely used in every culture throughout the world. In fact, currently up to 70,000 plant species have been screened for biological activities and about 70% ends up for commercialization. Therefore, this study was aimed to evaluate the potential cytotoxic and antibacterial effect of Syzygium polyanthum leaves which are local Malaysia plants, against 4T1 and MCF-7 mammary carcinoma cells, respectively, and also against bacteria causing mastitis in cows. The cytotoxic effect of hydromethanolic extract of S. polyanthum against 4T1 and MCF-7 mammary carcinoma cells was evaluated using 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The cells were treated with the concentration of extracts ranging from 15.63 µg/mL to 1000 µg/ml for 72 h, and the percentage of cell survivability was determined based on minimum concentration that was able to allow at least 50% growth of cancer cells (IC50) after 72 h. The antibacterial activity was tested against common bacteria causing mastitis in cow. The bacteria were isolated from milk samples. The antibacterial activity of the extract was determined by disk diffusion method and susceptibility test based on minimum inhibitory concentration (MIC). Staphylococcus aureus, Staphylococcus hyicus, and Staphylococcus intermedius were isolated from the milk samples that positive for mastitis. The MIC values range from 7.12 mm to 13.5 mm. The extract exhibits the widest zone of inhibition (13.5±0.20 mm) at 1000 mg/ml of concentrations. The extract relatively has low cytotoxicity effect against 4T1 and MCF-7 cells with IC50 values ranging from 672.57±59.42 and 126.05±50.89 µg/ml, respectively. S. polyanthum exerts weak antibacterial activity and cytotoxic effect to mammary carcinoma cells. The extract does not toxic to cells. However, further study is recommended, especially, this plant should be tested for in vivo.


Treatment of acute exacerbations with non-invasive ventilation in chronic hypercapnic COPD patients with pulmonary hypertension.
Chronic Obstructive Pulmonary Disease (COPD) is a slowly progressive airways disorder characterized by not fully reversible airflow obstruction, often presenting exacerbations of respiratory symptoms requiring hospitalization. Non-Invasive Ventilation (NIV) has been shown to be an effective adjunct to standard medical therapy in the treatment of acute respiratory failure. Secondary pulmonary hypertension leads to a rapid progression of the disease. To evaluate the effect of NIV treatment in patients with acute exacerbation of COPD, with or without respiratory acidosis, and its effect in patients with pulmonary hypertension. We enrolled 61 consecutive subjects (M 41; F 20) with COPD admitted to our respiratory ward for acute respiratory exacerbation. Patients were divided into two groups on the basis of arterial pH (group A: 26 individuals with pH <7.35; group B: 35 with pH > or =7.35) and treated with optimal medical therapy (oxygen-therapy, systemic corticosteroids, bronchodilators, antibiotics) and NIV. Moreover, we evaluated functional autonomy thought Six Minute Walking Test (6 mWT), and pulmonary arterial pressure (by transthoracic echocardiography). In group A NIV treatment was associated to a total regression of uncompensated respiratory acidosis (pH 7.36 vs. 7.29). In both groups we observed a significant reduction of PaCO2 (group A: 77.14 +/- 10.4 vs. 45.1 +/- 2.8 mmHg; group B: 70.1 vs. 44 +/- 3.9 mmHg) and an improvement in PaO2 (group A: 51.2 +/- 10.3 vs 84.2 mmHg; group B: 59 +/- vs. 87 +/- 3.3 mmHg). Total average duration of NIV administration was longer in Group A than in Group B (81.14 hours vs 55.83 hours). At the end of NIV treatment, we observed improvement in the autonomy of walking (175.1 meters vs 118.4 meters) in both groups. Patients with severe pulmonary hypertension (PASP > or =55 mmHg) showed a lower reduction of PaCO2 (47.8 vs. 43.7 mmHg) and a minor improvement of arterial pH (7.37 vs. 7.41) compared to patients with a lower value of pulmonary hypertension. In this study we showed that NIV is useful in patients with or without uncompensated respiratory acidosis, through the improvement of symptoms, blood gases parameters, and walking autonomy. Patients with severe pulmonary hypertension are associated with poorer response to NIV treatment.


