Classification of Myopathy and Amyotrophic Lateral Sclerosis Electromyograms Using Bat Algorithm and Deep Neural Networks.
Electromyograms (EMG) are a recorded galvanic action of nerves and muscles which assists in diagnosing the disorders associated with muscles and nerves. The efficient discrimination of abnormal EMG signals, myopathy and amyotrophic lateral sclerosis, engage crucial role in automatic diagnostic assistance tools, since EMG signals are nonstationary signals. Hence, for computer-aided identification of abnormalities, extraction of features, selection of superlative feature subset, and developing an efficient classifier are indispensable. Initially, time domain and Wigner-Ville transformed time-frequency features were extracted from abnormal EMG signals for experiments. The selection of substantial characteristics from time and time-frequency features was performed using bat algorithm. Extensively, deep neural network classifier is modelled for selected feature subset using bat algorithm from extracted time and time-frequency features. The performance of deep neural network exerting selected features from bat algorithm was compared with conventional artificial neural network. Results demonstrate that the deep neural network modelled with layers 2 and 3 (neurons = 2 and 4) using time domain features is efficient in classifying the abnormalities of EMG signals with an accuracy, sensitivity, and specificity of 100% and also exhibited finer performance. Correspondingly, the developed conventional single layer artificial neural network (neurons = 7) with time domain features has shown an accuracy of 83.3%, sensitivity of 100%, and specificity of 71.42%. The work materializes the significance of conventional and deep neural network using time and time-frequency features in diagnosing the abnormal signals exists in neuromuscular system using efficient classification.


Flight and molecular modeling study on the response of codling moth, Cydia pomonella (Lepidoptera: Tortricidae) to (E,E)-8,10-dodecadien-1-ol and its geometrical isomers.
In a previous study we have reported that both (E,Z)-8,10-dodecadienol (E,Z) and (Z,Z)-8,10-dodecadienol (Z,Z) isomers inhibit the attraction of male codling moth, Cydia pomonella L. when added to (E,E)-8,10-dodecadienol (E,E) while the (Z,E)-8,10-dodecadienol (Z,E) isomer induces slight increase in the number of males attracted to the pheromone source. In the present study, we have tested the behavioral activity of the individual geometrical isomers E,Z; Z,E and Z,Z. A few number of codling moth males flew to the Z,E-isomer while the other two isomers (i.e. E,Z and Z,Z) did not elicit any upwind orientation. Analysis of the flight behavior to the E,E- and Z,E-isomer showed significant differences in most of the flight parameters evaluated. Based on the biological observations and molecular modeling, we suggest that the behavioral activity of the Z,E-isomer is due to presence of specific receptors for this isomer on male antennae and not to its structural resemblance to the E,E-isomer. These results underline the importance of the Z,E-isomer in sex attraction of male codling moth.


The effect of a moderate level of hypoxia on human color vision.
This study reports the effect of a moderate level of hypoxia on human color discimination. We found a generalized loss of color vision affecting both red-green and blue-yellow discrimination at an altitude of 12,000 feet. Although the residual color discrimination at this altitude was within age-matched, sea-level norms, a statistically significant increase over sea level error scores was measured on the Farnsworth-Munsell 100-Hue test and the Pickford-Nicolson anomaloscope. An analysis of psychophysical and electrophysiological studies indicates that hypoxia acts by depressing retinal ganglion cell activity and that it can affect photopic visual processes as well as scotopic vision. We conclude that studies evaluating man's visual performance at altitude must consider post-receptoral processes.


Upregulation of D-myo-inositol transport in diabetic rat glomerular cells.
In the streptozotocin (STZ)-treated diabetic rat, reduced glomerular arteriolar resistance leads to raised intraglomerular pressure. Because vasoconstrictor hormones, such as angiotensin II, stimulate arteriolar smooth muscle and mesangial cell contraction via the D-myo-inositol (MI)-dependent transmembrane signaling pathway, in diabetes extracellular D-glucose may inhibit MI transport causing MI depletion, reduced signaling, and hypocontractility. Therefore we studied the regulation of Na-dependent MI transport in the intact cells (mesangial and endothelial) of isolated glomeruli from STZ rats after 2 wk of diabetes, with and without insulin, compared with controls. Specific [3H]MI uptake per milligram glomerular protein (10-150 min, 37 degrees C) was observed in the presence of 0, 5.5, and 30 mM D-glucose using L-[14C]glucose as a marker of nonspecific uptake. D-Glucose competitively inhibited Na-dependent MI transport (maximum velocity) into diabetic and normal glomerular cells. At 5.5 mM D-glucose, MI uptake by diabetic non-insulin-treated glomeruli was increased to 191 +/- 14% (SE) above normal glomeruli. Insulin treatment resulted in less upregulation (116 +/- 11%) of normal MI transport. High glucose concentration did not alter the rate of [3H]MI efflux from preloaded glomerular cells. To determine whether diabetes alters available substrate for transmembrane signaling, after incubation for 120 min, the incorporation of [3H]MI into cellular membrane phosphoinositides and soluble D-myo-inositol phosphates of isolated diabetic and control glomerular cells was compared. Diabetic glomerular cells displayed a significant increase (P less than 0.005) in [3H]MI incorporation into these fractions compared with controls.


Extinction of immunoglobulin gene expression in B cells upon fusion with HeLa cells is preceded by rapid nuclear depletion of essential transcription factors and is accompanied by widespread inactivation of genes expressed in a B cell-specific manner.
When immunoglobulin (Ig) expressing B cells are fused with non-B cells, Ig expression is rapidly suppressed at the level of transcription, a phenomenon termed extinction. Here we demonstrate that fusion of HeLa cells with either diploid or tetraploid B cells (Daudi) results in widespread extinction of several other B cell-encoded genes that are expressed in a B cell-specific manner. In contrast, expression of B cell-expressed genes that are not dependent on cell-specific controls is unaffected. We show that the molecular mechanism(s) underlying Ig gene extinction can be explained, at least in part, by a lack of transcription factors that are essential for Ig gene transcription. These transcription factors are either not produced due to block of transcription of their respective genes (Oct-2, OBF-1, PU.1), or are rendered inactive posttranslationally (NF-kappa B, E47). By isolating Daudi x HeLa heterokaryons a few hours after fusion, we have studied the initial fate of two B cell-specific transcription factors involved in Ig gene transcription, Oct-2 and NF-kappa B. This report provides the first demonstration that upon fusion with HeLa cells, the nuclear contents of B cell-expressed transcription factors are depleted within a few hours with kinetics that are as fast or faster than that of Ig gene extinction. Thus, the extinguishing mechanism is effective very early after fusion. We suggest that extinction of Ig genes is part of a global mechanism that suppresses the differentiation program foreign to the HeLa phenotype.


Actin is involved in auxin-dependent patterning.
Polar transport of auxin has been identified as a central element of pattern formation. The polarity of auxin transport is linked to the cycling of pin-formed proteins, a process that is related to actomyosin-dependent vesicle traffic. To get insight into the role of actin for auxin transport, we used patterned cell division to monitor the polarity of auxin fluxes. We show that cell division in the tobacco (Nicotiana tabacum L. cv Bright-Yellow 2) cell line is partially synchronized and that this synchrony can be perturbed by inhibition of auxin transport by 1-N-naphthylphthalamic acid. To address the role of actin in this synchrony, we induced a bundled configuration of actin by overexpressing mouse talin. The bundling of actin impairs the synchrony of cell division and increases the sensitivity to 1-N-naphthylphthalamic acid. Addition of the polarly transported auxins indole-3-acetic acid and 1-naphthyl acetic acid (but not 2,4-dichlorophenoxyacetic acid) restored both the normal organization of actin and the synchrony of cell division. This study suggests that auxin controls its own transport by changing the state of actin filaments.


Increased flexibility and liposome-binding capacity of CD1e at endosomal pH.
The plasma membrane proteins CD1a, CD1b and CD1c are expressed by human dendritic cells, the professional antigen-presenting cells of the immune system, and present lipid antigens to T lymphocytes. CD1e belongs to the same family of molecules, but accumulates as a membrane-associated form in the Golgi compartments of immature dendritic cells and as a soluble cleaved form in the lysosomes of mature dendritic cells. In lysosomes, the N-terminal propeptide of CD1e is also cleaved, but the functional consequences of this step are unknown. Here, we investigated how the pH changes encountered during transport to lysosomes affect the structure of CD1e and its ligand-binding properties. Circular dichroism studies demonstrated that the secondary and tertiary structures of recombinant CD1e were barely altered by pH changes. Nevertheless, at acidic pH, guanidium chloride-induced unfolding of CD1e molecules required lower concentrations of denaturing agent. The nonfunctional L194P allelic variant was found to be structurally less stable at acidic pH than the functional forms, providing an explanation for the lack of its detection in lysosomes. The number of water-exposed hydrophobic patches that bind 8-anilinonaphthalene-1-sulfonate was higher in acidic conditions, especially for the L194P variant. CD1e molecules interacted with lipid surfaces enriched in anionic lipids, such as bis(monoacylglycero)phosphate, a late endosomal/lysosomal lipid, especially at acidic pH, or when the propeptide was present. Altogether, these data indicate that, in the late endosomes/lysosomes of DCs, the acid pH promotes the binding of lipid antigens to CD1e through increased hydrophobic and ionic interactions.


Adaptation to DNA damage as a bet-hedging mechanism in a fluctuating environment.
In response to DNA damage, efficient repair is essential for cell survival and genome integrity. In eukaryotes, the DNA damage checkpoint is a signalling pathway that coordinates this response and arrests the cell cycle to provide time for repair. However, when repair fails or when the damage is not repairable, cells can eventually bypass the DNA damage checkpoint and undergo cell division despite persistent damage, a process called adaptation to DNA damage. Interestingly, adaptation occurs with a delayed timing compared with repair and shows a large variation in time, two properties that may provide a survival advantage at the population level without interfering with repair. Here, we explore this idea by mathematically modelling cell survival in response to DNA damage and focusing on adaptation parameters. We find that the delayed adaptation timing indeed maximizes survival, but its heterogeneity is beneficial only in a fluctuating damage-inducing environment. Finally, we show that adaptation does not only contribute to survival but also to genome instability and mutations, which might represent another criterion for its selection throughout evolution. Overall, we propose that adaptation can act as a bet-hedging mechanism for cell survival in response to DNA damage.


