Evolution of limb bone loading and body size in varanid lizards.
Geometric scaling predicts that stresses on limb bones and muscles should increase with body size. Mammals counter this size-related increase in stress partially through changes in bone geometry, but largely through changes in posture, with larger species having a more erect stance. However, the ability to counter size-related stresses in this fashion may be limited to those taxa that have a parasagittal gait (such as mammals), where legs are swung underneath the body. We examined locomotor kinematics for 11 species of varanid lizards (from 0.04 to 8 kg body mass) that have a sprawling gait, to determine how they moderate size-related stresses. Posture, as indicated by femur adduction and hip heights, did not change significantly with body size, beyond that expected from geometrical scaling. Instead, lizards mitigated size-related increases in stress by increasing duty factor and possibly reducing femur rotation. Incorporating these factors in biomechanical models predicted that both bending (∝M(0.016), where M is mass) and torsional (∝M(-0.049)) stresses should be nearly independent of body size over the size range examined. However, increasing duty factor and reducing femur rotation probably have deleterious effects on speed, and this difference in kinematics with size may explain why speed scales lower for sprawling lizards than for parasagittal mammals (∝M(0.17) and ∝M(0.24), respectively). Further, paralleling conclusions for the synapsid lineage, these findings suggest that evolution from sprawling to upright posture did not occur in archosaurs as a response to larger size; rather, these archosaurs likely became upright first and larger later.


Cysteine auxotrophy drives reduced susceptibility to quinolones and paraquat by inducing the expression of efflux-pump systems and detoxifying enzymes in S. Typhimurium.
Currently, Salmonella enterica serovar Typhimurium (S. Typhimurium), is a major global public health problem, which has caused food-borne illnesses in many countries. Today, with the extensive use of antimicrobials, antimicrobial resistance is increasing at a serious rate in S. Typhimurium isolates. The present study sought the role of cysteine (Cys) auxotrophy on the resistance to quinolones and paraquat in S. Typhimurium. Cys auxotrophy was achieved by deleting either the cysDNC, cysJIH or cysQ loci. Deletion of these loci resulted in loss of susceptibility against nalidixic acid, levofloxacin, ciprofloxacin (CIP) and paraquat. Further studies with cysJIH mutant indicated increased expression of multi-antibiotic resistance genes marA and ramA, and consequently increased expression of efflux-pump systems. The cysJIH mutant presented a smaller increase of reactive oxygen species (ROS) in presence of paraquat or CIP. Expression of katG and sodA (expressing for a catalase and a superoxide dismutase, respectively) genes was increased in presence of paraquat in the cysJIH mutant; while expression of the superoxide dismutase gene sodB was decreased. These results indicate that deletion of cysDNC, cysJIH or cysQ genes of S. Typhimurium renders Cys auxotrophy along with decreased susceptibility in response to quinolone and paraquat. Overexpression of efflux-pump systems AcrB-TolC and SmvA-OmpD and antioxidant enzymes KatG and SodA could explain the mechanisms of antimicrobial resistance in the Cys auxotrophic mutants.


Effective accreditation in postgraduate medical education: from process to outcomes and back.
The accreditation of medical educational programs is thought to be important in supporting program improvement, ensuring the quality of the education, and promoting diversity, equity, and population health. It has long been recognized that accreditation systems will need to shift their focus from processes to outcomes, particularly those related to the end goals of medical education: the creation of broadly competent, confident professionals and the improvement of health for individuals and populations. An international group of experts in accreditation convened in 2013 to discuss this shift. Participants unequivocally supported the inclusion of more outcomes-based criteria in medical education accreditation, specifically those related to the societal accountability of the institutions in which the education occurs. Meaningful and feasible outcome metrics, however, are hard to identify. They are regionally variable, often temporally remote from the educational program, difficult to measure, and susceptible to confounding factors. The group identified the importance of health outcomes of the clinical milieu in which education takes place in influencing outcomes of its graduates. The ability to link clinical data with individual practice over time is becoming feasible with large repositories of assessment data linked to patient outcomes. This was seen as a key opportunity to provide more continuous oversight and monitoring of program impact. The discussants identified several risks that might arise should outcomes measures completely replace process issues. Some outcomes can be measured only by proxy process elements, and some learner experience issues may best be measured by such process elements: in brief, the "how" still matters. Accrediting bodies are beginning to view the use of practice outcome measures as an important step toward better continuous educational quality improvement. The use of outcomes will present challenges in data collection, aggregation, and interpretation. Large datasets that capture clinical outcomes, experience of care, and health system performance may enable the assessment of multiple dimensions of program quality, assure the public that the social contract is being upheld, and allow identification of exemplary programs such that all may improve. There remains a need to retain some focus on process, particularly those related to the learner experience.


Chronic inflammatory demyelinating polyneuropathy: immunopathological and ultrastructural study of peripheral nerve biopsy in 42 cases.
The authors recently reexamined the peripheral nerve biopsies from 42 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). There were 27 males and 15 females, aged from 9 to 84 years, and 13 had relapses. No patient had vasculitis, monoclonal gammopathy, tumor, diabetes mellitus, Lyme disease, familial neuropathy, HIV, or any other immune deficiency. In the endoneurium, perivascular inflammatory cell infiltrates were present in only one case, but scattered histiocytes marked by KP1 on paraffin-embedded fragments were present in every case and there were no T-lymphocytes. At ultrastructural examination macrophage-associated demyelination was observed in 17 cases, of which 6 had relapses separated by intervals of several months or years. Axonal lesions without associated primary demyelination were observed in 4 cases and 3 of these had relapses. Thirty-two patients had mixed lesions of demyelination and axonal involvement. This study confirms other recent data indicating that in all cases of CIDP, macrophages are present in the endoneurium. Macrophage-associated demyelination is the characteristic feature of demyelinating forms. On the other hand, isolated primary axonal forms, which have been known since 1989, are relatively frequent and prone to relapses.


Human Cdc7-related kinase complex. In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a criticial threonine residue of Cdc7 bY Cdks.
huCdc7 encodes a catalytic subunit for Saccharomyces cerevisae Cdc7-related kinase complex of human. ASK, whose expression is cell cycle-regulated, binds and activates huCdc7 kinase in a cell cycle-dependent manner (Kumagai, H., Sato, N., Yamada, M., Mahony, D. , Seghezzi, W., Lees, E., Arai, K., and Masai, H. (1999) Mol. Cell. Biol. 19, 5083-5095). We have expressed huCdc7 complexed with ASK regulatory subunit using the insect cell expression system. To facilitate purification of the kinase complex, glutathione S-transferase (GST) was fused to huCdc7 and GST-huCdc7-ASK complex was purified. GST-huCdc7 protein is inert as a kinase on its own, and phosphorylation absolutely depends on the presence of the ASK subunit. It autophosphorylates both subunits in vitro and phosphorylates a number of replication proteins to different extents. Among them, MCM2 protein, either in a free form or in a MCM2-4-6-7 complex, serves as an excellent substrate for huCdc7-ASK kinase complex in vitro. MCM4 and MCM6 are also phosphorylated by huCdc7 albeit to less extent. MCM2 and -4 in the MCM2-4-6-7 complex are phosphorylated by Cdks as well, and prior phosphorylation of the MCM2-4-6-7 complex by Cdks facilitates phosphorylation of MCM2 by huCdc7, suggesting collaboration between Cdks and Cdc7 in phosphorylation of MCM for initiation of S phase. huCdc7 and ASK proteins can also be phosphorylated by Cdks in vitro. Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks.


Geographic Information Systems, spatial analysis, and HIV in Africa: A scoping review.
Geographic Information Systems (GIS) and spatial analysis are emerging tools for global health, but it is unclear to what extent they have been applied to HIV research in Africa. To help inform researchers and program implementers, this scoping review documents the range and depth of published HIV-related GIS and spatial analysis research studies conducted in Africa. A systematic literature search for articles related to GIS and spatial analysis was conducted through PubMed, EMBASE, and Web of Science databases. Using pre-specified inclusion criteria, articles were screened and key data were abstracted. Grounded, inductive analysis was conducted to organize studies into meaningful thematic areas. The search returned 773 unique articles, of which 65 were included in the final review. 15 different countries were represented. Over half of the included studies were published after 2014. Articles were categorized into the following non-mutually exclusive themes: (a) HIV geography, (b) HIV risk factors, and (c) HIV service implementation. Studies demonstrated a broad range of GIS and spatial analysis applications including characterizing geographic distribution of HIV, evaluating risk factors for HIV, and assessing and improving access to HIV care services. GIS and spatial analysis have been widely applied to HIV-related research in Africa. The current literature reveals a diversity of themes and methodologies and a relatively young, but rapidly growing, evidence base.


New insight into environmental oxidation of phosmet insecticide initiated by HO˙ radicals in gas and water - a theoretical study.
Phosmet is an organophosphorus insecticide widely used in agriculture to control a range of insects; recently, it was banned by the European Union in 2022 due to its harmful effects. However, its environmental degradation and fate have not yet been evident. Thus, phosmet oxidation by HO˙ radicals was theoretically studied in this work using the DFT approach at the M06-2X/6-311++G(3df,3pd)//M06-2X/6-31+G(d,p) level of theory. Three different mechanisms were considered, including formal hydrogen transfer (FHT), radical adduct formation (RAF), and single electron transfer (SET). The mechanisms, kinetics, and lifetime were studied in the gas and aqueous phases, in addition to its ecotoxicity evaluation. The results show that FHT reactions were dominant in the gas phase, while RAF was more favourable in the aqueous phase at 298 K, while SET was negligible. The branching ratio indicated that H-abstractions at the methyl and the methylene groups were the most predominant, while the most favourable HO˙-addition was observed at the phosphorus atom of the dithiophosphate group. The overall rate constant values varied from 1.2 × 109 (at 283 K) to 1.40 × 109 M-1 s-1 (at 323 K) in the aqueous phase and from 6.29 × 1010 (at 253 K) to 1.32 × 1010 M-1 s-1 (at 323 K) in the gas phase. The atmospheric lifetime of phosmet is about 6 hours at 287 K, while it can persist from a few seconds to several years depending on the temperature and [HO˙] concentration in the aqueous environment. The QSAR-based ecotoxicity evaluation indicates that phosmet and its degradation products are all dangerous to aquatic organisms, although the products are less toxic than phosmet. However, they are generally developmental toxicants and mutagenicity-negative compounds.