Quantification of gray/white matter in neonates and adults.
Quantitation of gray/white matter is important in evaluation of cerebral blood flow, atrophy, and development of the brain. First-order statistical analysis of neonatal computed tomographic (CT) images revealed that there was only a 6 Hounsfield unit (H) difference between gray and white matter compared with the observed 3 H for the standard deviation over the field of a skull water phantom. Scene segmentation methods based on first-order statistics proved unsuccessful in separating gray and white matter. A new regional clustering algorithm based on local textural properties was developed for separation of these structures.


[Fusion of Bacillus subtilis and Bacillus licheniformis protoplasts. Interspecies recombination resulting from protoplast fusion].
Recombinants between B. subtilis and B. licheniformis were prepared by fusion of the bacterial protoplasts. Genetically marked strains SB25 trp C hisH and 168 ade-met-leu- of B. subtilis and 1001 ura-thr- and 1001 met- of B. licheniformis were used as the parent strains. The recombinants were selected with the indirect method followed by analysis of their nutrient requirements and cultural and morphological features. All the hybrids acquired the specific properties of B. subtilis. Apparently, their formation was based on the whole chromosome of B. subtilis and recombination of separate fragments of B. licheniformis with it. Hybrids with prototrophic properties with respect to one, two or three markers of the initial strains were detected independent of the genotype of the B. subtilis parent strains. Moreover, the protoplast fusion resulted in formation of hybrids which were prototrophic with respect to the amino acid markers of B. subtilis and deficient with respect to homoserine and thiamine or only thiamine, whereas the initial strains were not auxotrophic with respect to homoserine and thiamine. Thi-Hom- and a number of the prototrophic recombinants were characterized by the capacity for increased synthesis of riboflavin lacking in the initial cultures. Homologous and heterologous transformation appeared to be possible in the recombinants of the Thi-Hom- phenotype, while transformation of the initial strain SB25 by the intergenocytic markers was possible in reciprocal crossings. It is concluded that contrary to transformation of isolated DNA, protoplast fusion may result in formation of interspecies recombinants of B. subtilis and B. licheniformis with respect to different operones of amino acid synthesis.


Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNα antibody, in systemic lupus erythematosus.
Type I interferons are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Type I interferon-inducible mRNAs are widely and concordantly overexpressed in the periphery and involved tissues of a subset of SLE patients, and provide utility as pharmacodynamic biomarkers to aid dose selection, as well as potential indicators of patients who might respond favorably to anti-IFNα therapy in SLE. We implemented a three-tiered approach to identify a panel of type I interferon-inducible mRNAs to be used as potential pharmacodynamic biomarkers to aid dose selection in clinical trials of sifalimumab, an anti-IFNα monoclonal antibody under development for the treatment of SLE. In a single-dose escalation phase 1 trial, we observed a sifalimumab-specific and dose-dependent inhibition of the overexpression of type I interferon-inducible mRNAs in the blood of treated subjects. Inhibition of expression of type I interferon-inducible mRNAs and proteins was also observed in skin lesions of SLE subjects from the same trial. Inhibiting IFNα resulted in a profound downstream effect in these SLE subjects that included suppression of mRNAs of B-cell activating factor belonging to the TNF family and the signaling pathways of TNFα, IL-10, IL-1β, and granulocyte-macrophage colony-stimulating factor in both the periphery and skin lesions. A scoring method based on the expression of type I interferon-inducible mRNAs partitioned SLE patients into two distinct subpopulations, which suggests the possibility of using these type I interferon-inducible genes as predictive biomarkers to identify SLE patients who might respond more favorably to anti-type I interferon therapy.