Frailty index trajectories in Chinese older adults with diverse levels of social participation: findings from a national population-based longitudinal study.
Aging and frailty pose significant challenges globally, placing a substantial burden on healthcare and social services due to their adverse consequences. The primary objective of this study was to investigate the relationship between social participation and development of frailty transition and trajectory. This study utilized data from the CLHLS Cohort, a 10-year follow-up study involving 6713 participants, to investigate the association between social participation and development of frailty. Frailty reflects a comprehensive decline in various body functions. The study employed a group-based trajectory model to analyze the development trajectory of the frailty index and used logistic regression to assess the odds ratio (OR) of frailty risk. We identified two distinct groups of frailty progression trajectories: the "stable development group" and the "rapid growth group." Individuals who engaged in social activities at least once a month, but not daily, exhibited a significant association with an increased risk of transitioning into the "rapid growth group" (OR 1.305, 95% CI 1.032-1.649). Those with social participation less than once a month had an even greater risk (OR 1.872, 95% CI 1.423-2.463). Moreover, low social participation frequency (occasionally/never) has a more pronounced impact on frailty progression in males. A higher frequency of social participation is associated with a lower risk of being classified into the "rapid growth group" and a slower rate of frailty index progression. Preventing the progression of frailty can contribute to enhanced support for healthy aging among older adults.


Characteristics of English-speaking trance channelers.
Historical records suggest that channeling has existed globally, in a variety of cultures, for thousands of years, and recent research suggests that channeling is more prevalent than most people realize. The present study used an online survey to explore mental health factors, personality characteristics, subjective experiences, and the impact of channeling on 83 participants who self-identified as trance channelers. Most participants endorsed being spiritual but not religious as adults, and on average the channeling experiences began at middle age. The majority of participants did not report pathological levels of dissociative or psychotic symptoms, anxiety or depression. Compared to relevant norms, participants reported similar scores on most personality factors, psychological absorption and empathy. Participants' average scores on emotional and environmental sensitivity corresponded to being designated as sensory-processing sensitives. Participants reported high levels of noetic beliefs and experiences, particularly beliefs in life after death, non-local consciousness, and telepathy. Most participants reported that their channeling process is willful and consensual and that they are consciously aware of the channeling state while it occurs. The majority of participants also reported a positive impact of channeling on their lives. Lower psychotic symptoms, older age when the trance channeling experiences began, and higher sensitivity scores predicted a greater positive impact of trance on participants' lives. Given that trance channeling has played a role in religious and spiritual traditions around the world throughout history, the present study provides an important exploration of the trance channeling phenomenon.


Nicotine exposure leads to deficits in differential cued fear conditioning in mice and humans: A potential role of the anterior cingulate cortex.
Stress and anxiety disorders such as posttraumatic stress disorder (PTSD) are characterized by disrupted safety learning. Tobacco smoking has been strongly implicated in stress and anxiety disorder symptomatology, both as a contributing factor and as a vulnerability factor. Rodent studies from our lab have recently shown that acute and chronic nicotine exposure disrupts safety learning. However, it is unknown if these effects of nicotine translate to humans. The present studies addressed this gap by administering a translational differential cued fear conditioning paradigm to both mice and humans. In mice, we found that chronic nicotine exposure reduced discrimination between a conditioned stimulus (CS) that signals for danger (CS+) and another CS that signals for safety (CS-) during both acquisition and testing. We then employed a similar differential cued fear conditioning paradigm in human smokers and non-smokers undergoing functional magnetic resonance imaging (fMRI). Smokers showed reduced CS+/CS- discrimination during fear conditioning compared to non-smokers. Furthermore, using fMRI, we found that subgenual and dorsal anterior cingulate cortex activations were lower in smokers than in non-smokers during differential cued fear conditioning. These results suggest a potential biological mechanism underlying a dysregulated ability to discriminate between danger and safety cues. Our results indicate a clear parallel between the effects of nicotine exposure on safety learning in mice and humans and therefore suggest that smoking might represent a risk factor for inability to process information related to danger and safety related cues.


RELMα Licenses Macrophages for Damage-Associated Molecular Pattern Activation to Instigate Pulmonary Vascular Remodeling.
Pulmonary hypertension (PH) is a debilitating disease characterized by remodeling of the lung vasculature. In rodents, resistin-like molecule-α (RELMα, also known as HIMF or FIZZ1) can induce PH, but the signaling mechanisms are still unclear. In this study, we used human lung samples and a hypoxia-induced mouse model of PH. We found that the human homolog of RELMα, human (h) resistin, is upregulated in macrophage-like inflammatory cells from lung tissues of patients with idiopathic PH. Additionally, at PH onset in the mouse model, we observed RELMα-dependent lung accumulation of macrophages that expressed high levels of the key damage-associated molecular pattern (DAMP) molecule high-mobility group box 1 (HMGB1) and its receptor for advanced glycation end products (RAGE). In vitro, RELMα/hresistin-induced macrophage-specific HMGB1/RAGE expression and facilitated HMGB1 nucleus-to-cytoplasm translocation and extracellular secretion. Mechanistically, hresistin promoted HMGB1 posttranslational lysine acetylation by preserving the NAD+-dependent deacetylase sirtuin (Sirt) 1 in human macrophages. Notably, the hresistin-stimulated macrophages promoted apoptosis-resistant proliferation of human pulmonary artery smooth muscle cells in an HMGB1/RAGE-dependent manner. In the mouse model, RELMα also suppressed the Sirt1 signal in pulmonary macrophages in the early posthypoxic period. Notably, recruited macrophages in the lungs of these mice carried the RELMα binding partner Bruton tyrosine kinase (BTK). hResistin also mediated the migration of human macrophages by activating BTK in vitro. Collectively, these data reveal a vascular-immune cellular interaction in the early PH stage and suggest that targeting RELMα/DAMP-driven macrophages may offer a promising strategy to treat PH and other related vascular inflammatory diseases.


Growing in Antarctica, a challenge for white adipose tissue development in Adelie penguin chicks (Pygoscelis adeliae).
Rapid growth is of crucial importance for Adélie penguin chicks reared during the short Antarctic summer. It partly depends on the rapid ontogenesis of fat stores that are virtually null at hatching but then develop considerably (x40) within a month to constitute both an isolative layer against cold and an energy store to fuel thermogenic and growth processes. The present study was aimed at identifying by RT-PCR the major transcriptional events that chronologically underlie the morphological transformation of adipocyte precursors into mature adipocytes from hatching to 30 days of age. The peak expression of GATA binding protein 3, a marker of preadipocytes, at day 7 posthatch indicates a key proliferation step, possibly in relation to the expression of C/EBPalpha (C/EBPalpha). High plasma total 3,5,3'-triiodo-l-thyronine (T(3)) levels and high levels of growth hormone receptor transcripts at hatching suggested that growth hormone and T(3) play early activating roles to favor proliferation of preadipocyte precursors. Differentiation and growth of preadipocytes may occur around day 15 in connection with increased abundance of transcripts encoding IGF-1, proliferator-activated receptor-gamma, and C/EBPbeta, gradually leading to functional maturation of metabolic features of adipocytes including lipid uptake and storage (lipoprotein lipase, fatty-acid synthase) and late endocrine functions (adiponectin) by day 30. Present results show a close correlation between adipose tissue development and chick biology and a difference in the scheduled expression of regulatory factors controlling adipogenesis compared with in vitro studies using cell lines emphasizing the importance of in vivo approaches.


The clinical value of the delta finger to palm distance in systemic sclerosis.
Systemic sclerosis (SSc) is a collagen-vascular disorder characterized by fibrosis and vasculopathy. Delta finger to palm distance (delta FTP) is an index measuring the distance between the tip of the third finger to the distal palmar crease in the flexed and extended position. The present study aimed to evaluate the clinical value of delta FTP and to assess the correlation of delta FTP with modified Rodnan skin score (mRSS) and forced vital capacity (FVC) over the 12-month follow-up. This prospective longitudinal study began with 50 participants who were followed for twelve months. Lowess smoothing and linear regression were applied to detect and assess the relationship between delta FTP and mRSS. p-values were adjusted by the Benjamini-Hochberg method (BHM) as a control for false discovery rate. Delta FTP was lower among patients with higher disease duration (p-valueadj: 0.008), diffuse cutaneous SSc (p-valueadj: 0.006), digital ulcers (p-valueadj: 0.003), telangiectasia (p-valueadj: 0.006) and dysphagia (p-valueadj: 0.036). The mRSS has a significant negative linear effect on the delta FTP at the baseline and the end of the follow-up (r: -0.31 and -0.40, respectively). Moreover, changes of mRSS and delta FTP showed a negative linear association over time (r: -0.22). These linear effects remained significant after regrouping the patients based on their SSc subtype. Delta FTP and FVC were not correlated either at the baseline or at the end. It seems that the delta FTP can be a valuable clinical index, supported by its correlated changes with mRSS and other SSc clinical manifestations over the one-year follow-up.


Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease.
Abnormally low serum testosterone levels were recently associated with an increased mortality risk in male dialysis patients. However, the prevalence of testosterone deficiency in end-stage renal disease (ESRD) is not well defined. We hereby explore the prevalence and correlates of clinical testosterone deficiency in a large cohort of ESRD male patients. Two hundred and sixty ESRD men [median age 59 (25th-75th percentile 48-67) years] were included. Testosterone concentration and testosterone deficiency (<10 nmol/L) were studied in relation to clinically evident cardiovascular disease and markers of inflammation at baseline as well as deaths registered during the following 36 months. Testosterone deficiency was present in 44% of the patients, while 33% showed testosterone insufficiency (10-14 nmol/L), and only 23% had normal testosterone values (>14 nmol/L). Testosterone was strongly and inversely correlated to inflammatory markers (CRP, IL-6 and fibrinogen), even after correction for age and sex hormone-binding globulin. In a crude spline curve, low testosterone concentrations were associated with worse outcome. A clinical condition of testosterone deficiency was independently associated with cardiovascular co-morbidity [odds ratio (OR) 2.51; 95% confidence interval (CI) 1.32-4.76] and death (OR 2.00; 95% CI 1.01-3.97) in logistic regression analyses. Testosterone deficiency is a common finding among male ESRD patients, and it is independently associated with inflammation, cardiovascular co-morbidity and outcome. Future studies are needed to determine the potential adverse effects of male hypogonadism in ESRD and the possibility of improving risk profile, quality of life, and ultimately outcome with testosterone supplementation in these patients.


Parenteral nutrition in the intensive care unit: cautious use improves outcome.
Critical illness is characterised by nutritional and metabolic disorders, resulting in increased muscle catabolism, fat-free mass loss, and hyperglycaemia. The objective of the nutritional support is to limit fat-free mass loss, which has negative consequences on clinical outcome and recovery. Early enteral nutrition is recommended by current guidelines as the first choice feeding route in ICU patients. However, enteral nutrition alone is frequently associated with insufficient coverage of the energy requirements, and subsequently energy deficit is correlated to worsened clinical outcome. Controlled trials have demonstrated that, in case of failure or contraindications to full enteral nutrition, parenteral nutrition administration on top of insufficient enteral nutrition within the first four days after admission could improve the clinical outcome, and may attenuate fat-free mass loss. Parenteral nutrition is cautious if all-in-one solutions are used, glycaemia controlled, and overnutrition avoided. Conversely, the systematic use of parenteral nutrition in the ICU patients without clear indication is not recommended during the first 48 hours. Specific methods, such as thigh ultra-sound imaging, 3rd lumbar vertebra-targeted computerised tomography and bioimpedance electrical analysis, may be helpful in the future to monitor fat-free mass during the ICU stay. Clinical studies are warranted to demonstrate whether an optimal nutritional management during the ICU stay promotes muscle mass and function, the recovery after critical illness and reduces the overall costs.


Effect of nerve cuff electrode geometry on onset response firing in high-frequency nerve conduction block.
The delivery of high-frequency alternating currents has been shown to produce a focal and reversible conduction block in whole nerve and is a potential therapeutic option for various diseases and disorders involving pathological or undesired neurological activity. However, delivery of high-frequency alternating current to a nerve produces a finite burst of neuronal firing, called the onset response, before the nerve is blocked. Reduction or elimination of the onset response is very important to moving this type of nerve block into clinical applications since the onset response is likely to result in undesired muscle contraction and pain. This paper describes a study of the effect of nerve cuff electrode geometry (specifically, bipolar contact separation distance), and waveform amplitude on the magnitude and duration of the onset response. Electrode geometry and waveform amplitude were both found to affect these measures. The magnitude and duration of the onset response showed a monotonic relationship with bipolar separation distance and amplitude. The duration of the onset response varied by as much as 820% on average for combinations of different electrode geometries and waveform amplitudes. Bipolar electrodes with a contact separation distance of 0.5 mm resulted in the briefest onset response on average. Furthermore, the data presented in this study provide some insight into a biophysical explanation for the onset response. These data suggest that the onset response consists of two different phases: one phase which is responsive to experimental variables such as electrode geometry and waveform amplitude, and one which is not and appears to be inherent to the transition to the blocked state. This study has implications for nerve block electrode and stimulation parameter selection for clinical therapy systems and basic neurophysiology studies.


Loss of hypothermic and anti-pyretic action of paracetamol in cyclooxygenase-1 knockout mice is indicative of inhibition of cyclooxygenase-1 variant enzymes.
Paracetamol (acetaminophen), is a centrally-acting antipyretic analgesic drug, which can also lower body temperature. Despite a century of clinical use, its mechanism of pharmacological action has not been completely elucidated. Previously, we demonstrated significant attenuation in the paracetamol induced hypothermia in parallel with its inhibitory action on the synthesis of brain prostaglandin E2 (PGE2) in cyclooxygenase-1 (COX-1) knockout mice in comparison to wild-type mice. The above reported pharmacological actions by paracetamol were completely retained in COX-2 knockout mice. We thus concluded that the mechanism of hypothermic action of paracetamol is dependent on inhibition of a COX-1 gene-derived enzyme. In the current investigation, we provide further support for this notion by demonstrating that the paracetamol-induced hypothermia is not mediated through inhibition of COX-1 as neither the COX-1 selective inhibitor, SC560, nor the COX-1/COX-2 dual inhibitor, indomethacin, induced hypothermia at pharmacologically active doses in mice. In addition, using a COX-2-dependent and PGE2-mediated model of endotoxin-induced fever, paracetamol induced anti-pyretic and hypothermic actions in COX-1 wild-type mice. These effects were fully or partially attenuated in COX-1 knockout mice after prophylactic or therapeutic administration, respectively. Therapeutically-administered paracetamol also reduced hypothalamic PGE2 biosynthesis in febrile COX-1 wild-type mice, but not in febrile COX-1 knockout mice. In conclusion, we provide further evidence which suggests that the hypothermic and now anti-pyretic actions of paracetamol are mediated through inhibition of a COX-1 variant enzyme.


Injury rates in martial arts athletes and predictive risk factors for lower limb injuries.
Previous studies attempted to identify possible risk factors for acute and overuse injuries in several sports disciplines such as running, gymnastics or team sports. Given the lack of scientific works focused on risk factors for lower limb injuries in martial arts, the present study was aimed to investigate foot anatomy, anthropometric measures, and other background information as possible risk factors of injury in barefoot athletes practicing judo, karate, kung fu, Thai boxing, or aikido. In addition, the injury rates were evaluated in relation with the different martial art styles. One group of 130 martial artists was retrospectively evaluated. Data of three morphological variables of the foot were collected: navicular height (NH), navicular drop (ND), and the rear foot (RF). In addition, each participant filled an interview questionnaire providing the following information: age, sex, body weight, height, Body Mass Index, hours of training per week, the kind of injury occurred to the lower limbs in the preceding year. Of 130 subjects, 70 (53.8%) did not sustain injuries, 35 (27.0%) suffered an acute injury and the remaining 25 (19.2%) reported an overuse injury. No significant differences were observed in the injury rates in relation to style and kind of martial art. Age, training volume and BMI were found as significant predictors of injury, while NH, ND, and RF were not able to predict acute or overuse injury at lower limbs. The injury rates were similar in karate, judo, kung fu, aikido, and Thai boxing. The foot morphology variables were not related with the presence or absence of acute and overuse injuries. Conversely, older and heavier martial artists, performing more hours of barefoot training, are at higher risk of acute and overuse injury. Athletic trainers should strongly take into account the present information in order to develop more accurate and specific injury prevention programs for martial artists.


Pediatric measles vaccine expressing a dengue tetravalent antigen elicits neutralizing antibodies against all four dengue viruses.
Dengue disease is an increasing global health problem that threatens one-third of the world's population. To control this emerging arbovirus, an efficient preventive vaccine is still needed. Because four serotypes of dengue virus (DV) coexist and antibody-dependent enhanced infection may occur, most strategies developed so far rely on the administration of tetravalent formulations of four live attenuated or chimeric viruses. Here, we evaluated a new strategy based on the expression of a single minimal tetravalent DV antigen by a single replicating viral vector derived from pediatric live-attenuated measles vaccine (MV). We generated a recombinant MV vector expressing a DV construct composed of the four envelope domain III (EDIII) from the four DV serotypes fused with the ectodomain of the membrane protein (ectoM). After two injections in mice susceptible to MV infection, the recombinant vector induced neutralizing antibodies against the four serotypes of dengue virus. When immunized mice were further inoculated with live DV from each serotype, a strong memory neutralizing response was raised against all four serotypes. A combined measles-dengue vaccine might be attractive to immunize infants against both diseases where they co-exist.


Mechanisms of optic disc swelling with diffuse choroidal melanomas: clinicopathologic correlations.
The clinical and histopathological findings in the eyes of 2 patients with diffuse malignant melanoma of the choroid are described. The tumours were minimally elevated and nonpigmented in the peripapillary area, and both had an associated nonrhegmatogenous retinal detachment. Extension of the tumour into the region of the lamina choroidalis in each eye appeared to cause a localised constriction of the optic nerve and subsequent swelling of the optic nerve head. In addition tumour infiltration of the nerve head was present in one eye. Ophthalmoscopic, fluorescein angiographic, and ultrasonographic characteristics that differentiate between extensive tumour infiltration of the optic nerve head and swelling secondary to other causes are presented. The importance of appreciating this difference clinically is discussed.


Benzodiazepines predict use of opioids--a follow-up study of 17,074 men and women.
To evaluate the effect of the use of benzodiazepines on prescription of opioids 4-7 years later in patients with noncancer pain. A cohort of 7,991 men and 9,083 women aged 40, 45 and 60 years who reported no use of opioids in health surveys in 2000-2001 was linked to the nationwide Norwegian Prescription Database, and their prescriptions of opioids during 2004-2007 were analyzed. Moderate-high prescription frequency of opioids was defined as at least 12 prescriptions during the period January 2004-December 2007. The unadjusted odds ratio for moderate-high prescription frequency of opioids for individuals who had previously used benzodiazepines was 7.7 (95% confidence interval 5.6-10.5) as compared with previous nonusers. After adjustment for musculoskeletal pain, alcohol, smoking habits, and socioeconomic variables, the odds ratio was lowered to 3.1 (2.1-4.6). The analysis of the effect of benzodiazepines and chronic pain individually and in combination suggest that use of benzodiazepines is an even stronger predictor of later opioid use than self-reported chronic pain. Our study suggests that earlier use of benzodiazepines may predict repeated use of opioids. Before starting pain treatment with opioids, clinicians should take into consideration the possibility of substance abuse and mental health disorders. A central issue when prescribing opioids for chronic noncancer pain is to balance the risk of problematic use of these drugs with the benefits of pain relief.