The Choice of Leg During Pull Test in Parkinson's Disease: Not Mere Chance.
Background: Parkinson's disease (PD) starts asymmetrically and it maintains a certain degree of asymmetry throughout its course. Once functional disability proceeds, people with PD can change their dominant hand due to the increased disease severity. This is particularly true for hand dominance, while no studies have been performed so far exploring the behavioral changes of lower limb utilization in PD according to the lateralized symptom dominance. In the current study, we aim to track the foot preference of participants with PD to respond to the Pull Test. Methods: Forty-one subjects suffering from PD, with a H&Y scale ≤ 2, were recruited. A motor evaluation was performed, including the motor part of the MDS-UPDRS, its axial and lateralized scores (for more and less affected side), two Timed Tests, namely Time to Walk a standard distance (TW, in seconds) and Time Up and Go Test (TUG, in seconds), and the Pull Test. The preferred foot (right or left) involved in the step backward was recorded. Thirty-seven healthy controls underwent a motor assessment which included the Pull Test and the Timed Tests. Both participants with PD and controls were right-handed. To evaluate the relationship between the response to Pull-Test and PD-symptoms, subjects with PD were further divided into two groups: (1) Right more affected side (Right-MAS), and (2) Left more affected side (Left-MAS). Results: Both groups of subjects with PD (Right-MAS and Left-MAS) during the Pull Test shifted significantly their leg use preference toward the opposite side than the more affected side: Right-MAS used preferentially their left leg (71%) and vice versa (p < 0.001). The limb preference shift was especially true for Left-MAS group that almost invariably used their right, dominant leg to respond to the Pull Test (95%). Similar results were obtained comparing people with PD and Controls. Conclusions: This study shows that the limb used to respond to the Pull Test generally predicts the contralateral side of worse PD involvement. As the disease takes place, it prevails over hemispheric dominance: right-handed subjects with left side PD-onset and worse lateralization tend to be hyper-right-dominant, while right-handed subjects with right side PD-onset and worse impairment tend to behave as left-handers. Lateralization of symptoms in PD is still a mysterious phenomenon; more studies are needed to better understand this association and to optimize tailored rehabilitation programs for people with PD.


Repetition rate stabilization of an optical frequency comb based on solid-state laser technology with an intra-cavity electro-optic modulator.
The repetition rate stabilization of an optical frequency comb based on diode-pumped solid-state laser technology is demonstrated using an intra-cavity electro-optic modulator. The large feedback bandwidth of such modulators allows disciplining the comb repetition rate on a cavity-stabilized continuous-wave laser with a locking bandwidth up to 700 kHz. This surpasses what can be achieved with any other type of actuator reported so far. An in-loop integrated phase noise of 133 mrad has been measured and the PM-to-AM coupling of the electro-optic modulator has been investigated as well.


Implementing colorectal cancer screening in community health centers: addressing cancer health disparities through a regional cancer collaborative.
The population served by Federally Qualified Health Centers (FQHCs) has lower levels of cancer screening compared with the general population and suffers a disproportionate cancer burden. To address these disparities, 3 federal agencies and a primary care association established and tested the feasibility of a Regional Cancer Collaborative (RCC) in 2005. RCC faculty implemented a learning model to improve cancer screening across 4 FQHCs that met explicit organizational readiness criteria. Regional faculty trained "care process leaders," who worked with primary care teams to plan and implement practice changes. FQHCs monitored progress across the following measures of screening implementation: self-management goal-setting; number and percent screened for breast, cervical, and colorectal cancer; percent timely results notification; and percent abnormal screens evaluated within 90 days. Progress and plans were reviewed in regular teleconferences. FQHCs were encouraged to create local communities of practice (LCOP) involving community resources to support cancer screening and to participate in a monthly teleconference that linked the LCOPs into a regional community of practice. Summary reports and administrative data facilitated a process evaluation of the RCC. chi test and test of trends compared baseline and follow-up screening rates. The RCC taught the collaborative process using process leader training, teleconferences, 2 regional meetings, and local process improvement efforts. All organizations created clinical tracking capabilities and 3 of the 4 established LCOPs, which met monthly in an regional community of practice. Screening documentation increased for all 3 cancers from 2005 to 2007. Colorectal cancer screening increased from 8.6% to 21.2%. A regional plan to enable collaborative learning for cancer screening implementation is feasible, and improvements in screening rates can occur among carefully selected organizations.


Translating mosquito viromes into vector management strategies.
Mosquitoes are best known for transmitting human and animal viruses. However, they also harbour mosquito-specific viruses (MSVs) as part of their microbiota. These are a group of viruses whose diversity and prevalence overshadow their medically relevant counterparts. Although metagenomics sequencing has remarkably accelerated the discovery of these viruses, what we know about them is often limited to sequence information, leaving much of their fundamental biology to be explored. Understanding the biology and ecology of MSVs can enlighten our knowledge of virus-virus interactions and lead to new innovations in the management of mosquito-borne viral diseases. We retrace the history of their discovery and discuss research milestones that would line the path from mosquito virome knowledge to vector management strategies.


Energy turnover and heat exchange in mature lean and obese Zucker rats acutely exposed to three environmental temperatures for 24 hours.
Differences between lean (FA/?, n = 6) and obese (fa/fa, n = 6) mature male Zucker rats' energy turnover and heat storage were compared during a 24-h period when the animals were exposed to ambient temperatures of 30, 15 or 5 degrees C. Energy turnover was examined through measurements of heat production rates via indirect calorimetry and heat loss rates via direct calorimetry. Heat storage rates were calculated as the difference between heat production and heat loss rates. Predicted heat storage rates were also calculated as the product of the change in core temperature and the calculated specific heat of the animal based on body composition (carcass) analysis. A minimal heat loss rate was determined for each animal representing a period of least activity. Various comparisons were made: between groups (lean/obese), temperature (30, 15, 5 degrees C), calorimetry method (indirect/direct), period (light/dark), heat storage (experimental/predicted), and minimal heat loss. Immediately before a test, pretest weight and colonic temperature were obtained. Then, the animal was placed into the calorimeter chamber and remained there unrestrained for 24 h. Normal light/dark periods were maintained. On removal from the calorimeter, core temperature and body weight measurements were again obtained. Upon completion of all tests, body composition was analyzed and surface area determined. Energy turnover, i.e. both heat production and heat loss in the lean and obese animals differed among the 30, 15 and 5 degrees C exposures. The obese animals had relatively greater heat production rate and heat loss rate (kcal/day or kcal/kg (FFM)/day than the lean animals at 30, 15 and 5 degrees C. But, on a relative basis, the increments in heat production in the cold environments were greater for the lean animals. Both the lean and obese animals tended to be more active during the dark period when at 30 degrees C, but the difference was less at 15 degrees C and even less at 5 degrees C. Experimental heat storage rates did not differ significantly from predicted values at any of the temperatures with the possible exception of the animals at 5 degrees C. It was concluded that the mature obese Zucker rats had no major discernible defect in thermoregulation as revealed by rates of heat production and loss, although three of the obese rats did elicit a drop in colonic temperature during exposure to 5 degrees C, i.e. their excessive subcutaneous adiposity and thermal insulation did not prevent a fall in colonic temperature.(ABSTRACT TRUNCATED AT 400 WORDS)


Occupational health--a requirement for development.
Many people are at serious risk of ill-health and accidents because of the conditions they encounter in their workplaces. Combating these dangers requires a multidisciplinary approach and special attention to the elimination of hazards from the work environment. This is a long-standing concern of WHO.


Hypoxia increases the metastatic ability of breast cancer cells via upregulation of CXCR4.
Chemokine SDF1alpha and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers including breast cancer. Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. We hypothesized that hypoxia would upregulate CXCR4 expression and lead to increased chemotactic responsiveness to its specific ligand SDF1alpha. Three breast cancer cell lines MDA-MB-231, MCF7 and 4T1 were subjected to 48 hrs of hypoxia or normoxia. Cell surface receptor expression was evaluated using flow cytometry. An extracellular matrix invasion assay and microporous migration assay was used to assess chemotactic response and metastatic ability. CXCR4 surface expression was significantly increased in the two human breast cancer cell lines, MDA-MB-231 and MCF7, following exposure to hypoxia. This upregulation of CXCR4 cell surface expression corresponded to a significant increase in migration and invasion in response to SDF1-alpha in vitro. The increase in metastatic potential of both the normoxic and the hypoxic treated breast cancer cell lines was attenuated by neutralization of CXCR4 with a CXCR4 neutralizing mAb, MAB172 or a CXCR4 antagonist, AMD3100, showing the relationship between CXCR4 overexpression and increased chemotactic responsiveness. CXCR4 expression can be modulated by the tissue microenvironment such as hypoxia. Upregulation of CXCR4 is associated with increased migratory and invasive potential and this effect can be abrogated by CXCR4 inhibition. Chemokine receptor CXCR4 is a potential therapeutic target in the adjuvant treatment of breast cancer.