A formative research-guided educational intervention to improve the knowledge and attitudes of seniors towards influenza and pneumococcal vaccinations.
Adult influenza and pneumococcal vaccination rates in Singapore are low, and factors influencing knowledge and attitudes of seniors towards influenza, pneumonia and their respective vaccines are not well-known. Our study aims to understand the barriers and facilitators towards getting influenza and pneumococcal vaccinations among seniors in Singapore, and subsequently inform the conduct of a relevant community-based educational intervention, as well as evaluate the intervention outcomes. We performed a mixed methods study with two components: Firstly, formative research was conducted among community-dwelling seniors, using focus group discussions (FGDs), to understand their knowledge and attitudes towards influenza, pneumonia and their respective vaccines. Next, a quantitative study was conducted to evaluate knowledge of seniors and the effectiveness of an educational intervention. Four FGDs were organised with 32 participants, who were predominantly female, of lower educational background, and residing in government rental flats. Participants had varying levels of knowledge and many misconceptions about influenza, pneumonia and their respective vaccinations, with concerns about side effects and vaccine effectiveness. The formative research results were used to inform a community-based educational intervention for seniors. Our subsequent evaluation included 604 elderly participants, mainly from lower educational and socio-economic strata, who initially demonstrated poor knowledge scores (median score 5 out of 9, IQR 4-5). Following our intervention, median knowledge score improved to 7 (IQR 6-8) (p < .0001). Significant improvements in knowledge scores were observed across genders, age strata, education levels, and housing types. Our formative research identified knowledge gaps among community-dwelling seniors which affected their attitudes towards vaccination uptake. Key findings were taken into consideration when implementing the educational intervention. Our community-based intervention was effective in improving knowledge and attitudes, and could be used as a cue to action for short-term behaviour changes.


On the spatial foundations of the conceptual system and its enrichment.
A theory of how concept formation begins is presented that accounts for conceptual activity in the first year of life, shows how increasing conceptual complexity comes about, and predicts the order in which new types of information accrue to the conceptual system. In a compromise between nativist and empiricist views, it offers a single domain-general mechanism that redescribes attended spatiotemporal information into an iconic form. The outputs of this mechanism consist of types of spatial information that we know infants attend to in the first months of life. These primitives form the initial basis of concept formation, allow explicit preverbal thought, such as recall, inferences, and simple mental problem solving, and support early language learning. The theory details how spatial concepts become associated with bodily feelings of force and trying. It also explains why concepts of emotions, sensory concepts such as color, and theory of mind concepts are necessarily later acquisitions because they lack contact with spatial descriptions to interpret unstructured internal experiences. Finally, commonalities between the concepts of preverbal infants and nonhuman primates are discussed.


A role for the MAP kinase gene MKC1 in cell wall construction and morphological transitions in Candida albicans.
The Candida albicans MKC1 gene encodes a mitogen-activated protein (MAP) kinase, which has been cloned by complementation of the lytic phenotype associated with Saccharomyces cerevisiae slt2 (mpk1) mutants. In this work, the physiological role of this MAP kinase in the pathogenic fungus C. albicans was characterized and a role for MKC1 in the biogenesis of the cell wall suggested based on the following criteria. First, C. albicans mkc1 delta/mkc1 delta strains displayed alterations in their cell surfaces under specific conditions as evidenced by scanning electron microscopy. Second, an increase in specific cell wall epitopes (O-glycosylated mannoprotein) was shown by confocal microscopy in mkc1 delta/mkc1 delta mutants. Third, the sensitivity to antifungals which inhibit (1,3)-beta-glucan and chitin synthesis was increased in these mutants. In addition, evidence for a role for the MKC1 gene in morphological transitions in C. albicans is presented based on the impairment of pseudohyphal formation of mkc1 delta/mkc1 delta strains on Spider medium and on the effect of its overexpression on Sacch. cerevisiae colony morphology on SLADH medium. Using the two-hybrid system, it was also demonstrated that MKC1 is able to interact specifically with Sacch. cerevisiae Mkk1p and Mkk2p, the MAP-kinase kinases of the PKC1-mediated route of Sacch. cerevisiae, and to activate transcription in Sacch. cerevisiae when bound to a DNA-binding element. These results suggest a role for this MAP kinase in the construction of the cell wall of C. albicans and indicate its potential relevance for the development of novel antifungals.


Virilizing ovarian fibrothecoma with minor sex cord elements in a 13 year old girl: a rare case.
Fibrothecoma accounts for 3-4% of all ovarian neoplasms; it is usually hormonally inactive, but can be estrogenic or sometimes androgenic (11%); it is rare under 30 years. In a very few cases, minor sex cord elements (less than 10% of the tumor area) are present; therefore, it is considered as a separate subgroup of stromal tumors. The importance of immunohistochemistry in recognizing this kind of tumor has been fully documented, with variable results on inhibin staining, but specific positivity for calretenin in such cases. We report here the rare case of a 13-year-old child with ovarian fibrothecoma and minor sex cord stromal elements, who showed negativity for inhibin and positivity for calretenin.