[Classification of acute dysfunctions of organs and systems in multiple organ failure syndrome].
A classification of acute dysfunctions of the vital organs and systems in cases with multiple organ failure is proposed. It is suggested to assess the function as satisfactory, compensatory sufficiency, decompensated insufficiency, or failure. Clinical laboratory criteria of such rating are offered. Experience gained in the use of this classification is presented.


Ectopic expression of a BZR1-1D transcription factor in brassinosteroid signalling enhances carotenoid accumulation and fruit quality attributes in tomato.
The brassinosteroid (BR) response transcription factor Brassinazole resistant 1 (BZR1)-mediated BR signalling regulates many specific developmental processes including fruit ripening. Here, we report the effect of 2,4-epibrassinolide (EBR) and BZR1-1D overexpression on carotenoid accumulation and quality attributes of tomato (Solanum lycopersicum) fruit. EBR-treated pericarp discs of ethylene-insensitive mutant, Never ripe, accumulated significantly more carotenoid than those of the control. The results suggest that BR seems to be involved in modulating pigments accumulation. When three independent transgenic lines overexpressing the Arabidopsis BZR1-1D were used to evaluate the role of BZR1 in regulating tomato fruit carotenoid accumulation and quality attributes, fruits of all three transgenic lines exhibited enhanced carotenoid accumulation and increased soluble solid, soluble sugar and ascorbic acid contents during fruit ripening. In addition, the fruits of two transgenic lines showed dark green shoulder at mature green stage, in accordance with the up-regulated expression level of SlGLK2, which is involved in chloroplast development. Our results indicate the importance of BZR1-centred BR signalling in regulating carotenoid accumulation and quality attributes of tomato fruit and the potential application of the BZR1-like(s) for improvement of nutritional quality and flavour of tomato through genetic engineering.


Health behaviors of smokers, ex-smokers, and never smokers in an HMO.
The preponderance of evidence suggests that smokers do not engage in health-promoting lifestyles compared to nonsmokers. Few studies, however, have considered possible differences in health behaviors among smokers at different stages of intention to change. In this paper we examined the relationship of smoking stage of change to health behaviors in an HMO population. Data were obtained from a baseline health status and preventive service evaluation survey mailed to 8000 HMO members over the age of 40. The sample was stratified based on the presence of one or more chronic diseases. Regression analyses were performed adjusting for covariates and weighting based on the stratification. Smokers appear to vary by stage of change in their practice of health-promoting behaviors. After controlling for age, gender, professional advice, chronic disease, and education, smokers classified in early stages of change demonstrated significantly fewer positive health practices compared to never smokers. A consistent pattern emerged across health behaviors. Smokers in the earliest stages of change appear to have the most room for improvement compared to ex-smokers and never smokers. Behavior change other than smoking could be an opportunity to engage early stage smokers.


Quality of glycaemic control in ambulatory diabetics at the out-patient clinic of Kenyatta National Hospital, Nairobi.
Treatment of diabetes mellitus is based on the evidence that lowering blood glucose as close to normal range as possible is a primary strategy for reducing or preventing complications or early mortality from diabetes. This suggests poorer glycaemic control would be associated with excess of diabetes-related morbidity and mortality. This presumption is suspected to reach high proportions in developing countries where endemic poverty abets poor glycaemic control. There is no study published on Kenyan patients with diabetes mellitus about their glycaemic control as an audit of diabetes care. To determine the glycaemic control of ambulatory diabetic patients. Cross-sectional study on each clinic day of a randomly selected sample of both type 1 and 2 diabetic patients. Kenyatta National Hospital. Over a period of six months, January 1998 to June 1998. During routine diabetes care in the clinic, mid morning random blood sugar and glycated haemoglobin (HbA1c) were obtained. A total of 305 diabetic patients were included, 52.8% were females and 47.2% were males. 58.3% were on Oral Hypoglycaemic Agent (OHA) only, 22.3% on insulin only; 9.2% on OHA and insulin and 4.6% on diet only. 39.5% had mean HbA1c < or = 8% while 60.5% had HbA1c > or = 8%. Patients on diet-only therapy had the best mean HbA1c = 7.04% while patients on OHA-only had the worst mean HbA1c = 9.06%. This difference was significant (p=0.01). The former group, likely, had better endogenous insulin production. The influence of age, gender and duration of diabetes on the level of glycaemic control observed did not attain statistically significant proportions. The majority of ambulatory diabetic patients attending the out-patient diabetic clinic had poor glycaemic control. The group with the poorest level of glycaemic control were on OHA-only, while best control was observed amongst patients on diet-only, because of possible fair endogenous insulin production. Poor glycaemic control was presumed to be due to sub-optimal medication and deteriorating diabetes. There is need to empower patients with knowledge and resources to enhance their individual participation in diabetes self-care. Diabetes care providers and facilities also need capacity building to improve care of patients with diabetes.


Public preferences for health care facilities in rural China: A discrete choice experiment.
To successfully tackle the problems with the underutilization of primary care in rural China, it is important to align resource allocation with the preferences of the rural population. However, despite growing interest in the factors influencing the rural population's choice of facility, it is unclear how much weight should be placed on these factors, especially under different scenarios of disease severity. In the first study to elicit quantified trade-offs among influential factors in choosing health care facilities, we carried out a discrete choice experiment (DCE) in rural China. We used a Bayesian efficient design to construct 36 choice sets, and then divided them into three blocks. Each block formed one version of questionnaire that contained 12 choice questions. Each question was assigned a hypothetical perceived severity scenario of either minor or severe disease. 559 Rural residents completed the DCE through face-to-face interviews in December 2017-March 2018. We used mixed logit models to analyze the choice data. The factors regarding the availability and affordability of a facility, such as visit time, travel time, and out-of-pocket cost, were highly valued. When the facilities changed simultaneously from the worst to the best case, a huge increase (from 4.8% to 66.5%) in the predicted choice probability of choosing to visit a facility was observed under perceived minor disease scenario, whereas there was no significant change under perceived severe disease scenario. Improvements to drug availability, medical professional skill and equipment in rural primary care system can induce potential medical care seeking, and redirect patient flow from higher level hospitals to primary level. Especially, township health centers, which provide service to the residents in rural communities, have great potential to be the ideal facilities for first-contact care.


Chronic Hyperglycemia Drives Functional Impairment of Lymphocytes in Diabetic INSC94Y Transgenic Pigs.
People with diabetes mellitus have an increased risk for infections, however, there is still a critical gap in precise knowledge about altered immune mechanisms in this disease. Since diabetic INSC94Y transgenic pigs exhibit elevated blood glucose and a stable diabetic phenotype soon after birth, they provide a favorable model to explore functional alterations of immune cells in an early stage of diabetes mellitus in vivo. Hence, we investigated peripheral blood mononuclear cells (PBMC) of these diabetic pigs compared to non-diabetic wild-type littermates. We found a 5-fold decreased proliferative response of T cells in INSC94Y tg pigs to polyclonal T cell mitogen phytohemagglutinin (PHA). Using label-free LC-MS/MS, a total of 3,487 proteins were quantified, and distinct changes in protein abundances in CD4+ T cells of early-stage diabetic pigs were detectable. Additionally, we found significant increases in mitochondrial oxygen consumption rate (OCR) and higher basal glycolytic activity in PBMC of diabetic INSC94Y tg pigs, indicating an altered metabolic immune cell phenotype. Thus, our study provides new insights into molecular mechanisms of dysregulated immune cells triggered by permanent hyperglycemia.


Musculoskeletal disorders in labor-intensive agriculture.
This paper gives an overview of the extent of musculoskeletal disorders (MSDs) in agriculture, and a historical perspective on how ergonomics has been used to reduce the health effects of labor-intensive agriculture. A summary of exposure to MSD physical risk factors within various classes of crops, along with various administrative and engineering controls for abating MSDs in agriculture is given. These controls range from programmed rest breaks to mechanized or partially-mechanized operations. Worker-based approaches such as prone carts and platforms, and load transfer devices hold promise in combating the prevalent stooped work in agriculture. Including the worker as an integral contributor to all aspects of developing and implementing an intervention, and considering the psychosocial and socio-cultural aspects of the work environment are crucial elements of effective interventions for reducing MSDs. Despite the advent progress in new technologies in agricultural practices, reliance on labor, especially in fresh market fruits and vegetables, will always be a major cornerstone of agriculture for at least the foreseen future. It is encouraging to see the increased interest among health and safety professionals, epidemiologists, engineers, social scientists, and ergonomists throughout the world who are committed to the plight of reducing MSDs and other health problems among agricultural workers.


Isolation and characterization of alpha-1-antitrypsin from rhesus-monkey serum.
A simple, relatively gentle, procedure for isolation of rhesus-monkey alpha-1-antitrypsis from serum is described. The method consists of chromatographic separation of the fraction precipitated by 50-75%-satd. (NH4)2SO4 from pooled monkey serum on DEAE-cellulose followed by affinity chromatography on Sepharose-bound concanavalin A. Approx. 30% of the trypsin-inhibitory activity present in the original serum was recovered when alpha-1-antitrypsin was reconstituted with physiological saline (0.85% NaCl). Pure alpha-1-antitrypsin exhibitied a single band on sodium docecyl sulphate/polyacrylamide-gel electrophoresis, with an estimated mol.wt. of 60000 and four bands in acid/starch-gel electrophoresis. The acid/starch-gel-electrophoretic pattern and mobility of isolated material were identical with those of the alpha-1-antitrypsin bands in the original serum sample. The most rapdily migrating bands resembled the pattern and mobility for the normal human phenotype PiM in 28 monkeys. A starch strip from the acid/starch-gel-electrophoresis as the origin for antigen-antibody electrophoresis was used to examine alpha-1-antitrypsin for microheterogeneity; no evidence for microheterogeneity was observed in samples from 18 monkeys. In addition, isolated alpha-1-antitrypsin exhibited a single arc when subjected to immunoelectrophoresis. Amino acid and carbohydrate compositions of isolated monkey alpha-1-antitrypsin were similar to those of human alpha-1-antitrypsin.