Changes in the control of skin blood flow with exercise training: where do cutaneous vascular adaptations fit in?
Heat is the most abundant byproduct of cellular metabolism. As such, dynamic exercise in which a significant percentage of muscle mass is engaged generates thermoregulatory demands that are met in part by increases in skin blood flow. Increased skin blood flow during exercise adds to the demands on cardiac output and confers additional circulatory strain beyond that associated with perfusion of active muscle alone. Endurance exercise training results in a number of physiological adaptations which ultimately reduce circulatory strain and shift thermoregulatory control of skin blood flow to higher levels of blood flow for a given core temperature. In addition, exercise training induces peripheral vascular adaptations within the cutaneous microvasculature indicative of enhanced endothelium-dependent vasomotor function. However, it is not currently clear how (or if) these local vascular adaptations contribute to the beneficial changes in thermoregulatory control of skin blood flow following exercise training. The purpose of this Hot Topic Review is to synthesize the literature pertaining to exercise training-mediated changes in cutaneous microvascular reactivity and thermoregulatory control of skin blood flow. In addition, we address mechanisms driving changes in cutaneous microvascular reactivity and thermoregulatory control of skin blood flow, and pose the question: what (if any) is the functional role of increased cutaneous microvascular reactivity following exercise training?


ViSEN: methodology and software for visualization of statistical epistasis networks.
The nonlinear interaction effect among multiple genetic factors, i.e. epistasis, has been recognized as a key component in understanding the underlying genetic basis of complex human diseases and phenotypic traits. Due to the statistical and computational complexity, most epistasis studies are limited to interactions with an order of two. We developed ViSEN to analyze and visualize epistatic interactions of both two-way and three-way. ViSEN not only identifies strong interactions among pairs or trios of genetic attributes, but also provides a global interaction map that shows neighborhood and clustering structures. This visualized information could be very helpful to infer the underlying genetic architecture of complex diseases and to generate plausible hypotheses for further biological validations. ViSEN is implemented in Java and freely available at https://sourceforge.net/projects/visen/.


[Experimental study of cardiotoxic effect of the pesticide sulfocarbathione].
Cardiotoxic and atherogenic effects of sulfocarbathione++ administered perorally and by inhalation to sexually mature white rats were studied. Besides, cardiotoxic effect was studied on the embryos and offspring of the exposed dams. Unfavourable effects of the pesticide on the myocardium of sexually mature animals, embryos, offspring were detected, as well as biochemical disorders of atherogenic character.


Iron chelation and supplementation: A comparison in the management of inflammatory bowel disease using drosophila.
Inflammatory Bowel Disease (IBD) is associated with systemic iron deficiency and has been managed with iron supplements which cause adverse side effects. Conversely, some reports highlight iron depletion to ameliorate IBD. The underlying intestinal response and comparative benefit of iron depletion and supplementation in IBD is unknown. The aims of this work were to characterize and compare the effects of iron supplementation and iron depletion in IBD. IBD was induced in Drosophila melanogaster using 3 % dextran sodium sulfate (DSS) in diet for 7 days. Using this model, we investigated the impacts of acute iron depletion (using bathophenanthroline disulfonate, BPS) and supplementation (using ferrous sulphate, FS), before and after IBD induction, on gut iron homeostasis, cell death, gut permeability, inflammation, antioxidant defence, antimicrobial response and several fly phenotypes. DSS decreased fly mass (p < 0.001), increased gut permeability (p < 0.001) and shortened lifespan (p = 0.035) compared to control. The DSS-fed flies also showed significantly elevated lipid peroxidation (p < 0.001), and the upregulated expression of apoptotic marker- drice (p < 0.001), tight junction protein - bbg (p < 0.001), antimicrobial peptide - dpta (p = 0.002) and proinflammatory cytokine - upd2 (p < 0.001). BPS significantly (p < 0.05) increased fly mass and lifespan, decreased gut permeability, decreased lipid peroxidation and decreased levels of drice, bbg, dpta and upd2 in IBD flies. This iron chelation (using BPS) showed better protection from DSS-induced IBD than iron supplementation (using FS). Preventive and curative interventions, by BPS or FS, also differed in outcomes. This may inform precise management strategies aimed at tackling IBD and its recurrence.


Combining machine learning and optimization for the operational patient-bed assignment problem.
Assigning inpatients to hospital beds impacts patient satisfaction and the workload of nurses and doctors. The assignment is subject to unknown inpatient arrivals, in particular for emergency patients. Hospitals, therefore, need to deal with uncertainty on actual bed requirements and potential shortage situations as bed capacities are limited. This paper develops a model and solution approach for solving the patient bed-assignment problem that is based on a machine learning (ML) approach to forecasting emergency patients. First, it contributes by improving the anticipation of emergency patients using ML approaches, incorporating weather data, time and dates, important local and regional events, as well as current and historical occupancy levels. Drawing on real-life data from a large case hospital, we were able to improve forecasting accuracy for emergency inpatient arrivals. We achieved up to 17% better root mean square error (RMSE) when using ML methods compared to a baseline approach relying on averages for historical arrival rates. We further show that the ML methods outperform time series forecasts. Second, we develop a new hyper-heuristic for solving real-life problem instances based on the pilot method and a specialized greedy look-ahead (GLA) heuristic. When applying the hyper-heuristic in test sets we were able to increase the objective function by up to 5.3% in comparison to the benchmark approach in [40]. A benchmark with a Genetic Algorithm shows also the superiority of the hyper-heuristic. Third, the combination of ML for emergency patient admission forecasting with advanced optimization through the hyper-heuristic allowed us to obtain an improvement of up to 3.3% on a real-life problem.


The nitrogen costs of photosynthesis in a diatom under current and future pCO2.
With each cellular generation, oxygenic photoautotrophs must accumulate abundant protein complexes that mediate light capture, photosynthetic electron transport and carbon fixation. In addition to this net synthesis, oxygenic photoautotrophs must counter the light-dependent photoinactivation of Photosystem II (PSII), using metabolically expensive proteolysis, disassembly, resynthesis and re-assembly of protein subunits. We used growth rates, elemental analyses and protein quantitations to estimate the nitrogen (N) metabolism costs to both accumulate the photosynthetic system and to maintain PSII function in the diatom Thalassiosira pseudonana, growing at two pCO2 levels across a range of light levels. The photosynthetic system contains c. 15-25% of total cellular N. Under low growth light, N (re)cycling through PSII repair is only c. 1% of the cellular N assimilation rate. As growth light increases to inhibitory levels, N metabolite cycling through PSII repair increases to c. 14% of the cellular N assimilation rate. Cells growing under the assumed future 750 ppmv pCO2 show higher growth rates under optimal light, coinciding with a lowered N metabolic cost to maintain photosynthesis, but then suffer greater photoinhibition of growth under excess light, coincident with rising costs to maintain photosynthesis. We predict this quantitative trait response to light will vary across taxa.


Determination of aflatoxins B1, B2, G1, and G2 and ochratoxin A in ginseng and ginger by multitoxin immunoaffinity column cleanup and liquid chromatographic quantitation: collaborative study.
The accuracy, repeatability, and reproducibility characteristics of a method using multitoxin immunoaffinity column cleanup with liquid chromatography (LC) for determination of aflatoxins (AF; sum of aflatoxins B1, B2, G1, and G2) and ochratoxin A (OTA) in powdered ginseng and ginger have been established in a collaborative study involving 13 laboratories from 7 countries. Blind duplicate samples of blank, spiked (AF and OTA added) at levels ranging from 0.25 to 16.0 microg/kg for AF and 0.25 to 8.0 microg/kg for OTA were analyzed. A naturally contaminated powdered ginger sample was also included. Test samples were extracted with methanol and 0.5% aqueous sodium hydrogen carbonate solution (700 + 300, v/v). The extract was centrifuged, diluted with phosphate buffer (PB), filtered, and applied to an immunoaffinity column containing antibodies specific for AF and OTA. After washing the column with water, the toxins were eluted from the column with methanol, and quantified by high-performance LC with fluorescence detection. Average recoveries of AF from ginseng and ginger ranged from 70 to 87% (at spiking levels ranging from 2 to 16 microg/kg), and of OTA, from 86 to 113% (at spiking levels ranging from 1 to 8 microg/kg). Relative standard deviations for within-laboratory repeatability (RSDr) ranged from 2.6 to 8.3% for AF, and from 2.5 to 10.7% for OTA. Relative standard deviations for between-laboratory reproducibility (RSDR) ranged from 5.7 to 28.6% for AF, and from 5.5 to 10.7% for OTA. HorRat values were < or = 2 for the multi-analytes in the 2 matrixes.


Pyruvate suppresses PGC1alpha expression and substrate utilization despite increased respiratory chain content in C2C12 myotubes.
Sodium pyruvate can increase mitochondrial biogenesis in C2C12 myoblasts in a peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha)-independent manner. The present study examined the effect of 72-h treatment with sodium pyruvate (5-50 mM) or sodium chloride (50 mM) as an osmotic control on the regulation of mitochondrial substrate metabolism and biogenesis in C2C12 myotubes. Pyruvate (50 mM) increased the levels of fatty acid oxidation enzymes (CD36, 61%, and beta-oxidative enzyme 3-hydroxyacyl-CoA dehydrogenase, 54%) and the expression of cytochrome-c oxidase subunit I (220%) and cytochrome c (228%), consistent with its previous described role as a promoter of mitochondrial biogenesis. However, in contrast, pyruvate treatment reduced glucose transporter 4 (42%), phosphofructokinase (57%), and PGC1alpha (72%) protein content as well as PGC1alpha (48%) and PGC1beta (122%) mRNA. The decrease in PGC1alpha was compensated for by an increase in the PGC1alpha-related coactivator (PRC; 187%). Pyruvate treatment reduced basal and insulin-stimulated glucose uptake (41% and 31%, respectively) and palmitate uptake and oxidation (24% and 31%, respectively). The addition of the pyruvate dehydrogenase activator dichloroacetate (DCA) and the TCA precursor glutamine increased PGC1alpha expression (368%) and returned PRC expression to basal. Glucose uptake increased by 4.2-fold with DCA and glutamine and palmitate uptake increased by 18%. Coupled to this adaptation was an 80% increase in oxygen consumption. The data suggest that supraphysiological doses of pyruvate decrease mitochondrial function despite limited biogenesis and that anaplerotic agents can reverse this effect.


At the dawn of novel aromatics: "On the Synthesis of Hinokitiol" by Tetsuo Nozoe et al.
A paper titled "On the Synthesis of Hinokitiol" appeared in this journal in 1950 and marked the beginning of a new research field of novel aromatics.