Heat stress and poultry production: a comprehensive review.
The impact of global warming on poultry production has gained significant attention over the years. However, our current knowledge and understanding of the mechanisms through which heat stress (HS) resulting from global warming affects the welfare, behavior, immune response, production performance, and even transgenerational effects in poultry are still incomplete. Further research is needed to delve deeper into these mechanisms to gain a comprehensive understanding. Numerous studies have investigated various biomarkers of stress in poultry, aiming to identify reliable markers that can accurately assess the physiological status and well-being of birds. However, there is a significant amount of variation and inconsistency in the results reported across different studies. This inconsistency highlights the need for more standardized methods and assays and a clearer understanding of the factors that influence these biomarkers in poultry. This review article specifically focuses on 3 main aspects: 1) the neuroendocrine and behavioral responses of poultry to HS, 2) the biomarkers of HS and 3) the impact of HS on poultry production that have been studied in poultry. By examining the neuroendocrine and behavioral changes exhibited by poultry under HS, we aim to gain insights into the physiological impact of elevated temperatures in poultry.


Global analysis reveals families of chemical motifs enriched for HERG inhibitors.
Promiscuous inhibition of the human ether-à-go-go-related gene (hERG) potassium channel by drugs poses a major risk for life threatening arrhythmia and costly drug withdrawals. Current knowledge of this phenomenon is derived from a limited number of known drugs and tool compounds. However, in a diverse, naïve chemical library, it remains unclear which and to what degree chemical motifs or scaffolds might be enriched for hERG inhibition. Here we report electrophysiology measurements of hERG inhibition and computational analyses of >300,000 diverse small molecules. We identify chemical 'communities' with high hERG liability, containing both canonical scaffolds and structurally distinctive molecules. These data enable the development of more effective classifiers to computationally assess hERG risk. The resultant predictive models now accurately classify naïve compound libraries for tendency of hERG inhibition. Together these results provide a more complete reference map of characteristic chemical motifs for hERG liability and advance a systematic approach to rank chemical collections for cardiotoxicity risk.


Thalamic, subthalamic nucleus and internal pallidum stimulation in Parkinson's disease.
The limits of drug therapy in severe forms of Parkinson's disease have lead to a renewal of functional neurosurgery of the basal ganglia and the thalamus. Deep brain stimulation (DBS) of these structures was developed with the aims of reducing the morbidity of surgery and of offering an adaptative treatment. DBS was first applied to the thalamus in patients with severe tremor. Tremor of the hemibody is greatly reduced by stimulation of the contralateral electrode in 85% of the cases. There is little change in other symptoms. However, motor fluctuations and dyskinesias are a more frequent problem than severe tremor; in attempt to treat these symptoms, DBS has recently been applied to the subthalamic nucleus (STN) and the internal pallidum (GPi). STN stimulation greatly decreases off motor symptoms and motor fluctuations, which allows a reduction of drug dosage and consequently of dyskinesias. GPi stimulation decreases dyskinesias in most patients, but the effect on off motor symptoms is more variable from one series to another, from very good to nil. The severe morbidity of DBS applied to these 3 targets is low. Comparative studies of the cost and the efficacy of DBS and lesions applied to these different targets are now required.


Dose calculation accuracy of the Monte Carlo algorithm for CyberKnife compared with other commercially available dose calculation algorithms.
Monte Carlo dose calculation algorithms have the potential for greater accuracy than traditional model-based algorithms. This enhanced accuracy is particularly evident in regions of lateral scatter disequilibrium, which can develop during treatments incorporating small field sizes and low-density tissue. A heterogeneous slab phantom was used to evaluate the accuracy of several commercially available dose calculation algorithms, including Monte Carlo dose calculation for CyberKnife, Analytical Anisotropic Algorithm and Pencil Beam convolution for the Eclipse planning system, and convolution-superposition for the Xio planning system. The phantom accommodated slabs of varying density; comparisons between planned and measured dose distributions were accomplished with radiochromic film. The Monte Carlo algorithm provided the most accurate comparison between planned and measured dose distributions. In each phantom irradiation, the Monte Carlo predictions resulted in gamma analysis comparisons >97%, using acceptance criteria of 3% dose and 3-mm distance to agreement. In general, the gamma analysis comparisons for the other algorithms were <95%. The Monte Carlo dose calculation algorithm for CyberKnife provides more accurate dose distribution calculations in regions of lateral electron disequilibrium than commercially available model-based algorithms. This is primarily because of the ability of Monte Carlo algorithms to implicitly account for tissue heterogeneities, density scaling functions; and/or effective depth correction factors are not required.