The evolution of fitness in life-history theory.
Theory concerning the evolution of life history (the schedule of reproduction and survival) focuses on describing the life history which maximises fitness. Although there is an intuitive link between life history and fitness, there are in fact several measures of the 'black box' concept of fitness. There has been a debate in the bio-mathematical literature on the predictive difference between the two most commonly used measures; intrinsic rate of increase r and net reproductive ratio R0. Although both measures aim to describe fitness, models using one of the measures may predict the opposite of similar models using the other measure, which is clearly undesirable. Here, I review the evolution of these fitness measures over the last four decades, the predictive differences between these measures and the resulting shift of the fitness concept. I focus in particular on some recent developments, which have solved the dilemma of predictive differences between these fitness measures by explicitly acknowledging the game-theoretical nature of life-history evolution.


Measuring protein stability in living zebrafish embryos using fluorescence decay after photoconversion (FDAP).
Protein stability influences many aspects of biology, and measuring the clearance kinetics of proteins can provide important insights into biological systems. In FDAP experiments, the clearance of proteins within living organisms can be measured. A protein of interest is tagged with a photoconvertible fluorescent protein, expressed in vivo and photoconverted, and the decrease in the photoconverted signal over time is monitored. The data is then fitted with an appropriate clearance model to determine the protein half-life. Importantly, the clearance kinetics of protein populations in different compartments of the organism can be examined separately by applying compartmental masks. This approach has been used to determine the intra- and extracellular half-lives of secreted signaling proteins during zebrafish development. Here, we describe a protocol for FDAP experiments in zebrafish embryos. It should be possible to use FDAP to determine the clearance kinetics of any taggable protein in any optically accessible organism.


E2F1, DIAP1, and the presence of a homologous chromosome promote while JNK inhibits radiation-induced Loss of Heterozygosity in Drosophila melanogaster.
Loss of Heterozygosity (LOH) can occur when a heterozygous mutant cell loses the remaining wild type allele to become a homozygous mutant. LOH can have physiological consequences if, for example, the affected gene encodes a tumor suppressor. We used fluorescent reporters to study mechanisms of LOH induction by X-rays, a type of ionizing radiation (IR), in Drosophila melanogaster larval wing discs. IR is used to treat more than half of cancer patients, so understanding its effects is of biomedical relevance. Quantitative analysis of IR-induced LOH at different positions between the telomere and the centromere on the X chromosome showed a strong sex-dependence and the need for a recombination-proficient homologous chromosome whereas, paradoxically, position along the chromosome made little difference in LOH incidence. We propose that published data documenting high recombination frequency within centromeric heterochromatin on the X chromosome can explain these data. Using a focused screen, we identified E2F1 as a key promotor of LOH and further testing suggests a mechanism involving its role in cell cycle regulation. We leveraged the loss of a transcriptional repressor through LOH to express transgenes specifically in cells that have already acquired LOH. This approach identified JNK signaling and apoptosis as key determinants of LOH maintenance. These studies reveal previously unknown mechanisms for generation and elimination of cells with chromosome aberrations after exposure to IR.


Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: Results of a multicenter, prospective, open-label clinical trial.
The recurrence rate of anti-SSA/Ro-associated congenital heart block (CHB) is 17%. Sustained reversal of third-degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB. A multicenter, prospective, open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included the presence of anti-SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with < or = 20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second-degree or third-degree CHB. Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues. This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.


Heterologous expression of a Streptomyces cyaneus laccase for biomass modification applications.
Laccases are used for the conversion of biomass into fermentable sugars but it is difficult to produce high yields of active laccases in heterologous expression systems. We overcame this challenge by expressing Streptomyces cyaneus CECT 3335 laccase in Escherichia coli (ScLac) and we achieved a yield of up to 104 mg L-1 following purification by one-step affinity chromatography. Stability and activity assays using simple lignin model substrates showed that the purified enzyme preparation was active over a broad pH range and at high temperatures, suggesting it would be suitable for biomass degradation. The reusability of ScLac was also demonstrated by immobilizing the enzyme on agarose beads with a binding yield of 33%, and by the synthesis of cross-linked enzyme aggregates with an initial activity recovery of 72%.


Pressure prediction model for compression garment design.
Based on the application of Laplace's law to compression garments, an equation for predicting garment pressure, incorporating the body circumference, the cross-sectional area of fabric, applied strain (as a function of reduction factor), and its corresponding Young's modulus, is developed. Design procedures are presented to predict garment pressure using the aforementioned parameters for clinical applications. Compression garments have been widely used in treating burning scars. Fabricating a compression garment with a required pressure is important in the healing process. A systematic and scientific design method can enable the occupational therapist and compression garments' manufacturer to custom-make a compression garment with a specific pressure. The objectives of this study are 1) to develop a pressure prediction model incorporating different design factors to estimate the pressure exerted by the compression garments before fabrication; and 2) to propose more design procedures in clinical applications. Three kinds of fabrics cut at different bias angles were tested under uniaxial tension, as were samples made in a double-layered structure. Sets of nonlinear force-extension data were obtained for calculating the predicted pressure. Using the value at 0° bias angle as reference, the Young's modulus can vary by as much as 29% for fabric type P11117, 43% for fabric type PN2170, and even 360% for fabric type AP85120 at a reduction factor of 20%. When comparing the predicted pressure calculated from the single-layered and double-layered fabrics, the double-layered construction provides a larger range of target pressure at a particular strain. The anisotropic and nonlinear behaviors of the fabrics have thus been determined. Compression garments can be methodically designed by the proposed analytical pressure prediction model.


Small Animal Multivariate Brain Analysis (SAMBA) - a High Throughput Pipeline with a Validation Framework.
While many neuroscience questions aim to understand the human brain, much current knowledge has been gained using animal models, which replicate genetic, structural, and connectivity aspects of the human brain. While voxel-based analysis (VBA) of preclinical magnetic resonance images is widely-used, a thorough examination of the statistical robustness, stability, and error rates is hindered by high computational demands of processing large arrays, and the many parameters involved therein. Thus, workflows are often based on intuition or experience, while preclinical validation studies remain scarce. To increase throughput and reproducibility of quantitative small animal brain studies, we have developed a publicly shared, high throughput VBA pipeline in a high-performance computing environment, called SAMBA. The increased computational efficiency allowed large multidimensional arrays to be processed in 1-3 days-a task that previously took ~1 month. To quantify the variability and reliability of preclinical VBA in rodent models, we propose a validation framework consisting of morphological phantoms, and four metrics. This addresses several sources that impact VBA results, including registration and template construction strategies. We have used this framework to inform the VBA workflow parameters in a VBA study for a mouse model of epilepsy. We also present initial efforts towards standardizing small animal neuroimaging data in a similar fashion with human neuroimaging. We conclude that verifying the accuracy of VBA merits attention, and should be the focus of a broader effort within the community. The proposed framework promotes consistent quality assurance of VBA in preclinical neuroimaging, thus facilitating the creation and communication of robust results.


Oxidative injury in the lungs of neonatal rats following short-term exposure to ultrafine iron and soot particles.
Greater risk of adverse effects from particulate matter (PM) has been noted in susceptible subpopulations, such as children. However, the physicochemical components responsible for these biological effects are not understood. As critical constituents of PM, transition metals were postulated to be involved in a number of pathological processes of the respiratory system through free radical-medicated damage. The purpose of this study was to examine whether oxidative injury in the lungs of neonatal rats could be induced by repeated short-term exposure to iron (Fe) and soot particles. Sprague Dawley rats 10 d of age were exposed by inhalation to two different concentrations of ultrafine iron particles (30 or 100 microg/m(3)) in combination with soot particles adjusted to maintain a total particle concentration of 250 microg/m(3). Exposure at 10 d and again at 23 d of age was for 6 h/d for 3 d. Oxidative stress was observed at both Fe concentrations in the form of significant elevations in glutathione disulfide (GSSG) and GSSG/glutathione (GSH) ratio and a reduction in ferric/reducing antioxidant power in bronchoalveolar lavage. A significant decrease in cell viability associated with significant increases in lactate dehydrogenase (LDH) activity, interleukin-1-beta (IL-1beta), and ferritin expression was noted following exposure to particles containing the highest Fe concentration. Iron from these particles was shown to be bioavailable in an in vitro assay using the physiologically relevant chelator, citrate. Data indicate that combined Fe and soot particle exposure induces oxidative injury, cytotoxicity and pro-inflammatory responses in the lungs of neonatal rats.


The conditional stimulus effects of nicotine vary as a function of training dose.
Although past research has shown that the interoceptive effects of nicotine serve as a conditional stimulus using sucrose as the unconditioned stimulus, very little is known about the importance of dose. Accordingly, rats were assigned to 0.1, 0.2, or 0.4 mg nicotine base/kg as the training dose. Sucrose (4-s access) was delivered 36 times on nicotine sessions; sucrose was withheld on intermixed saline sessions. The discrimination was acquired for all groups, as measured by more photobeam breaks in the dipper receptacle before the first sucrose delivery on nicotine sessions, compared with a similar interval on saline sessions. Thirty nicotine sessions without sucrose deliveries (extinction) decreased conditioned responding with the 0.4 mg/kg dose maintaining higher responding than the lower doses. After reestablishing discrimination performance, rats were tested with their training dose at various injection-to-placement intervals. Conditioned responding diminished with longer intervals; 0.4 mg/kg nicotine-evoked conditioned responding at longer intervals. Subsequent generalization testing with nicotine or saline at the 5-min training interval found that conditioned responding was evoked by lower test doses in the 0.1 mg/kg group than in the other groups. Combined, this research demonstrates that the nicotine conditional stimulus shows some variation with training dose.