Environmentally driven epizootics.
Environmental conditions can be the driving force behind an epizootic. Environmental changes may favor growth of a particular species, which results in increased contact rates and spread of a disease. We examine this particular phenomenon in SI and SIS models and use it to explain the possible disease outbreaks in nature. Either infected individuals recover from the disease (SIS model) or suffer disease fatalities (SI model). Epizootic models for a single population are examined where contact rate depends on population size. A reproductive number R is defined that depends on environmental carrying capacity. The single-population models are coupled to form three different two-species models with intra- and interspecies contact rates that depend on the population sizes of both populations. The stability results show that it is possible for the disease to drive one of the populations to extinction, the one with disease fatalities. The surviving species serves as a reservoir for the disease. Single- and two-species epizootic models are examined in a particular case where the contact rates are assumed to be constant. This leads to a new definition for the contact rate. A complete global analysis is possible in these latter cases. The results are compared and contrasted with the models with variable contact rates. The prototype for the models is the spread of disease in wildlife populations, which includes such diseases as plague or Lyme disease.


Combination therapy with glucagon-like peptide-1 and gastrin induces beta-cell neogenesis from pancreatic duct cells in human islets transplanted in immunodeficient diabetic mice.
Pancreatic islet transplantation as a treatment for type 1 diabetes is limited by human donor tissue availability. We investigated whether the beta-cell mass in human isolated islets could be expanded by treatments with glucagon-like peptide-1 (GLP-1) and gastrin, peptides reported to stimulate beta-cell growth in mice and rats with deficits in beta-cell mass. Human islets with low endocrine cell purity (7% beta-cells, 4% alpha-cells) and abundant exocrine cells (29% duct cells and 25% acinar cells) were implanted under the renal capsule of nonobese diabetic-severe combined immune deficiency (NOD-scid) mice made diabetic with streptozotocin. The mice were treated with GLP-1 and gastrin, separately and together, daily for 5 weeks. Blood glucose was significantly reduced only in mice implanted with human pancreatic cells and treated with GLP-1 plus gastrin. Correction of hyperglycemia was accompanied by increased insulin content in the human pancreatic cell grafts as well as by increased plasma levels of human C-peptide in the mice. Immunocytochemical examination revealed a fourfold increase in insulin-positive cells in the human pancreatic cell grafts in GLP-1 plus gastrin-treated mice, and most of this increase was accounted for by the appearance of cytokeratin 19-positive pancreatic duct cells expressing insulin. We conclude that combination therapy with GLP-1 and gastrin expands the beta-cell mass in human islets implanted in immunodeficient diabetic mice, largely from pancreatic duct cells associated with the islets, and this is sufficient to ameliorate hyperglycemia in the mice.


Influx of kininogens into nasal secretions after antigen challenge of allergic individuals.
We have recently demonstrated that kinins are generated in vivo after nasal challenge with antigen of allergic, but not nonallergic, individuals. The present study was undertaken as a first step in determining the mechanism(s) of kinin formation during the allergic reaction and was directed towards establishing the availability and origin of kininogens in nasal secretions. Allergic individuals (n = 6) and nonallergic controls (n = 5) were challenged with antigen; and by using specific radioimmunoassays, nasal washes, obtained before and after challenge, were assayed for high molecular weight kininogen (HMWK), total kininogen (TK), albumin, and kinins. Dramatic increases in HMWK (1,730 +/- 510 ng/ml), TK (3,810 +/- 1035 ng/ml), kinin (9.46 +/- 1.75 ng/ml), and albumin (0.85 +/- 0.2 mg/ml) were observed after challenge of allergic individuals which correlated (P less than 0.001) with increases in histamine and N-alpha-tosyl-L-arginine methyl esterase activity and with the onset of clinical symptoms. For nonallergic individuals, levels of kininogens, albumin, and all mediators after antigen challenge were not different from base line. Linear regression analysis revealed excellent correlations (P less than 0.001 in each case) between increases in HMWK, TK, kinin, and albumin during antigen titration experiments and between the time courses of appearance and disappearance of HMWK, TK, kinin, and albumin after antigen challenge. Gel filtration revealed no evidence of degradation products of kininogens in nasal washes. For each allergic individual the ratio of HMWK/TK in postchallenge nasal washes was similar to the ratio of these two proteins in the same individual's plasma. These data suggest that, during the allergic reaction, there is an increase in vascular permeability and a transudation of kininogens from plasma into nasal secretions, where they can provide substrate for kinin-forming enzymes.


Current concepts on the theories of the mechanism of action of fluoride.
The caries-preventive effect of fluoride is mainly attributed to the effects on demineralization/remineralization at the tooth oral fluids interface. Sub ppm levels of fluoride in saliva are effective in shifting the balance from demineralization, leading to caries, to remineralization. This is attributed to the fluoride-enhanced precipitation of calcium phosphates, and the formation of fluorhydroxyapatite in the dental tissues. Low fluoride levels are found in saliva after toothbrushing with fluoride containing dentifrices. Similar concentrations are ineffective in interfering with processes of growth and metabolism of bacteria, and also do not result in a significantly reduced dissolution of tooth mineral as a result of (firmly bound) fluoride incorporation. Comparative studies of fluoride efficacy have shown that higher concentrations in solution are needed in pH-cycling studies of dentine than in enamel to maintain the mineral balance or to induce remineralization. This is attributed to the greater solubility of the dentine and the smaller size of the dentine crystallites compared to enamel. Fluoride slow-release devices, in the form of fluoride-releasing restorative materials, may serve to increase the fluoride levels in saliva and plaque to levels at which caries can be prevented, also in high-risk patients. Research questions for the next millennium and future perspectives for fluoride applications should be found in the retention and slow release of fluoride after various combinations of fluoride treatment, the combination of fluoride and anti-microbial treatment, the individualization of caries prevention, and the combination of preventive schemes with new developments in caries diagnosis.


Rapidly growing massive abdominal sarcomatoid carcinoma on F18-FDG PET-CT scan.
Sarcomatoid carcinoma is a rare type of tumour and most commonly arises in the lungs. However, rarely can it also be found in the abdomen. Sarcomatoid tumours are aggressive with large tumoural volume showing cancerous epithelial cells mixed with sarcomatous (nerve, muscle, fat etc.) features on histopathology. Most of the carcinosarcomas arise in the background of pleomorphic adenoma, originating from a myoepithelial precursor. These tumours are resistant to treatment and rapidly metastasize. We present a unique case of hepatocellular sarcomatoid sarcoma, evaluated through F18-FDG PET/CT.


Changes in economic status of households associated with catastrophic health expenditures for cancer in South Korea.
Cancer imposes significant economic challenges for individuals, families, and society. Households of cancer patients often experience income loss due to change in job status and/or excessive medical expenses. Thus, we examined whether changes in economic status for such households is affected by catastrophic health expenditures. We used the Korea Health Panel Survey (KHPS) Panel 1st-4th (2008- 2011 subjects) data and extracted records from 211 out of 5,332 households in the database for this study. To identify factors associated with catastrophic health expenditures and, in particular, to examine the relationship between change in economic status and catastrophic health expenditures, we conducted a generalized linear model analysis. Among 211 households with cancer patients, 84 (39.8%) experienced catastrophic health expenditures, while 127 (40.2%) did not show evidence of catastrophic medical costs. If a change in economic status results from a change in job status for head of household (job loss), these households are more likely to incur catastrophic health expenditure than households who have not experienced a change in job status (odds ratios (ORs)=2.17, 2.63, respectively). A comparison between households with a newly-diagnosed patient versus households with patients having lived with cancer for one or two years, showed the longer patients had cancer, the more likely their households incurred catastrophic medical costs (OR=1.78, 1.36, respectively). Change in economic status of households in which the cancer patient was the head of household was associated with a greater likelihood that the household would incur catastrophic health costs. It is imperative that the Korean government connect health and labor policies in order to develop economic programs to assist households with cancer patients.


Physiological and biochemical aspects of the resistance of banana plants to Fusarium wilt potentiated by silicon.
Silicon amendments to soil have resulted in a decrease of diseases caused by several soilborne pathogens affecting a wide number of crops. This study evaluated the physiological and biochemical mechanisms that may have increased resistance of banana to Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense, after treatment with silicon (Si) amendment. Plants from the Grand Nain (resistant to F. oxysporum f. sp. cubense) and "Maçã" (susceptible to F. oxysporum f. sp. cubense) were grown in plastic pots amended with Si at 0 or 0.39 g/kg of soil (-Si or +Si, respectively) and inoculated with race 1 of F. oxysporum f. sp. cubense. Relative lesion length (RLL) and asymptomatic fungal colonization in tissue (AFCT) were evaluated at 40 days after inoculation. Root samples were collected at different times after inoculation with F. oxysporum f. sp. cubense to determine the level of lipid peroxidation, expressed as equivalents of malondialdehyde (MDA), hydrogen peroxide (H(2)O(2)), pigments (chlorophyll a, chlorophyll b, total chlorophyll, and carotenoids), total soluble phenolics (TSP), and lignin-thioglycolic acid (LTGA) derivatives; the activities of the enzymes phenylalanine ammonia-lyases glucanases (PALs), peroxidases (POXs), polyphenoloxidases (PPOs), β-1,3-glucanases (GLUs), and chitinases (CHIs); and Si concentration in roots. Root Si concentration was significantly increased by 35.3% for the +Si treatment compared with the -Si treatment. For Grand Nain, the root Si concentration was significantly increased by 12.8% compared with "Maçã." Plants from Grand Nain and "Maçã" in the +Si treatment showed significant reductions of 40.0 and 57.2%, respectively, for RLL compared with the -Si treatment. For the AFCT, there was a significant reduction of 18.5% in the +Si treatment compared with the -Si treatment. The concentration of MDA significantly decreased for plants from Grand Nain and "Maçã" supplied with Si compared with the -Si treatment while the concentrations of H(2)O(2) on roots and pigments on leaves significantly increased. The concentrations of TSP and LTGA derivatives as well as the PALs, PPOs, POXs, GLUs, and CHIs activities significantly increased on roots of plants from Grand Nain and "Maçã" from the +Si treatment compared with the -Si treatment. Results of this study suggest that the symptoms of Fusarium wilt on roots of banana plants supplied with Si decreased due to an increase in the concentrations of H(2)O(2), TSP, and LTGA derivatives and greater activities of PALs, PPOs, POXs, GLUs, and CHIs.