Physical function decline predictors in nursing home residents using new national quality indicators.
To determine the predictors of physical function (PF) decline among nursing home residents using items from the Long-term care Information system For Evidence (LIFE), a system launched in 2021 to ensure the quality of long-term care. The LIFE data of 1648 residents from 45 nursing homes in Japan were retrospectively collected in July 2021 (T0) and January 2022 (T1), including demographics, PF assessed by the Barthel index (BI), nutrition and oral health, and cognitive function. The Dementia Behavior Disturbance scale was used to assess the frequency of certain behaviors, such as "waking at midnight." The predictors of PF decline, defined as a decrease ≥5 in the BI score at T1 compared with that at T0, were determined using mixed-effects logistic regression analyses. PF at T0 was classified into high (>60 BI) and low (≤60 BI) groups. The participants' mean age was 87.2 ± 7.1 years, and 45.3% experienced PF decline. The significant predictors of PF decline were age ≥ 90 years, body mass index <18.5 kg/m2 , dementia diagnosis, moderate and severe cognitive impairments, not vocalizing reciprocal exchanges at will, always "waking at midnight," and high PF at T0. The LIFE items predicted PF decline among nursing home residents, suggesting that LIFE data can be used to ensure the quality of long-term care. Geriatr Gerontol Int 2023; ••: ••-••.


Proteoglycans of the knee-joint cartilage of young normal and lame pigs.
Intensive rearing, and restricted activity, induce rapid growth in pigs, but they often become lame. Groups of normal and lame pigs reared intensively were killed when 10 or 25 weeks old. Although there were no differences in the overall composition of the knee-joint cartilage of lame and sound animals, the proteoglycans in the cartilage of the lame pigs were extracted more easily by a standardized sequential procedure and contained a higher proportion of molecules of smaller size as assessed by gel chromatography on 6% agarose and Sepharose 4B. These increased at the expense of both the larger and mediumsized molecules. Differences were most evident at 10 weeks of age, when there was twice as much of the smaller proteoglycans in the cartilage of lame pigs. Despite these size-differences, the compositions of the proteoglycans in corresponding sequential extracts of cartilage of lame and normal groups were the same, as were the changes in chemical composition that accompany development. Proteoglycans from lame animals may have undergone limited proteolysis, thus decreasing their size without changing their composition detectably. As the differences between normal and lame groups were greater at 10 weeks than at 25 weeks of age, the first weeks after birth (when the greatest changes occur in the proteoglycans and in the cartilage) may be a critical period in the maturation of articular cartilage in this species. At this time, rapid gain in weight produced by intensive rearing may be too great for the immature cartilage to bear.


Relationship Between Respiratory Muscle Strength, Handgrip Strength, and Muscle Mass in Hospitalized Patients.
Minimal information is available to validate measurement of respiratory muscle strength (RMS) in the clinical setting. The purpose of this study was to determine the correlation between maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and sniff nasal inspiratory pressure (SNIP) with handgrip strength (HGS) and cross sectional muscle area obtained via diagnostic abdominal computed tomography (CT). Measures of MIP, MEP, SNIP, and HGS were obtained from individuals that participated in a previously published study; individuals who had an abdominal CT completed with (±)7 days of obtaining RMS measures were included. Both RMS and HGS were measured within 48-72 hours of admission; for RMS, the highest absolute (cm H2 O) and percent predicted values were recorded, and the average of 3 HGS measurements (kg) was documented. Cross-sectional muscle area (cm2 ) at the third lumbar region was recorded. Spearman's correlation coefficient was used to assess the relationship between variables. A total of 35 participants were included. HGS was correlated to absolute MIP (rs = 0.62, rs = 0.61), MEP (rs = 0.74, rs = 0.73), and SNIP (rs = 0.58, rs = 0.54) for males and females, respectively. Crosss-sectional muscle area was correlated with absolute MIP (rs = 0.66), MEP (rs = 0.58), and SNIP (rs = 0.783) for men and absolute SNIP (rs = 0.56) among women. Measures of RMS represent a promising assessment of muscle mass and function among hospitalized patients.