Cortical stimulation for treatment of neurological disorders of hyperexcitability: a role of homeostatic plasticity.
Hyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management of them is to suppress this hyperexcitability, such as having been exemplified by the use of certain antiepileptic drugs, their frequent refractoriness to drug treatment suggests likely different pathophysiological mechanism. Because the pathogenesis in these disorders exhibits a transition from an initial activity loss after injury or sensory deprivation to subsequent hyperexcitability and paroxysmal discharges, this process can be regarded as a process of functional compensation similar to homeostatic plasticity regulation, in which a set level of activity in neural network is maintained after injury-induced activity loss through enhanced network excitability. Enhancing brain activity, such as cortical stimulation that is found to be effective in relieving symptoms of these disorders, may reduce such hyperexcitability through homeostatic plasticity mechanism. Here we review current evidence of homeostatic plasticity in the mechanism of acquired epilepsy, neuropathic pain, and tinnitus and the effects and mechanism of cortical stimulation. Establishing a role of homeostatic plasticity in these disorders may provide a theoretical basis on their pathogenesis as well as guide the development and application of therapeutic approaches through electrically or pharmacologically stimulating brain activity for treating these disorders.


Dynamic changes in TAP1 expression levels in newborn to weaning piglets, and its association with Escherichia coli F18 resistance.
The transporter associated with antigen processing (TAP) transports peptides from the cytosol into the endoplasmic reticulum for subsequent loading onto the major histocompatibility complex (MHC) class I molecules. This study showed the dynamic changes in the TAP1 expression level in newborn to weaning piglets. Tissue expression profiles revealed that the TAP1 gene was expressed at low levels in all tissues, and the expression levels were relatively higher in the lung, spleen, lymph, and thymus; further, no significant difference was observed in the expression in each tissue among the 3 unweaned stages (8, 18, and 30 days). Nevertheless, the postweaning (35 days) expression levels in tissues, including the spleen, lung, lymph, duodenum, and jejunum were significantly higher than those in the unweaned stages. Furthermore, gene ontology and pathway analysis showed that TAP1 took part in 38 biological functions and 5 pathway processes, including ABC transporters and antigen processing and presentation. These analyses showed that the TAP1 gene, which was related to MHC I immune regulation, had a stable and low expression level in unweaned stages; however, its expression increased in the postweaning stages. The high expression level of TAP1 indicated that the gene might play an important role in Escherichia coli F18 resistance.


DDD pacemaker implantation after Fontan-type operations.
Bradyarrhythmias developing after Fontan-type operations impair the function of the univentricular heart causing fatigue, headaches, ascites, and protein-losing enteropathy (PLE). Transvenous inaccessibility, requiring epicardial implantation, accounts for the reluctance to implant a pacemaker (PM). Between 1997 and 2000, 24 patients (mean age 9.5 years, range 6 months to 19 years) with Fontan-type operations received DDD pacing systems with atrial steroid-eluting stitch-on electrodes (mean capture threshold 1.9 V/0.5 ms, range 0.4-3.5 V) and ventricular screw-in electrodes (mean capture threshold 1.7 V/0.5 ms, range 0.1-3 V). The systems were implanted at the time of conversion from atrio- to cavopulmonary connections in 5 patients, at the time of a total cavopulmonary Fontan operation in 6, and 1-50 months thereafter (mean = 18) in 13 patients. A right ventricular anatomy was present in 13 (54%) of 24 of PM recipients, versus 35% of the overall population. After a mean follow-up of 3.5 years, the PM were functioning in DDD mode in 23 of the 24 patients. Length of hospital stay in the ten patients who underwent repeat sternotomy was 5 days, without procedure related complications. In three children a repeat sternotomy was avoided by implanting the atrial electrodes during the Fontan operation. All patients improved clinically, including resolution of PLE in four patients. Bradyarrhythmias may lead to significant morbidity after Fontan-type operations. Electrophysiological evaluation is advised at follow-up. The indication for implantation of a DDD pacemaker system should be liberal. Placing atrial electrodes during the Fontan operation, especially in the presence of a right ventricular anatomy, avoids repeat sternotomy.


State-space Model Based Inverse Reinforcement Learning for Reward Function Estimation in Brain-machine Interfaces.
The use of reinforcement learning (RL) in brain machine interfaces (BMIs) is considered to be a promising method for neural decoding. One key component of RL-based BMIs is the reward signal, which is used to guide decoders to update the parameters. However, designing effective and efficient rewards can be challenging, especially for complex tasks. Inverse reinforcement learning (IRL) is a method that has been proposed to estimate the internal reward function from subjects' neural activity. However, multi-channel neural activity, which may encode many sources of information, builds a large dimensions of state-action space, making it difficult to directly apply IRL methods in BMI systems. In this paper, we propose a state-space model based inverse Q-learning (SSM-IQL) method to improve the performance of the existing IRL method. The state-space model is designed to extract hidden brain state from high-dimensional neural activity. We tested the proposed method on real data collected from rats during a two-lever discrimination task. Preliminary results show that SSM-IQL provides a more accurate and stable estimation of the internal reward function than the traditional IQL algorithm. This suggests that the use of state-space model in IRL method has potential to improve the design of RL-based BMIs.


SMALL PLANT AND ORGAN 1 (SPO1) Encoding a Cellulose Synthase-like Protein D4 (OsCSLD4) Is an Important Regulator for Plant Architecture and Organ Size in Rice.
Plant architecture and organ size are considered as important traits in crop breeding and germplasm improvement. Although several factors affecting plant architecture and organ size have been identified in rice, the genetic and regulatory mechanisms remain to be elucidated. Here, we identified and characterized the small plant and organ 1 (spo1) mutant in rice (Oryza sativa), which exhibits narrow and rolled leaf, reductions in plant height, root length, and grain width, and other morphological defects. Map-based cloning revealed that SPO1 is allelic with OsCSLD4, a gene encoding the cellulose synthase-like protein D4, and is highly expressed in the roots at the seedling and tillering stages. Microscopic observation revealed the spo1 mutant had reduced number and width in leaf veins, smaller size of leaf bulliform cells, reduced cell length and cell area in the culm, and decreased width of epidermal cells in the outer glume of the grain. These results indicate the role of SPO1 in modulating cell division and cell expansion, which modulates plant architecture and organ size. It is showed that the contents of endogenous hormones including auxin, abscisic acid, gibberellin, and zeatin tested in the spo1 mutant were significantly altered, compared to the wild type. Furthermore, the transcriptome analysis revealed that the differentially expressed genes (DEGs) are significantly enriched in the pathways associated with plant hormone signal transduction, cell cycle progression, and cell wall formation. These results indicated that the loss of SPO1/OsCSLD4 function disrupted cell wall cellulose synthase and hormones homeostasis and signaling, thus leading to smaller plant and organ size in spo1. Taken together, we suggest the functional role of SPO1/OsCSLD4 in the control of rice plant and organ size by modulating cell division and expansion, likely through the effects of multiple hormonal pathways on cell wall formation.


New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design, Synthesis and Biological Evaluation.
Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure-activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.


CYP1A2 phenotype and genotype in a population from the Carboniferous Region of Coahuila, Mexico.
CYP1A2 regulation by polycyclic aromatic hydrocarbons (PAHs) exposure and polymorphism was investigated in 46 male volunteers from the Carboniferous Region in northern Coahuila, Mexico. PAH exposure was estimated by the urinary excretion of 1-hydroxypyrene (1-OHP), whereas the regulatory effects were assessed by the caffeine metabolic ratio (CMR). Genotype was evaluated by determining 5'-flanking region (-2964) and intron I (734) polymorphisms. A statistically significant difference in the urinary 1-OHP geometric means of Barroterán, Cloete and Juárez (2.30, 0.45 and 0.04, respectively) was observed. As for the genotype, the intron I distribution was 0% C/C, 46% C/A and 54% A/A, whereas that of the 5'-flanking region was 26% G/G, 42% G/A and 32% A/A. Both distributions were in agreement with the Hardy-Weinberg equilibrium model. A greater enzyme activity was observed in the A/A compared to C/A individuals according to the CMR (P<0.001), whereas the 5'-flanking region polymorphism showed no effect on CYP1A2 enzymatic activity. These results suggest that intron I polymorphism and PAH exposure are relevant factors that modulate CYP1A2 enzymatic activity.


Alogliptin in combination with metformin and pioglitazone for the treatment of type 2 diabetes mellitus.
Alogliptin is a selective dipeptidyl peptidase-4 inhibitor recently marketed for once-daily administration in the treatment of type 2 diabetes mellitus (T2DM). Fixed-dose combinations of alogliptin with both metformin and pioglitazone are also commercially available, providing a measure of convenience in addition to an effective mode of delivering combination therapy to improve glycemic control. Alogliptin has been studied clinically as initial therapy in treatment-naïve patients with T2DM and as initial therapy or add-on in combination with other antidiabetic agents. Clinical trial data with alogliptin demonstrate clinical efficacy in terms of glycosylated hemoglobin A1c and fasting plasma glucose reductions when used both as monotherapy and as a component of two- or three-drug combination regimens for the treatment of T2DM. Extensive Phase II and Phase III clinical trial data support the use of alogliptin in combination with metformin and pioglitazone. Glycemic reduction with both combinations is similar to the sum of the respective monotherapies, with adverse event rates similar - or more moderate - than those observed with up-titration of monotherapy or the addition of other antihyperglycemic agents.