Complete response of mediastinal clear cell sarcoma to pembrolizumab with radiotherapy.
Clear cell sarcoma (CCS) is a rare, aggressive soft tissue sarcoma thought to derive from neural crest and characterized by a 12;22 translocation. The resulting fusion protein directly activates expression of the melanocyte master transcription factor and drives the same down-stream pathways in CCS and melanoma leading to significant clinical parallels between these malignancies. Striking success of immune checkpoint blockade in melanoma has promoted interest in immunotherapy of CCS. We report the first complete clinical response of a bulky chest wall recurrence of mediastinal CCS in a young woman to anti-PD1 checkpoint blockade with pembrolizumab combined with standard fractionation radiotherapy to enhance regional control and potentially boost the systemic immune response. The treatment was well tolerated with grade 2 skin toxicity within the range expected with radiation alone. Significant reduction in tumor bulk occurred after only 2 radiation fractions and complete response was achieved at 50 Gray. The complete clinical response observed in our patient suggests synergy between concurrent radiotherapy and PD1 blockade in CCS. This case and the striking parallels between CCS and melanoma indicate the need for prospective trials of immune checkpoint blockade combined with radiotherapy in this rare malignancy.


A timer for analyzing temporally dynamic changes in transcription during differentiation in vivo.
Understanding the mechanisms of cellular differentiation is challenging because differentiation is initiated by signaling pathways that drive temporally dynamic processes, which are difficult to analyze in vivo. We establish a new tool, Timer of cell kinetics and activity (Tocky; or toki [time in Japanese]). Tocky uses the fluorescent Timer protein, which spontaneously shifts its emission spectrum from blue to red, in combination with computer algorithms to reveal the dynamics of differentiation in vivo. Using a transcriptional target of T cell receptor (TCR) signaling, we establish Nr4a3-Tocky to follow downstream effects of TCR signaling. Nr4a3-Tocky reveals the temporal sequence of events during regulatory T cell (Treg) differentiation and shows that persistent TCR signals occur during Treg generation. Remarkably, antigen-specific T cells at the site of autoimmune inflammation also show persistent TCR signaling. In addition, by generating Foxp3-Tocky, we reveal the in vivo dynamics of demethylation of the Foxp3 gene. Thus, Tocky is a tool for cell biologists to address previously inaccessible questions by directly revealing dynamic processes in vivo.


Assessing Mineral Availability in Fish Feeds using Complementary Methods Demonstrated with the Example of Zinc in Atlantic Salmon.
Assessing the availability of dietary micro-minerals is a major challenge in mineral nutrition of fish species. The present article aims to describe a systematic approach combining different methodologies to assess the availability of zinc (Zn) in Atlantic salmon (Salmo salar). Considering that several Zn chemical species can be present in an Atlantic salmon feed, it was hypothesised that Zn availability is influenced by the Zn chemical species present in the feed. Thus, in this study, the first protocol is about how to extract the different Zn chemical species from the feed and to analyze them by a size exclusion chromatography-inductively coupled plasma mass spectroscopy (SEC-ICP-MS) method. Subsequently, an in vitro method was developed to evaluate the solubility of dietary Zn in Atlantic salmon feeds. The third protocol describes the method to study the impact of changing Zn chemical species composition on the uptake of Zn in a fish intestinal epithelial model using a rainbow trout gut cell line (RTgutGC). Together, the findings from the in vitro methods were compared with an in vivo study examining the apparent availability of inorganic and organic sources of Zn supplemented to Atlantic salmon feeds. The results showed that several Zn chemical species can be found in feeds and the efficiency of an organic Zn source depends very much on the amino acid ligand used to chelate Zn. The findings of the in vitro methods had less correlation with that outcome of the in vivo study. Nevertheless, in vitro protocols described in this article provided crucial information regarding Zn availability and its assessment in fish feeds.


The concentration dependence of active K+ transport in the turkey erythrocyte. Hill analysis and evidence for positive cooperativity between ion binding sites.
A mathematical model is presented which describes the theoretical relationship between ligand concentration and physiological response for systems in which the response is dependent upon simultaneous occupancy of two receptor ligand-binding sites. The treatment considers both the possibility of intrinsic differences between the binding sites with regard to ligand affinity, as well as the possibility of mutually induced changes in affinity resulting from allosteric interactions. Unlike the Monod-Wyman-Changeux formulation for allosteric enzymes, the general model put forward here makes double occupancy an absolute requirement for enzymatic function. It is shown that such a model leads to the prediction of a curvilinear Hill plot from which one can obtain an explicit estimate of the degree of allosteric interaction between the two ligand binding sites as well as the Gibbs standard free energy change for the overall binding reaction. It is then shown that, in the specific instance of Na, K-ATPase-mediated K+ transport by the turkey erythrocyte, the configuration of the Hill curve describing the rate of ouabain-sensitive K+ transport as a function of external K+ concentration conforms closely to that predicted by the model described above. The results are of particular interest because they indicate a strongly cooperative interaction between the two K+ binding sites on the transport protein such that occupancy of one site results in an enhancement of the affinity of the other site for K+ by a minimum of 15- to 20-fold. Finally, we consider in detail a model of the Monod-Wyman-Changeux type in which, by contrast, both singly and doubly occupied forms of the enzyme are assumed to be catalytically active, and which we analogously extend to allow for the possibility of asymmetry between the two ligand binding sites. Although it is shown that the two models can not be differentiated from each other in the present experimental system, they yield virtually identical estimates for the degree of positive cooperativity between the two K+ binding sites.


Medical Students' Perceived Interests and Concerns for a Career in Neurosurgery.
The factors that attract and concern medical students about a career in neurosurgery have never been clearly characterized or delineated in a large nationwide cohort of medical students intending to pursue a career in neurosurgery. The objective of the present study was to characterize the factors that influence medical student interest in neurosurgery and assess the effects of a formal neurosurgery training course on participants' perceptions of a career in neurosurgery. Before the Medical Student Neurosurgery Training Camp for subinternship preparation, registered students were surveyed about their interest level in neurosurgery, factors that attracted or concerned them about a career in neurosurgery, attendance at a national neurosurgery conference or course, formal clinical neurosurgery exposure in medical school, and whether they had a resident or attending mentor in neurosurgery. At the end of the course, all the participants completed the surveyed again. P < 0.05 was considered significant on Pearson's χ2 and Fisher's exact tests for categorical variables and 2-tailed paired Student's t tests for continuous variables. Of the training camp attendees, >95% completed both pre- and postcourse surveys, including 41 first-year, 19 second-year, 30 third-year, and 5 fourth-year medical school students. The most common factors that concerned students about a career in neurosurgery were work-life balance (76%) and competitiveness (56%). All factors of concern were decreased in the postcourse survey, except for competitiveness. A small cohort (8.4%) of students had no concerns about a career in neurosurgery; this cohort had doubled to 17% after the course (P < 0.05). The students that indicated no concern had a greater postcourse interest level in neurosurgery (95.8 ± 8.7 vs. 86.7 ± 20.5; P < 0.05). Student reasons for an interest in neurosurgery included intellectually stimulating work (94%), interest in neurosciences (93%), effect on patients (84%), innovation and new technology (80%), research opportunities (77%), and prestige (24%). All reasons increased after the course, with the exception of prestige, which decreased to 22%. A training camp for students pursuing a neurosurgery subinternship was effective in providing transparency and positively influencing the factors that attract and concern students about a career in neurosurgery. Characterization of medical student perceptions of neurosurgery from a large, nationwide cohort of students pursuing a subinternship has provided novel data and could help identify factors protecting against burnout later in life.


The midterm effectiveness of extracorporeal shockwave therapy in the management of chronic calcific shoulder tendinitis.
This systematic review explored the midterm effectiveness of extracorporeal shockwave therapy (ESWT) in reducing pain and improving shoulder function. Calcified rotator cuff tendinitis is a common cause of chronic shoulder pain that leads to significant pain and functional limitations. ESWT is an alternative to surgery when conservative treatments such as nonsteroidal antiinflammatory drugs, steroidal injections, and physiotherapy fail to relieve symptoms. It is hypothesised that ESWT is effective in the midterm for reducing pain and improving function for patients with chronic calcific tendinitis and that a dose-response relationship exists in the treatment parameters for effectiveness. Articles were electronically searched from the Cochrane Controlled Trials Register, MEDLINE, CINAHL, PUBMED, EMBASE, SPORTSDiscus and PEDro using a comprehensive search strategy. Studies were included if they were randomized controlled trials testing the midterm effectiveness of ESWT for chronic calcific tendonitis. Methodologic quality was assessed by PEDro (total score = 10). The strength of the evidence was reported using the National Health and Medical Research Council body of evidence framework. Six of the nine included studies scored 7 or more for methodologic quality. All studies had follow-up periods of at least 6 months. Common methodologic flaws were insufficient blinding of clinicians and assessors. There was consistent evidence of midterm effectiveness of ESWT in reducing pain and improving shoulder function for patients with chronic calcified tendinitis. ESWT is a potential alternative to surgery with good mid-term effectiveness and minimal side effects. This review noted several limitations with the current body of evidence. Studies were mainly from a few European countries involving medical doctors, with a lack of diverse perspectives and effectiveness evaluation from other health professionals who might use this treatment option for patients with chronic calcific tendinitis. Further, the different outcome measures used and inadequate reporting details in the included studies did not permit a quantitative synthesis of the effectiveness of this treatment. A lack of follow up period beyond one year in the studies also precluded conclusion to be made on the longer term effectiveness of ESWT. Due to variable treatment parameters (eg dosage), this review was unable to provide clear guidance of the dose-effect of the midterm effectiveness of ESWT. Studies of better methodologic design using standardized treatment protocols and studies with longer follow-up are required.