Pharmacoeconomic burden in the treatment of psoriatic arthritis: from systematic reviews to real clinical practice studies.
The economic assessment of treatment options in a chronic and severe disease like Psoriatic Arthritis (PsA) is crucial to estimate the burden of costs. In particular, the impact of new costly medications such as biologic agents have been studied to figure this important aspect of a multifaceted disease. In a previous observational, longitudinal multicentre cost evaluation study, the results showed that biologic agents are cost-effective. This study was obtained from the real clinical practice and encompassed PsA patients refractory to traditional treatments. Similar data were also obtained from reviews analysis of Randomized Controlled Trials (RCTs). Recently, Cawson et al. performed a systematic review, network meta-analysis and economic evaluation of biological therapy for the management of active PsA. The review was conducted to identify relevant, recently published studies and the new trial data were synthesized, via a Bayesian network meta-analysis (NMA), to estimate the relative efficacy of the TNF-α inhibitors in terms of Psoriatic Arthritis Response Criteria (PsARC) response, Health Assessment Questionnaire (HAQ) scores and Psoriasis Area and Severity Index (PASI). In particular the analysis showed that, on average, etanercept was the most cost-effective treatment and, at the National Institute for Health and Care Excellence willingness-to-pay threshold of between £20,000 to £30,000, etanercept is the preferred option. This study, as a systematic review, has been focused on main RCTs on active PsA treated by biological DMARDs and limitations to this analysis arise from a paucity of data on long-term follow up, as well as radiological progression and long-term safety. These interesting results reflected the important role of biologic agents in the management of PsA, highlighting their efficacy and cost-effectiveness. However, there are some unmet needs for pharmacoeconomic considerations based on prospective and/or on real clinical practice studies, as well as considering all the intriguing aspects of this challenging disease.


Masked hypertension is associated with end organ damage in geriatric age: Geriatric MASked Hypertension and End organ damage (G-MASH-End organ Study).
Purpose: It is a question whether masked hypertension (MH) leads to end-organ damage in the geriatric age group. The aim of this study is to evaluate the associations between MH and end-organ damage such as left ventricular hypertrophy (LVH) and proteinuria in geriatric population.Materials and methods: One hundred and two patients who were admitted to the outpatient clinic were included in the study. These patients were also included in the GMASH-Cog study in 2016, which examined the relationship between MH and cognitive function. All patients underwent ambulatory blood pressure measurement procedures. Cardiac functions of all patients were determined by echocardiography. Spot urine albumin/creatinine ratio (ACR) was measured in all patients.Results: Forty four of 102 patients (43%) were diagnosed with MH. ACR was 9.61 mg/gr in the MH group and 7.12 mg/gr in the normal group (p = .021). In addition, left ventricular mass index (LVMI) was found to be higher in the MH group than in the normal group. Mean LVMI scores were 107.76 ± 16.37 in patients with MH and 100.39 ± 19.32 in the normotensive group (p = .046).Conclusion: MH is associated with end-organ damage in geriatric patients. Urinary albumin excretion and LVH which are the parameters of end-organ damage were significantly higher in MH patients. MH may cause end-organ damage and should not be overlooked in geriatric patients.


Fibrinolysis, inflammation, and regulation of the plasminogen activating system.
The maintenance of a given physiological process demands a coordinated and spatially regulated pattern of gene regulation. This applies to genes encoding components of enzyme cascades, including those of the plasminogen activating system. This family of proteases is vital to fibrinolysis and dysregulation of the expression pattern of one or more of these proteins in response to inflammatory events can impact on hemostasis. Gene regulation occurs on many levels, and it is apparent that the genes encoding the plasminogen activator (fibrinolytic) proteins are subject to both direct transcriptional control and significant post-transcriptional mechanisms. It is now clear that perturbation of these genes at either of these levels can dramatically alter expression levels and have a direct impact on the host's response to a variety of physiological and pharmacological challenges. Inflammatory processes are well known to impact on the fibrinolytic system and to promote thrombosis, cancer and diabetes. This review discusses how inflammatory and other signals affect the transcriptional and post-transcriptional expression patterns of this system, and how this modulates fibrinolysis in vivo.