The protective effect of huperzine A against hepatic ischemia reperfusion injury in mice.
Nowadays, hepatic ischemia reperfusion (HI/R) injury is regarded as a serious concern in clinical practices. Huperzine A (HupA) is an alkaloid isolated from the Chinese folk medicine huperzia serrate, which has possessed diverse pharmacological actions. A mouse model of HI/R was caused by clamping the hepatic artery, the hepatoportal vein, and the bile duct with a vascular clamp for 30 minutes followed by reperfusion for 6 hours under anesthesia. The sham group experienced the identical procedure without hepatic ischemia. The HupA group received an injection into the tail vein 5 minutes prior to HI/R at the doses of 167 and 500 μg/kg. The vehicle group was injected with physiological saline instead of HupA. The liver function was assessed by determinations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Tissue levels of superoxide dismutase (SOD), catalase (CAT), malondiadehyde (MDA), and glutathione (GSH) were also measured spectrophotometrically. In addition, the activities of hepatic inflammatory mediators such as nuclear factor kappa B (NF-κB) p65, tumor necrosis factors-α (TNF-α, interleukin-1β (IL-1β) and IL-6 were also measured. Furthermore, the apoptotic damage was evaluated by measuring caspase-3 activity in hepatic tissues. Treatment with HupA in mice at the doses of 167 and 500 μg/kg remarkably reduced serum ALT and AST activities in HupA-treated ischemic mice. Furthermore, HupA treatment could enhance the activities of hepatic tissue SOD, CAT, and GSH but decrease MDA tissue content. The activities of inflammatory cytokines including NF-κB p65, TNF-α, IL-1β and IL-6 were all decreased in ischemic mice treated with HupA. Colorimetric test results illustrated that a marked reduction of caspase-3 activity was found in the HupA-treated group compared with the vehicle group. Our present data suggest that HupA has a protective role against HI/R injury of mice and antioxidative, anti-inflammatory, and antiapoptotic actions are involved in its protection.


Synthesis, biological activities, and docking study of novel chalcone-pleuromutilin derivatives.
The issue of antibiotic resistance is becoming progressively serious these days, and the feasible solution to address it is to develop and discover novel antibiotics. The diterpene natural pleuromutilin is a prominent candidate for its special mode of action by inhibiting protein synthesis. In this study, a series of novel pleuromutilin derivatives with chalcone moiety was designed and synthesized, and their antibacterial activities were assessed in vitro. As suggested from the results, most of compounds exhibited potent activities against two methicillin-resistant Staphylococcus aureus (MRSA) ATCC 33591 and 43300. The further modification of the chalcone structure, aza-cyclic derivatives were afforded and then assessed, and potent activities against the tested strains were reported. The preliminary docking studies were conducted to explore the interactions between target molecules and binding site.


Relationship between menstruation status and work conditions in Japan.
Menstrual problems can significantly impact daily and work life. In reaction to a shrinking population, the Japanese government is encouraging more women to participate in the labor force. Actual success in achieving this aim, however, is limited. Specifically, participation in the workforce by women during their reproductive years is impacted by their health, which involves not only work conditions, but also traditional family circumstances. Therefore, it is important to further assess and gather more information about the health status of women who work during their reproductive years in Japan. Specifically, women's health can be represented by menstruation status, which is a pivotal indicator. In this study, we assessed the association between short rest periods in work intervals and menstruation and other health status indicators among female workers in Japan. Study participants were recruited from the alumnae of a university, which provided a uniform educational level. All 9864 female alumnae were asked to join the survey and 1630 (17%) accepted. The final sample of study participants (n = 505) were aged 23-43 years, had maintained the same job status for at least 1 year, and were not shift workers, had no maternal status, and did not lack any related information. The participants were divided into two groups according to interval time, with 11 h between end of work and resumption of daily work as a benchmark. This interval time was based on EU regulations and the goal set by the government of Japan. Health outcomes included: menstrual cycle, dysmenorrhoea symptoms, anxiety regarding health, and satisfaction in terms of health. Multiple logistic regression analyses were conducted to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for health indexes in association with interval time by adjusting for confounding variables that included both psychosocial and biological factors. We compared the health status of women in the workforce with and without a sufficient interval time of 11 h/day. Workers who had a short interval time had a significantly higher prevalence of anxiety about health and dissatisfaction with their health. For menstruation status, only abnormal menstruation cycles were observed more often among workers in the short interval group than those of the long interval group. However, this association disappeared when biological confounding factors were adjusted in a multivariable regression model. Dysmenorrhea symptoms did not show a statistically significant association with short interval time. This study found a significant association between a short interval time of less than 11 h/day and subjective health indicators and the menstrual health status of women in the workforce. Menstrual health was more affected by biological factors than social psychological factors. A long work time and short interval time could increase worker anxiety and dissatisfaction and may deteriorate the menstrual cycle.


Nanoplatforms for the Delivery of Nucleic Acids into Plant Cells.
Nanocarriers are widely used for efficient delivery of different cargo into mammalian cells; however, delivery into plant cells remains a challenging issue due to physical and mechanical barriers such as the cuticle and cell wall. Here, we discuss recent progress on biodegradable and biosafe nanomaterials that were demonstrated to be applicable to the delivery of nucleic acids into plant cells. This review covers studies the object of which is the plant cell and the cargo for the nanocarrier is either DNA or RNA. The following nanoplatforms that could be potentially used for nucleic acid foliar delivery via spraying are discussed: mesoporous silica nanoparticles, layered double hydroxides (nanoclay), carbon-based materials (carbon dots and single-walled nanotubes), chitosan and, finally, cell-penetrating peptides (CPPs). Hybrid nanomaterials, for example, chitosan- or CPP-functionalized carbon nanotubes, are taken into account. The selected nanocarriers are analyzed according to the following aspects: biosafety, adjustability for the particular cargo and task (e.g., organelle targeting), penetration efficiency and ability to protect nucleic acid from environmental and cellular factors (pH, UV, nucleases, etc.) and to mediate the gradual and timely release of cargo. In addition, we discuss the method of application, experimental system and approaches that are used to assess the efficiency of the tested formulation in the overviewed studies. This review presents recent progress in developing the most promising nanoparticle-based materials that are applicable to both laboratory experiments and field applications.


Whole-body vibration: is there a causal relationship to specific imaging findings of the spine?
Systematic review. To perform a systematic review of the available literature for those studies that evaluated the role of whole-body vibration (WBV) on the spine, using imaging modalities as well as an estimation of WBV exposure. Numerous comparative studies have reported a possible association between the occurrence of spinal symptoms and exposure to WBV. These exposures have commonly been examined in the work environment largely through self-reported questionnaires only. From a scientific perspective, the majority of studies emphasize symptoms and lack objective medical evidence, such as spinal imaging, to help establish a specific spinal disorder. Because both neck and low back pain comprise symptoms that can arise from a host of factors including age, a casual link between spinal disorders and WBV cannot be affirmed. MEDLINE and EMBASE were searched for studies related to WBV and spinal symptoms, diagnosis, and/or disorders. Our searches were limited to studies published prior to August 2011. The resulting 700 citations (after excluding 354 duplicates) were then screened by 3 independent reviewers on the basis of the following predetermined inclusion and exclusion criteria: inclusion-clinical studies with imaging evaluation (radiographs, computed tomographic scans, and/or magnetic resonance images) and documented WBV exposure (occupation, amount of WBV, and/or duration); exclusion-reliance solely on self-reporting of symptoms (neck pain, low back pain, and/or sciatica), those articles based on a clinical diagnosis without use of imaging, and in vitro/animal/biomechanical studies. Only 7 studies met the inclusion criteria for this systematic review. Included were 5 retrospective cohort and 2 cross-sectional studies. Although mixed results and conclusions were found, the majority of studies did not identify an association between WBV exposure and an abnormal spinal imaging finding indicating damage of the spine. We should also stress that each included study has limitations secondary to quantifying WBV exposure accurately, both as a single encounter and as a total exposure over years. Based on our results from this systematic review, no causality can be shown between WBV and abnormal spinal imaging findings. With the conflicting data available in the literature, WBV has not been established as a cause for objective spinal pathological changes on a scientific basis.


Peripheral phenotype and gene expression profiles of combined liver-kidney transplant patients.
The beneficial effect of one graft on another has been reported in combined transplantation but the associated mechanisms and biological influence of each graft have not yet been established. In multiple analyses, we explored the PBMC phenotype and signature of 45 immune-related messenger RNAs and 754 microRNAs from a total of 235 patients, including combined liver-kidney transplant recipients (CLK), patients with a liver (L-STA) or kidney (K-STA) graft only under classical immunosuppression and patients with tolerated liver (L-TOL) or kidney grafts (K-TOL). CLK show an intermediary phenotype with a higher percentage of peripheral CD19(+) CD24(+) CD38(Low) memory B cells and Helios(+) Treg cells, two features associated with tolerance profiles, compared to L-STA and K-STA (P < 0.05, P < 0.01). Very few miRNA were significantly differentially expressed in CLK vs. K-STA and even fewer when compared to L-STA (35 and 8, P < 0.05). Finally, CLK are predicted to share common miRNA targets with K-TOL and even more with L-TOL (344 and 411, P = 0.005). Altogether CLK display an intermediary phenotype and gene profile, which is closer to that of liver transplant patients, with possible similarities with the profiles of tolerant patients. These data suggest that CLK patients show the immunological influence of both allografts with liver having a greater influence.