Efficacy and safety of definitive chemoradiotherapy with or without induction immune checkpoint inhibitors in patients with stage III non-small cell lung cancer.
In the era of immunotherapy, the optimal combination of immune checkpoint inhibitors (ICIs) and chemoradiotherapy (CRT) for stage III non-small cell lung cancer (NSCLC) is not defined. The current study investigated the efficacy and safety of definitive CRT(dCRT) plus consolidation ICIs with or without induction ICIs in stage III NSCLC. 123 consecutive patients treated with dCRT followed by consolidation ICIs at our institution from 2018 to 2022 were retrospectively reviewed. Failure patterns, survival outcomes, and toxicity profiles were analyzed. The 1- and 2- year PFS rates were 75.3% and 56.9%, respectively, and median PFS was 30.83 months from the start of treatment. In-field failure (18.7%) was the most common failure pattern. The most common adverse event (AE) was pneumonitis caused by ICIs or RT. The incidence of Grade 3-4 and Grade 5 pneumonitis was 5.7% and 1.6%, respectively. Further analysis showed that the induction plus consolidation ICIs group has significantly lower cumulative incidence of distant metastasis rates (HR: 0.30, 95%CI: 0.09-1.00, p=0.043) and higher incidence of pneumonitis (p=0.039) compared with patients in the consolidation ICIs group. Combined CRT and consolidation ICIs achieved encouraging efficacy and manageable toxicity in patients with stage III NSCLC in China. Induction plus consolidation ICIs might reduce distant metastasis and deserve further investigation.


[Functional capacity and referred morbidity of elderly in an area covered by the Family Health Program].
This study aimed at characterizing the health perception, functional capacity and prevalence of self-referred diseases among the elderly in an area covered by the Family Health Strategy. The sample consisted of 86 elderly people (75 years or older) from a city in the north of Paraná, Brazil. The data were collected in the second semester of 2004 by means of an adapted version of the OARS. 47.7% evaluated their health between good and excellent; 77.9% were independent; 76.7% presented co-morbidities. This article discusses the importance of the family health teams in the adoption of health preventive and promotional measures for the elderly and their families.


Size-selected synthesis of PtRu nano-catalysts: reaction and size control mechanism.
A rapid synthesis method for the preparation of PtRu colloids and their subsequent deposition on high surface area carbons is presented. The reaction mechanism is shown to involve the oxidation of the solvent, ethylene glycol, to mainly glycolic acid or, depending on the pH, its anion, glycolate, while the Pt(+IV) and Ru(+III) precursor salts are reduced. Glycolate acts as a stabilizer for the PtRu colloids and the glycolate concentration, and hence the size of the resulting noble metal colloids is controlled via the pH of the synthesis solution. Carbon-supported PtRu catalysts of controlled size can be prepared within the range of 0.7-4 nm. Slow scan X-ray diffraction and high-resolution transmission electron microscopy show the PtRu catalysts to be crystalline. The Ru is partly dissolved in the face-centered cubic Pt lattice, but the catalysts also consist of a separate, hexagonal Ru phase. The PtRu catalysts appear to be of the same composition independent of the catalyst size in the range of 1.2-4 nm. Particular PtRu catalysts prepared in this work display enhanced activities for the CH(3)OH electro-oxidation reaction when compared to two commercial catalysts.


Differences in the Transcriptomic Response of Campylobacter coli and Campylobacter lari to Heat Stress.
Campylobacter spp. are one of the most important food-borne pathogens, which are quite susceptible to environmental or technological stressors compared to other zoonotic bacteria. This might be due to the lack of many stress response mechanisms described in other bacteria. Nevertheless, Campylobacter is able to survive in the environment and food products. Although some aspects of the heat stress response in Campylobacter jejuni are already known, information about the stress response in other Campylobacter species are still scarce. In this study, the stress response of Campylobacter coli and Campylobacter lari to elevated temperatures (46°C) was investigated by survival assays and whole transcriptome analysis. None of the strains survived at 46°C for more than 8 h and approximately 20% of the genes of C. coli RM2228 and C. lari RM2100 were differentially expressed. The transcriptomic profiles showed enhanced gene expression of several chaperones like dnaK, groES, groEL, and clpB in both strains, indicating a general involvement in the heat stress response within the Campylobacter species. However, the pronounced differences in the expression pattern between C. coli and C. lari suggest that stress response mechanisms described for one Campylobacter species might be not necessarily transferable to other Campylobacter species.


Development of biodegradable poly(propylene fumarate)/poly(lactic-co-glycolic acid) blend microspheres. I. Preparation and characterization.
We developed poly(propylene fumarate)/poly(lactic-co-glycolic acid) (PPF/PLGA) blend microspheres and investigated the effects of various processing parameters on the characteristics of these microspheres. The advantage of these blend microspheres is that the carbon-carbon double bonds along the PPF backbone could be used for their immobilization in a PPF scaffold. Microspheres containing the model drug Texas red dextran were fabricated using a double emulsion-solvent extraction technique. The effects of the following six processing parameters on the microsphere characteristics were investigated: PPF/PLGA ratio, polymer viscosity, vortex speed during emulsification, amount of internal aqueous phase, use of poly(vinyl alcohol) (PVA) in the internal aqueous phase, and PVA concentration in the external aqueous phase. Our results showed that the microsphere surface morphology was affected most by the viscosity of the polymer solution. Microspheres fabricated with a kinematic viscosity of 39 centistokes had a smooth, nonporous surface. In most microsphere formulations, the model drug was dispersed uniformly in the polymer matrix. For all fabricated formulations, the average microsphere diameter ranged between 19.0 and 76.9 microm. The external PVA concentration and vortex speed had most effect on the size distribution. Entrapment efficiencies varied from 60 to 98% and were most affected by the amount of internal aqueous phase, vortex speed, and polymer viscosity. Overall, we demonstrated the ability to fabricate PPF/PLGA blend microspheres with similar surface morphology, entrapment efficiency, and size distribution as conventional PLGA microspheres.


Investigation into the causes of indwelling urethral catheter implementation and its effects on clinical outcomes and health care resources among dementia patients with pneumonia: A retrospective cohort study.
There is a possibility that unnecessary treatments and low-quality medical care, such as inappropriate indwelling urethral catheter use, are being provided to older Japanese individuals.The aim of this study was to investigate contextual effects relating to indwelling urethral catheters in older people with dementia and to clarify the effects of indwelling urethral catheter use on patients' mortality, length of stay (LOS), and health care spending. This retrospective cohort study involved 4501 male and female Japanese participants. Those who were aged 75 or older with dementia and had a primary diagnosis of acute lower respiratory disease with antibiotics administered during hospitalization were eligible for inclusion. Patient mortality, LOS, and total charge during hospitalization were the main study outcomes. This study showed that indwelling urethral catheter use was significantly associated with higher mortality, longer LOS, and higher total charge for hospitalization. The pattern of indwelling urethral catheter use was clustered by care facility level. Physician density was significantly associated with indwelling urethral catheter use; the relationship was not linear but U-shaped, such that the approximate median had the lowest rate of urethral catheter use and this increased gradually toward both lower and higher physician densities. Our study found considerable variation in indwelling urethral catheter use between care facilities in older people with dementia. Additionally, indwelling urethral catheter use was related to poor outcomes. Based on these findings, we consider there to be an urgent need for constructing a framework to measure, report on, and promote the improvement of care quality for older individuals in Japan.


A deep learning approach to identify missing is-a relations in SNOMED CT.
SNOMED CT is the largest clinical terminology worldwide. Quality assurance of SNOMED CT is of utmost importance to ensure that it provides accurate domain knowledge to various SNOMED CT-based applications. In this work, we introduce a deep learning-based approach to uncover missing is-a relations in SNOMED CT. Our focus is to identify missing is-a relations between concept-pairs exhibiting a containment pattern (ie, the set of words of one concept being a proper subset of that of the other concept). We use hierarchically related containment concept-pairs as positive instances and hierarchically unrelated containment concept-pairs as negative instances to train a model predicting whether an is-a relation exists between 2 concepts with containment pattern. The model is a binary classifier leveraging concept name features, hierarchical features, enriched lexical attribute features, and logical definition features. We introduce a cross-validation inspired approach to identify missing is-a relations among all hierarchically unrelated containment concept-pairs. We trained and applied our model on the Clinical finding subhierarchy of SNOMED CT (September 2019 US edition). Our model (based on the validation sets) achieved a precision of 0.8164, recall of 0.8397, and F1 score of 0.8279. Applying the model to predict actual missing is-a relations, we obtained a total of 1661 potential candidates. Domain experts performed evaluation on randomly selected 230 samples and verified that 192 (83.48%) are valid. The results showed that our deep learning approach is effective in uncovering missing is-a relations between containment concept-pairs in SNOMED CT.


Botulinum toxin A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity/neurogenic overactive bladder: a systematic literature review.
This systematic literature review discusses the efficacy and safety of botulinum toxin type A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity (NDO) and urinary incontinence or overactive bladder symptoms of neurogenic origin (NOAB). A MEDLINE and EMBASE search for clinical studies with botulinum toxin A injected into the detrusor of adults with NDO was performed. For several efficacy and safety variables data were extracted by one person and independently quality-controlled by another person. Extracted data were reviewed to propose recommendations for use in clinical practice based on level of evidence and expert opinion. A total of 18 articles evaluating the efficacy or safety of Botox in patients with NDO and incontinence/NOAB resistant to antimuscarinic therapy, with or without clean intermittent self-catheterisation (CIC), were selected. The amount of Botox injected was mostly 300 U, usually as 30 injections of 10 U/ml in the bladder (excluding the trigone) under cystoscopic guidance and with different types of anaesthesia. Most of the studies reported a significant improvement in clinical (approximately 40-80% of patients became completely dry between CICs) as well as urodynamic (in most studies mean maximum detrusor pressure was reduced to < or =40 cm H(2)O) variables and in the patients' quality of life, without major adverse events. Botox injections into the detrusor provide a clinically significant improvement in adults with NDO and incontinence/NOAB refractory to antimuscarinics. It seems to be very well tolerated. However, more adequately powered, well-designed, randomised, controlled studies evaluating the optimal dose, number and location of injections, impact on antimuscarinic regimen and CIC use, duration of effect, and when to perform repeat injections are warranted.