Commentary: Treatment Considerations for Patients With Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Brain Metastases in the Era of Tyrosine Kinase Inhibitors.
Brain metastasis is a serious complication of non-small cell lung cancer (NSCLC) affecting up to 40% of NSCLC patients. A subset of NSCLC tumors has mutations in the epidermal growth factor receptor (EGFR) gene, and determination of tumor EGFR mutation status is essential in guiding treatment decisions, as it directly affects the treatment approach. Patients with EGFR-mutated NSCLC have a higher cumulative incidence of brain metastases, and are especially sensitive to EGFR tyrosine kinase inhibitors (TKIs). Patients with newly diagnosed EGFR-mutated lung cancer presenting to a neurosurgeon with a new diagnosis of brain metastases now have a variety of treatment options available, including whole brain radiation therapy, stereotactic radiosurgery, surgical resection, chemotherapy, and targeted therapeutics such as the EGFR TKIs. In this review, we discuss the impact of EGFR mutation status on brain and leptomeningeal metastasis treatment considerations. Additionally, we present clinical cases of patients treated with EGFR TKIs alone and in combination with other therapies to highlight treatment alternatives.


Retroperitoneal pelvic packing in the management of hemodynamically unstable pelvic fractures: a level I trauma center experience.
Our objective is to evaluate the mortality and outcomes of hemodynamically unstable patients with pelvic fractures treated with a protocol that directs the patient to either early pelvic angiography or early retroperitoneal pelvic packing. This is a retrospective review of prospectively collected database at a local trauma center. Hemodynamically unstable pelvic fracture patients received treatment according to our hospital protocol during two different time periods. Before June 2008, these patients underwent early angiography (ANGIO group, n=13), and from June 2008 onward, these patients underwent early pelvic packing and subsequent angiography if there was continued hemorrhage from the pelvis (PACKING group, n=11). The mechanism of injury, physiologic parameters, blood transfusion requirements, time to intervention, trauma scores, and mortality were recorded. Mean time to intervention in the ANGIO group was longer than that in the PACKING group, although this was not statistically significant (139.5 minutes vs. 78.8 minutes, respectively, p=0.248). Mortality in the ANGIO group was higher than that in the PACKING group; however, this was also not significant (69.2% vs. 36.3%, p=0.107). After univariate analysis, factors associated with mortality included systolic blood pressure, Glasgow Coma Score, Injury Severity Score, Revised Trauma Score, Trauma and Injury Severity Score, pH, and base excess. In the PACKING group, one patient died of uncontrolled hemorrhage from a liver laceration. In the ANGIO group, three patients died of uncontrolled hemorrhage from the pelvic fracture. Early experience in our institution suggests that early pelvic packing with subsequent angiography if needed is as good as angiography with embolization in treating patients with hemodynamically unstable pelvic fractures.


A necessity for MAP kinase activation in mammalian spatial learning.
Although the biochemical mechanisms underlying learning and memory have not yet been fully elucidated, mounting evidence suggests that activation of protein kinases and phosphorylation of their downstream effectors plays a major role. Recent findings in our laboratory have shown a requirement for the mitogen-activated protein kinase (MAPK) cascade in hippocampal synaptic plasticity. Therefore, we used an inhibitor of MAPK activation, SL327, to test the role of the MAPK cascade in hippocampus-dependent learning in mice. SL327, which crosses the blood-brain barrier, was administered intraperitoneally at several concentrations to animals prior to cue and contextual fear conditioning. Administration of SL327 completely blocked contextual fear conditioning and significantly attenuated cue learning when measured 24 hr after training. To determine whether MAPK activation is required for spatial learning, we administered SL327 to mice prior to training in the Morris water maze. Animals treated with SL327 exhibited significant attenuation of water maze learning; they took significantly longer to find a hidden platform compared with vehicle-treated controls and also failed to use a selective search strategy during subsequent probe trials in which the platform was removed. These impairments cannot be attributed to nonspecific effects of the drug during the training phase; no deficit was seen in the visible platform task, and injection of SL327 following training produced no effect on the performance of these mice in the hidden platform task. These findings indicate that the MAPK cascade is required for spatial and contextual learning in mice.