Dental Hygiene Students' Perceptions Regarding the Importance of and Confidence with Using Brief Motivational Interviewing during HPV Patient Counseling.
Purpose: Human papillomavirus (HPV), a sexually transmitted virus that has been identified in over two-thirds of all oropharyngeal cancers. Oral health care professionals play a key role in educating the public regarding HPV and the role of vaccinations. The purpose of this study was to examine dental hygiene and dental therapy students' perceptions of the importance of and their confidence with applying brief motivational interviewing (BMI) during patient counseling regarding the human papilloma virus (HPV).Methods: A convenience sample of dental hygiene and dual degree dental hygiene/dental therapy students (n=32) participated in an enhanced BMI curriculum that included a 90-minute HPV BMI coaching and role-playing session on the use of eight MI strategies and the technique of elicit-provide-elicit. Questionnaires assessing participants' perceptions were disseminated at three time points; prior to the HPV BMI training (pre-test), immediately after the coaching and role-playing session (post-test 1) and after the participants had applied their HPV BMI skills during two patient interactions that included self-assessment and faculty feedback (post-test 2).Results: All the students in the sample (n=32) completed the three questionnaires. While participants' perception of the importance of BMI increased for three of the eight strategies (pre-test to post-test 2), it was not statistically significant. Perceptions of confidence in applying of BMI increased for seven of the strategies (pre-test to post-test 1). Statistical significance was achieved for the "Use of the Importance Ruler" strategy (p=0.003) from pretest to posttest 1 and pre-test to post-test 2 (p=0.003).Conclusion: Results indicate that an enhanced HPV BMI coaching curriculum in addition and two HPV BMI sessions with patients is not enough training to retain confidence overtime. Future research should investigate strategies, such as additional coaching and role-playing sessions, for retaining confidence with applying BMI for HPV discussions during patient care.


A New Perspective of Neuromyopathy to Explain Intractable Pancreatic Cancer Pains; Dry Needling as an Effective Adjunct to Neurolytic Blocks.
We present a new perspective of neuromyopathy in pancreatic cancer pain (PCP) referral to bodywall; proposal of new rationale to include ultrasound guided dry needling (USGDN) of body wall muscles as an effective adjunct to neurolytic coeliac plexus block (NCPB) or splanchnic nerve radiofrequency ablation (SRF) for comprehensive interventional management. PCP response to SRF in 2 patients and NCPB in 3 patients was documented on numerical rating scale (NRS) on post procedure days 3 and 15. If the residual pain was >5 NRS on day 15, USGDN of abdominal and back muscles was started on a thrice weekly basis. The response to USGDN documented on day 30 after approximately 6 sessions of DN, showed a significant pain reduction (0-2 NRS) with 50% reduction of pre-treatment opioid consumption. This was sustained at 6 months or till their demise. Convergence of visceral and somatic nerves at the dorsal horn (viscerosomatic neurons) causes referral of visceral pain to the back and abdominal muscles. This leads to formation of myofascial trigger points (MTrPs) in the muscles which sets up a parallel network of sensitized peripheral and central motor nociceptive processing (neuromyopathy). USGDN specifically addressed the MTrPs that develop as an epiphenomenon of self-perpetuating neuromyopathy while SRF/NCPB, analgesics and neuromodulators could address only visceral nociceptive afferents (pain mediated through celiac plexus) which forms a meagre 10% of the total spinal cord afferent input. Thus, we conclude that combination of neuromyopathy and viscerosomatic convergence in PCP indicate a specific role for DN as an adjunct to SRF/NCPB in our patients.


Spatial biases in motion extrapolation for manual interception.
The exact mechanisms by which humans control the manual interception of moving targets are currently unknown. Here, the authors explored the behaviors associated with the spatial control for manual interception. The examined task required controlling a cursor to intercept moving targets on a touch screen. They explored the effects of target motion direction, curvature and occlusion on manual interception. They observed occlusion-dependent spatial errors and arrival times for curved and diagonal trajectories (larger errors and earlier arrival of the finger at its final position with longer occlusion). These effects were particularly apparent for targets moving away from screen center at interception due to curve. In a follow-up experiment, the authors showed that the outward curve effects on spatial errors were absent because the associated trajectories appears to move toward positions that participants could expect the target to never reach. Their analyses also revealed occlusion-dependent spatial errors for diagonal trajectories, which is the well-known angle-of-approach effect. Follow-up experiments demonstrated that this effect was not due to the central initial cursor position acting as a visual reference point or the initial ocular pursuit. Most importantly, the angle-of-approach effect persisted in a judgment task. The authors thus concluded that this effect does not stem from online information-based modulations of movement speed, but from target information used to control aiming (i.e., movement direction). Moreover, processing for diagonal target motion appears to be biased toward straight downward. (PsycINFO Database Record


Comparison of urea space, deuterium oxide space and body composition in growing pigs.
Urea and deuterium oxide (D2O) space were compared by simultaneous infusion into pigs weighing approximately 55 or 90 kg. Urea was cleared from the plasma pool more rapidly than D2O and appeared to equilibrate at a relative concentration which was lower than that of D2O. Consequently, urea and D2O space values were closest when extrapolated to zero time values. Correlations between urea space and D2O space were highest at 15 minutes post infusion (R2 = .75) or between urea space at 15 minutes and D2O at equilibrium (R2 = .86). Results of urea and D2O space measurements were compared with water, lipid and protein content of the carcass. Urea space at 15 minutes and D2O space at 35 minutes most closely approximated total body water while D2O space at 15 minutes was nearly equivalent to empty body water. Overall, D2O space at equilibrium had the highest correlations with carcass values of water, lipid and protein and appears to be preferable to urea space for estimating carcass composition in pigs.


Instanton theory of ground-state tunneling splittings with general paths.
We derive a multidimensional instanton theory for calculating ground-state tunneling splittings in Cartesian coordinates for general paths. It is an extension of the method by Mil'nikov and Nakamura [J. Chem. Phys. 115, 6881 (2001)] to include asymmetric paths that are necessary for calculating tunneling splitting patterns in multi-well systems, such as water clusters. The approach avoids multiple expensive matrix diagonalizations to converge the fluctuation prefactor in the ring-polymer instanton (RPI) method, and instead replaces them by an integration of a Riccati differential equation. When combined with the string method for locating instantons, we avoid the need to converge the calculation with respect to the imaginary time period of the semiclassical orbit, thereby reducing the number of convergence parameters of the optimized object to just one: the number of equally spaced system replicas used to represent the instanton path. The entirety of the numerical effort is thus concentrated in optimizing the shape of the path and evaluating hessians along the path, which is a dramatic improvement over RPI. In addition to the standard instanton approximations, we neglect the coupling of vibrational modes to external rotations. The method is tested on the model potential of malonaldehyde and on the water dimer and trimer, giving close agreement with RPI at a much-reduced cost.


Verrucous carcinoma of the larynx. - A study of its pathologic anatomy.
In the 10 years between 1964 and 1974, 276 patients with infiltrating carcinoma of the larynx included 31 cases of varrucous carcinoma (11 per cent of the series). This tumor is characterized by the pushing invasion of well differentiated squamous epithelium growing in a vertically folded invasive pattern. The tumor appears most frequently in the two decades between 50 and 69 years of age. The ratio of male to female patients was 3.4:1. Verrucous carcinoma has a predilection for the supraglottic regions of the larynx. Cut surface of the tumor shows clefting and sharp margins. Lymph node metastasis occurred in five cases. The marked inflammatory host reaction can cause misleading cervical lymphadenopathy. Problems in diagnosis are discussed.


An automated, high-throughput, 384 well Cytochrome P450 cocktail IC50 assay using a rapid resolution LC-MS/MS end-point.
The current study focused on the development of an automated IC50 cocktail assay in a miniaturized 384 well assay format. This was developed in combination with a significantly shorter high pressure liquid chromatography (HPLC) separation and liquid chromatography-mass spectrometry (LC-MS/MS) run-time; than those currently reported in the literature. The 384-well assay used human liver microsomes in conjunction with a cocktail of probe substrates metabolized by the five major CYPs (tacrine for CYP1A2, diclofenac for CYP2C9, (S)-mephenytoin for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4). To validate the usefulness of the automated and analytical methodologies, IC50 determinations were performed for a series of test compounds known to exhibit inhibition across these five major P450s. Eight compounds (sertraline, disulfuram, ticlopidine fluconazole, fluvoxamine, ketoconazole, miconazole, paroxetine, flunitrazepam) were studied as part of a cocktail assay, and against each CYPs individually. The data showed that the IC50s generated with cocktail incubations did not differ to a great extent from those obtained in the single probe experiments and hence unlikely to significantly influence the predicted clinical DDI risk. In addition the present method offered a significant advantage over some of the existing cocktail analytical methodology in that separation can be achieved with run times as short as 1 min without compromising data integrity. Although numerous studies have been reported to measure CYP inhibition in a cocktail format the need to support growing discovery libraries not only relies on higher throughput assays but quicker analytical run times. The current study reports a miniaturized high-throughput cocktail IC50 assay, in conjunction with a robust, rapid resolution LC-MS/MS end-point offered increased sample throughput without compromising analytical sensitivity or analyte resolution.


Phenilpropanoate identification in young wheat plants by liquid chromatography/tandem mass spectrometry: monomeric and dimeric compounds.
Metabolomic approach has become a very important tool for determining the actual gene expression and protein activity. Metabolism via the shikimate pathway in plant gives rise to a large number of aromatic compounds, including p-hydroxycinnamates, which are mainly associated with their cell walls in complex structures, ester-linked to heteroxilans. In this work, ferulate dehydrodimers and related compounds were extracted from the cell walls of young lyophilized wheat plants with 2 mol/l NaOH for 4 h at 25 °C under N(2). After solid phase extraction, samples were analysed by high-performance liquid chromatography-quadrupole-linear ion trap tandem mass spectrometry with the electrospray source operating in negative mode. Nineteen dehydrodiferulates, 2 hydrate forms, 3 oxo- forms, 2 decarboxilated forms and 1 dihydroxysinapate, were identified by mass spectra interpretation. In addition, five mixed dehydrodimers of ferulic-sinapic, ferulic-coumaric and ferulic-syringic acids were also identified. Reproducibility of peak areas was usually better than 10% but some minor components which may be procedural artefacts, although relatively mild conditions were used.


[Changes in respiratory function tests of healthy miners in accordance with length of service].
The study covered respiratory function tests in healthy miners with variable length of service. Findings are that the first year of mining is characterized by slower interchange of gases in respiratory parts of lungs, by induced protective reaction that increases dilution of inspired air. The years from second to fifth demonstrate stabilized changes and external respiratory system fixed in new functional state kept over next 15-18 years. After 20 years of service in mine, the external respiration system becomes overstrained with intensified compensatory pulmonary ventilation and protective reaction.