Improved insulin sensitivity after treatment with PPARγ and PPARα ligands is mediated by genetically modulated transcripts.
We aimed to define the effects of peroxisomal proliferator-activated receptor γ (PPARγ) and PPARα agonist mono and combination therapy on adipose tissue and skeletal muscle gene expression in relation to insulin sensitivity. We further investigated the role of genetic polymorphisms in PPAR ligand-modulated genes in transcriptional regulation and glucose homeostasis. Genome-wide transcript profiles of subcutaneous adipose and skeletal muscle and metabolic phenotypes were assessed before and after 10 weeks of pioglitazone and fenofibrate mono or combination therapy in 26 patients with impaired glucose tolerance. To establish the functional role of single nucleotide polymorphisms (SNPs) in genes modulated by pioglitazone alone or in combination with fenofibrate, we examined genome-wide association data of continuous glycemic phenotypes from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium study and adipose eQTL data from the Multi Tissue Human Expression Resource study. PPARγ, alone or in combination with PPARα agonists, mediated upregulation of genes involved in the TCA cycle, branched-chain amino acid (BCAA) metabolism, fatty acid metabolism, PPAR signaling, AMPK and cAMP signaling, and insulin signaling pathways, and downregulation of genes in antigen processing and presentation, and immune and inflammatory response in adipose tissue. Remarkably few changes were found in muscle. Strong enrichment of genes involved in propanoate metabolism, fatty acid elongation in the mitochondria, and acetyl-CoA metabolic process were observed only in adipose tissue of the combined pioglitazone and fenofibrate treatment group. After examining Meta-Analyses of Glucose and Insulin-Related Traits Consortium data, SNPs in 22 genes modulated by PPAR ligands were associated with fasting plasma glucose and the expression of 28 transcripts modulated by PPAR ligands was under control of local genetic regulators (cis-eQTLs) in adipose tissue of Multi Tissue Human Expression Resource study twins. We found differences in transcriptional mechanisms that may describe the insulin-sensitizing effects of PPARγ agonist monotherapy or in combination with a PPARα agonist. The regulatory and glucose homeostasis trait-associated SNPs in PPAR agonist-modulated genes are important candidates for future studies that may explain the interindividual variability in response to thiazolidinedione and fenofibrate treatment.


Detection of new and persistent Streptococcus uberis and Streptococcus dysgalactiae intramammary infections by polymerase chain reaction-based DNA fingerprinting.
Polymerase chain reaction-based DNA fingerprinting was used as a tool to differentiate new and persistent Streptococcus uberis and Streptococcus dysgalactiae intramammary infections (IMI) in dairy cows. The same subtype of S. uberis or S. dysgalactiae was detected from some infected mammary glands from one lactation to the next documenting the persistence of these infections. Conversely, some streptococci isolated from mammary glands during a lactation or from one lactation to the next were different subtypes suggesting that a new IMI occurred. These new streptococcal IMI would never have been detected using phenotypic methods of streptococcal identification. Results of this study indicate that PCR-based DNA fingerprinting can be used as an effective procedure to differentiate new and persistent S. uberis and S. dysgalactiae IMI in dairy cows. This technique will be useful in epidemiological investigations, and drug and vaccine efficacy studies when attempting to delineate new and persistent IMI.


The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer.
We identified a regulatory system that acts downstream of Wnt/β-catenin signaling in salivary gland and head and neck carcinomas. We show in a mouse tumor model of K14-Cre-induced Wnt/β-catenin gain-of-function and Bmpr1a loss-of-function mutations that tumor-propagating cells exhibit increased Mll1 activity and genome-wide increased H3K4 tri-methylation at promoters. Null mutations of Mll1 in tumor mice and in xenotransplanted human head and neck tumors resulted in loss of self-renewal of tumor-propagating cells and in block of tumor formation but did not alter normal tissue homeostasis. CRISPR/Cas9 mutagenesis and pharmacological interference of Mll1 at sequences that inhibit essential protein-protein interactions or the SET enzyme active site also blocked the self-renewal of mouse and human tumor-propagating cells. Our work provides strong genetic evidence for a crucial role of Mll1 in solid tumors. Moreover, inhibitors targeting specific Mll1 interactions might offer additional directions for therapies to treat these aggressive tumors.


Prevention of disability in leprosy.
Leprosy is curable now-a-days if initiatives are taken for prevention of disability along with complete and regular chemotherapy. Common disabilities encountered in leprosy are: Claw hand, foot drop, lagophthalmos, plantar ulcers and depressed bridge of nose. Objectives of prevention of disabilities are preservation of nerve function, preservation of vision, to regain functional ability and self-esteem. Measures to prevent disabilities include early diagnosis and treatment with effective chemotherapy, to train leprosy cases to perform self-care practices, providing them with protective aids and referring the cases for surgery if indicated. Lepra reactions are episodes of sudden increase in the activity of the disease. Lepra reactions are treated by bed rest, analgesics rest to affected nerve by splints and a suggested course of prednisolone. Besides, leprosy-affected persons should be encouraged for self-care practices. Counselling and holding care and concern camps (POD camps) are very much integrated wtih the prevention of disabilities.


Characterisation of human articular cartilage link proteins from normal and osteoarthritic cartilage.
Proteoglycan link proteins were isolated from human articular cartilage obtained from normal and osteoarthritic femoral heads and purified to homogeneity employing a method previously described by this laboratory. The link proteins were analysed for amino acid composition, molecular weight on sodium dodecyl sulphate polyacrylamide gels, and ability to stabilise proteoglycan aggregates. The results of these studies were compared with those obtained with bovine link proteins. Two link proteins were identified in the purified fraction from normal and osteoarthritic human cartilage with apparent molecular weights of 54 000 (link 1) and 48 000 (link 2). Functionally the link proteins, isolated from osteoarthritic and normal cartilage, were indistinguishable as measured by their ability to stabilise aggregate. The amino acid compositions of normal and osteoarthritic link proteins were also found to be similar to each other but significantly different from the amino acid composition reported for the bovine link proteins. The quantities of these proteins in extracts from normal and diseased tissue were similar, as was the ratio of link protein 1 to link protein 2.


Transcriptional regulation by p53.
Inactivation of p53 is critical for the formation of most tumors. Illumination of the key function(s) of p53 protein in protecting cells from becoming cancerous is therefore a worthy goal. Arguably p53's most important function is to act as a transcription factor that directly regulates perhaps several hundred of the cell's RNA polymerase II (RNAP II)-transcribed genes, and indirectly regulates thousands of others. Indeed p53 is the most well studied mammalian transcription factor. The p53 tetramer binds to its response element where it can recruit diverse transcriptional coregulators such as histone modifying enzymes, chromatin remodeling factors, subunits of the mediator complex, and components of general transcription machinery and preinitiation complex (PIC) to modulate RNAPII activity at target loci (Laptenko and Prives 2006). The p53 transcriptional program is regulated in a stimulus-specific fashion (Murray-Zmijewski et al. 2008; Vousden and Prives 2009), whereby distinct subsets of p53 target genes are induced in response to different p53-activating agents, likely allowing cells to tailor their response to different types of stress. How p53 is able to discriminate between these different loci is the subject of intense research. Here, we describe key aspects of the fundamentals of p53-mediated transcriptional regulation and target gene promoter selectivity.


[The possibilities of x-ray study in assessing the results of the radiation treatment of laryngeal cancer].
The paper is devoted to comparing laryngoscopy findings and the results of x-ray investigation in its time course (prior to, during and after radiation therapy) in 65 laryngeal cancer patients. Both methods are mutually complementary, and thorough comparison of their results helped to overcome diagnostic difficulties. The basal point and spreading of exophytic supralaryngeal tumors can be determined by x-ray only. The greatest diagnostic difficulties occur after therapy to differentiate between postradiation mucosal edema and a tumor relapse.


Polypeptide organic radical batteries.
In only a few decades, lithium-ion batteries have revolutionized technologies, enabling the proliferation of portable devices and electric vehicles1, with substantial benefits for society. However, the rapid growth in technology has highlighted the ethical and environmental challenges of mining lithium, cobalt and other mineral ore resources, and the issues associated with the safe usage and non-hazardous disposal of batteries2. Only a small fraction of lithium-ion batteries are recycled, further exacerbating global material supply of strategic elements3-5. A potential alternative is to use organic-based redox-active materials6-8 to develop rechargeable batteries that originate from ethically sourced, sustainable materials and enable on-demand deconstruction and reconstruction. Making such batteries is challenging because the active materials must be stable during operation but degradable at end of life. Further, the degradation products should be either environmentally benign or recyclable for reconstruction into a new battery. Here we demonstrate a metal-free, polypeptide-based battery, in which viologens and nitroxide radicals are incorporated as redox-active groups along polypeptide backbones to function as anode and cathode materials, respectively. These redox-active polypeptides perform as active materials that are stable during battery operation and subsequently degrade on demand in acidic conditions to generate amino acids, other building blocks and degradation products. Such a polypeptide-based battery is a first step to addressing the need for alternative chemistries for green and sustainable batteries in a future circular economy.