Eight-year secular trends of pedometer-determined physical activity in young Swedish adolescents.
To explore the secular trends (time change) of pedometer-determined physical activity (steps per day) in Swedish young adolescents 13 to 14 years of age from 2000 to 2008. The study was analyzed between 2 cross-sectional cohorts carried out in October 2000 (235,111 girls) and October 2008 (186,107 girls) in the same school, using identical procedures. Data of mean steps per day were collected during 4 consecutive weekdays (sealed pedometer Yamax SW-200 Tokyo, Japan) and in addition height and weight were measured. When comparing cohort 2000 with cohort 2008 no significant difference in physical activity were found neither among girls (12,989 vs 13,338 [t = -0.98, P < .325]) nor boys (15,623 vs 15,174 [t = 0.78, P = .436]). The share of girls and boys meeting weight control recommendations was none significantly higher in 2008 both among girls (68% versus 62%) and among boys (69% versus 65%). There was no significant difference of young adolescents' physical activity during school weekdays in 2008 compared with 2000. This stabilized physical activity level, in an internationally comparison regarded as high, is promising. Enhanced focus on physical activity in society and at school might have influenced the result.


Evidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon.
POLG, located on nuclear chromosome 15, encodes the DNA polymerase γ(Pol γ). Pol γ is responsible for the replication and repair of mitochondrial DNA (mtDNA). Pol γ is the only DNA polymerase found in mitochondria for most animal cells. Mutations in POLG are the most common single-gene cause of diseases of mitochondria and have been mapped over the coding region of the POLG ORF. Using PhyloCSF to survey alternative reading frames, we found a conserved coding signature in an alternative frame in exons 2 and 3 of POLG, herein referred to as ORF-Y that arose de novo in placental mammals. Using the synplot2 program, synonymous site conservation was found among mammals in the region of the POLG ORF that is overlapped by ORF-Y. Ribosome profiling data revealed that ORF-Y is translated and that initiation likely occurs at a CUG codon. Inspection of an alignment of mammalian sequences containing ORF-Y revealed that the CUG codon has a strong initiation context and that a well-conserved predicted RNA stem-loop begins 14 nucleotides downstream. Such features are associated with enhanced initiation at near-cognate non-AUG codons. Reanalysis of the Kim et al. (2014) draft human proteome dataset yielded two unique peptides that map unambiguously to ORF-Y. An additional conserved uORF, herein referred to as ORF-Z, was also found in exon 2 of POLG. Lastly, we surveyed Clinvar variants that are synonymous with respect to the POLG ORF and found that most of these variants cause amino acid changes in ORF-Y or ORF-Z. We provide evidence for a novel coding sequence, ORF-Y, that overlaps the POLG ORF. Ribosome profiling and mass spectrometry data show that ORF-Y is expressed. PhyloCSF and synplot2 analysis show that ORF-Y is subject to strong purifying selection. An abundance of disease-correlated mutations that map to exons 2 and 3 of POLG but also affect ORF-Y provides potential clinical significance to this finding.


Superconducting topological surface states in the noncentrosymmetric bulk superconductor PbTaSe2.
The search for topological superconductors (TSCs) is one of the most urgent contemporary problems in condensed matter systems. TSCs are characterized by a full superconducting gap in the bulk and topologically protected gapless surface (or edge) states. Within each vortex core of TSCs, there exists the zero-energy Majorana bound states, which are predicted to exhibit non-Abelian statistics and to form the basis of the fault-tolerant quantum computation. To date, no stoichiometric bulk material exhibits the required topological surface states (TSSs) at the Fermi level (EF) combined with fully gapped bulk superconductivity. We report atomic-scale visualization of the TSSs of the noncentrosymmetric fully gapped superconductor PbTaSe2. Using quasi-particle scattering interference imaging, we find two TSSs with a Dirac point at E ≅ 1.0 eV, of which the inner TSS and the partial outer TSS cross EF, on the Pb-terminated surface of this fully gapped superconductor. This discovery reveals PbTaSe2 as a promising candidate for TSC.