Understanding the context of delays in seeking appropriate care for children with symptoms of severe malaria in Uganda.
A large proportion of children with uncomplicated malaria receive appropriate treatment late, contributing to progression of illness to severe disease. We explored contexts of caregiver delays in seeking appropriate care for children with severe malaria. This qualitative study was conducted at the Children's Ward of Jinja Hospital, where children with severe malaria were hospitalized. A total of 22in-depth interviews were conducted with caregivers of children hospitalized with severe malaria. Issues explored were formulated based on the Partners for Applied Social Sciences (PASS) model, focusing on facilitators and barriersto caregivers'promptseeking and accessing ofappropriate care. The data were coded deductively using ATLAS.ti (version 7.5). Codes were then grouped into families based on emerging themes. Caregivers' rating of initial symptoms as mild illness lead to delays in response. Use of home initiated interventions with presumably ineffective herbs or medicines was common, leading to further delay. When care was sought outside the home, drug shops were preferred over public health facilities for reasons of convenience. Drug shops often provided sub-optimal care, and thus contributed to delays in access to appropriate care. Public facilities were often a last resort when illness was perceived to be progressing to severe disease. Further delays occurred at health facilities due to inadequate referral systems. Communities living in endemic areas need to be sensitized about the significance of fever, even if mild, as an indicator of malaria. Additionally, amidst ongoing efforts at bringing antimalarial treatment services closer to communities, the value of drug shops as providers ofrationalantimalarialtreatment needs to be reviewed.


Potential for the spread of Escherichia coli O157, Salmonella, and Campylobacter in the lairage environment at abattoirs.
Prevalences of Escherichia coli O157, Salmonella spp., and Campylobacter spp. were examined in 270 swabs taken from selected sites along the unloading-to-slaughter routes of animal movement in lairages of six commercial abattoirs, three for cattle and three for sheep. The overall prevalences of the pathogens in the respective lairage environments were compared with those for 270 swabs from the pelts of 90 lambs examined in the present study and 270 swabs from the hides of 90 cattle examined in a previous study that were slaughtered at the same abattoirs on the same days. Also, the results obtained were analyzed with the aim of identifying critical points at which animal-environment-animal transfer of the pathogens in lairages occurs. The results showed that (i) the overall prevalences of E. coli O157, Salmonella spp., and Campylobacter spp. were 27.2, 6.1, and 1.1%, respectively, in cattle lairages and 2.2, 1.1, and 5.6%, respectively, in sheep lairages; (ii) the overall prevalences of the three pathogens on cow hides (28.8, 17.7, and 0%, respectively) and sheep pelts (5.5, 7.8, and 0%, respectively) were higher than the overall prevalences in the respective lairage environments; (iii) the most frequently contaminated sites in cattle lairages were holding pen floors (50% of swabs positive for one or more pathogens), entrance gates of stun boxes (27.8% of swabs positive for one or more pathogens), and stun box floors (22.2% of swabs positive for one or more pathogens); (iv) the most frequently contaminated sites in sheep lairages were unloading ramp floors, holding pen floors, and water troughs (33.3, 22.2, and 22.2%, respectively); and (v) overall, cattle lairages and cow hides were more frequently contaminated with the pathogens than were lamb lairages and lamb pelts. Further research is needed to develop strategies for the incorporation of pathogen control in lairages into integrated microbial meat safety systems.


Oral antibiotic use and risk of colorectal cancer in the United Kingdom, 1989-2012: a matched case-control study.
Microbiome dysbiosis predisposes to colorectal cancer (CRC), but a population-based study of oral antibiotic exposure and risk patterns is lacking. To assess the association between oral antibiotic use and CRC risk. A matched case-control study (incident CRC cases and up to five matched controls) was performed using the Clinical Practice Research Datalink from 1989 to 2012. 28 980 CRC cases and 137 077 controls were identified. Oral antibiotic use was associated with CRC risk, but effects differed by anatomical location. Antibiotic use increased the risk of colon cancer in a dose-dependent fashion (ptrend <0.001). The risk was observed after minimal use, and was greatest in the proximal colon and with antibiotics with anti-anaerobic activity. In contrast, an inverse association was detected between antibiotic use and rectal cancers (ptrend=0.003), particularly with length of antibiotic exposure >60 days (adjusted OR (aOR), 0.85, 95% CI 0.79 to 0.93) as compared with no antibiotic exposure. Penicillins, particularly ampicillin/amoxicillin increased the risk of colon cancer (aOR=1.09 (1.05 to 1.13)), whereas tetracyclines reduced the risk of rectal cancer (aOR=0.90 (0.84 to 0.97)). Significant interactions were detected between antibiotic use and tumour location (colon vs rectum, pinteraction<0.001; proximal colon versus distal colon, pinteraction=0.019). The antibiotic-cancer association was found for antibiotic exposure occurring >10 years before diagnosis (aOR=1.17 (1.06 to 1.31)). Oral antibiotic use is associated with an increased risk of colon cancer but a reduced risk of rectal cancer. This effect heterogeneity may suggest differences in gut microbiota and carcinogenesis mechanisms along the lower intestinal tract.


The effect of permutations of time samples in the speech waveform on intelligibility.
This paper describes the effect of two types of temporal permutations of the speech waveform on speech intelligibility. Using an overlap-add procedure with triangular-shaped windows for frame lengths of 1/8 to 2048 ms, the temporal order of the speech samples within each frame was subjected to either of two types of permutations: time-reversal or randomization. For both permutations, speech intelligibility tests expectantly show 100% intelligibility for the very short frame lengths containing only a few speech samples. Intelligibility drops to essentially zero toward longer frame lengths of around 1 ms. Interestingly, only for the reverse condition, intelligibility recovers to essentially 100% for frame lengths in the 4-32 ms range, dropping again to zero for frame lengths exceeding about 100 ms. Tests for the Japanese and the English language show essentially similar results. The data are interpreted along the lines of a previous paper by Kazama and the present authors [J. Acoust. Soc. Am. 127(3), 1432-1439 (2010)]. As in that previous paper, the loss of temporal envelope correlation shows a pattern very similar to that of the intelligibility data, illustrating again the importance of the preservation of narrow-band envelopes for speech intelligibility.


Improving Cardiovascular Disease Knowledge among Rural Participants: The Results of a Cluster Randomized Trial.
Cardiovascular disease (CVD) is a major cause of death and disability, especially among people living in the rural, southern United States. Rural African Americans are often diagnosed with CVD earlier in life, and they bear a disproportionate burden of CVD risk factors, morbidity, and mortality. Health equity among historically underserved, rural populations can potentially be attained through culturally relevant interventions that teach people skills to stay well and avoid CVD-related risk and diagnoses. The purpose of this secondary analysis was to determine the effect of an evidence-based intervention on cardiovascular health knowledge and the stages of change toward the action and maintenance phases. The pre-test-post-test data were obtained during a cluster randomized trial involving twelve rural churches that were randomized to intervention (n = 6) and control (n = 6) groups. Participants (n = 115) in the intervention group received a cardiovascular health intervention, and those (n = 114) in the control group could receive the intervention following the study's completion. The data were analyzed using a linear mixed model to compare group differences from pre-test to post-test. The cardiovascular health promotion intervention significantly improved cardiovascular health knowledge and was associated with advancements in the stages of change toward the action and maintenance phases.


Regulation of 90-kilodalton ribosomal S6 kinase phosphorylation in the rat pineal gland.
In this study we investigated diurnal changes in the activation state of the 90-kDa ribosomal S6 kinase (p90RSK) in the rat pineal gland. In animals housed under a lighting regimen with 12 h of light, we found an increase in phosphorylated p90RSK during the dark phase, and this increase was abolished by treatment with propranolol or continuous exposure to light. To determine the intracellular mechanism involved, rat pinealocytes were treated with norepinephrine. Norepinephrine caused a parallel increase in phosphorylated p42/44 MAPK (p42/44(MAPK)) and p90RSK that was reduced by prazosin or propranolol, indicating involvement of both alpha(1)- and beta-adrenergic receptors. Treatment with dibutyryl cGMP, 4beta-phorbol 12-myristate 13-acetate, or ionomycin mimicked norepinephrine-stimulated p90RSK phosphorylation, whereas dibutyryl cAMP caused a decrease in p90RSK phosphorylation. Inhibition of p42/44(MAPK) activation by UO126 was effective in reducing norepinephrine-stimulated p90RSK phosphorylation. Moreover, UO126 had an inhibitory effect on norepinephrine-stimulated arylalkyl-N-acetyltransferase activity. These results indicate that the adrenergically regulated nocturnal increase in p90RSK phosphorylation is mainly mediated through a cGMP-->p42/44(MAPK)-dependent mechanism.


Animal models of ischemic stroke and their application in clinical research.
This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models.


Transcriptome dynamics of transgene amplification in Chinese hamster ovary cells.
Dihydrofolate reductase (DHFR) system is used to amplify the product gene to multiple copies in Chinese Hamster Ovary (CHO) cells for generating cell lines which produce the recombinant protein at high levels. The physiological changes accompanying the transformation of the non-protein secreting host cells to a high producing cell line is not well characterized. We performed transcriptome analysis on CHO cells undergoing the selection and amplification processes. A host CHO cell line was transfected with a vector containing genes encoding the mouse DHFR (mDHFR) and a recombinant human IgG (hIgG). Clones were isolated following selection and subcloned following amplification. Control cells were transfected with a control plasmid which did not have the hIgG genes. Although methotrexate (MTX) amplification increased the transcript level of the mDHFR gene significantly, its effect on both hIgG heavy and light chain genes was more modest. The subclones appeared to retain the transcriptome signatures of their parental clones, however, their productivity varied among those derived from the same clone. The transcript levels of hIgG transgenes of all subclones fall in a narrower range than the product titer, alluding to the role of many functional attributes, other than transgene transcript, on productivity. We cross examined functional class enrichment during selection and amplification as well as between high and low producers and discerned common features among them. We hypothesize that the role of amplification is not merely increasing transcript levels, but also enriching survivors which have developed the cellular machinery for secreting proteins, leading to an increased frequency of isolating high-producing clones. We put forward the possibility of assembling a hyper-productivity gene set through comparative transcriptome analysis of a wide range of samples.