The level of an intracellular antioxidant during development determines the adult phenotype in a bird species: a potential organizer role for glutathione.
Life-history traits are often involved in trade-offs whose outcome would depend on the availability of resources but also on the state of specific molecular signals. Early conditions can influence trade-offs and program the phenotype throughout the lifetime, with oxidative stress likely involved in many taxa. Here we address the potential regulatory role of a single intracellular antioxidant in life-history trade-offs. Blood glutathione levels were reduced in a large sample of birds (zebra finch Taeniopygia guttata) during development using the synthesis inhibitor buthionine sulfoximine (BSO). Results revealed several modifications in the adult phenotype. BSO-treated nestlings showed lower glutathione and plasma antioxidant levels. In adulthood, BSO birds endured greater oxidative damage in erythrocytes but stronger expression of a sexual signal. Moreover, adult BSO females also showed weaker resistance to oxidative stress but were heavier and showed better body condition. Results suggest that low glutathione values during growth favor the investment in traits that should improve fitness returns, probably in the form of early reproduction. Higher oxidative stress in adulthood may be endured if this cost is paid later in life. Either the presence of specific signaling mechanisms or the indirect effect of increased oxidative stress can explain our findings.


A case study of physicians' use of liver-spleen scans. Are we doing what we think we're doing?
We evaluated physicians' perceptions of the performance capabilities of the liver-spleen scan (LSS) in detecting metastases and the inferences physicians draw from LSS results. Physicians' perceptions of the sensitivity and specificity of the LSS in detection of metastases, as well as their estimates of likelihood ratios for various scan results, varied broadly over a range that could result in clinically important variations in patient treatment. In addition, independent of any variations in estimates of test performance characteristics, physicians had difficulty drawing appropriate probabilistic inferences from LSS results. Our findings suggest that data regarding the performance capabilities of the LSS and other diagnostic tests within a particular hospital should be made available to physicians and that physicians should be given microcomputer assistance in estimating the impact of test results on the probability of disease.


[Detectability of acute forms of coronary heart disease in real clinical practice].
The study was designed to evaluate the frequency of inapparent and/or unrecorded cases of acute coronary heart disease (CHD) and its influence on overall estimates of CHD mortality and morbidity. A specially developed algorithm was used to identify unrecorded cases in official medical documentation concerning 285,736 subjects. Their fraction was found to be 20.78 and 24.48% among men and women respectively. 89.43% of them died from acute CHD. Addition of the newly identified cases to official statistics increased overall CHD morbidity rates by 26.24 and 32.41% for men and women and mortality rates by 2.13 and 2.28 times respectively. These data indicate that acute CHD is poorly diagnosed in routine clinical practice and the real CHD mortality rate is grossly underestimated.


The Antimelanogenic Effect of Inularin Isolated from Flowers of Inula britannica on B16F10 Melanoma Cells and Zebrafish Embryos.
In the search for novel, natural melanogenesis inhibitors, a new sesquiterpene, inularin, was isolated from the flowers of Inula britannica, and the structure was determined using spectroscopic and chemical methods. The antimelanogenic effects of inularin on B16F10 melanoma cells and zebrafish embryos were evaluated. Inularin dose-dependently reduced melanocyte-stimulating hormone-induced melanin production and L-DOPA oxidation in B16F10 cells. Zebrafish embryos were used to confirm the antimelanogenic activity. Inularin significantly decreased the pigmentation of embryos compared with untreated controls.


[Histomorphological differential diagnosis between occupational and "idiopathic" pulmonary fibroses].
Pulmonary fibroses are terminal stages of exposure to a whole series of very diverse noxae. Both occupational and nonoccupational causes must be distinguished. Finally, there is the large collective category "idiopathic" fibroses. In terms of their systematics, fibroses can be classified in five largegroups. The classification criteria are etiological when the causes are known, and morphological-descriptive in cases of idiopathic fibrosis. Occupational and "idiopathic" fibroses often cannot be distinguished in biopsy material because of their great histomorphological similarity. In such circumstances, the result of further analyses is crucial. For this reason, the possibility that an occupational pulmonary fibrosis is present must also be considered even in "idiopathic" pulmonary fibroses in order to arrange for further analyses such as BAL, ashing and energy-dispersive X-ray analysis to be performed.


Childbirth confidence: validating the Childbirth Self-Efficacy Inventory (CBSEI) in an Australian sample.
This study examined the reliability and validity of the Childbirth Self-Efficacy Inventory (CBSEI) (Lowe 1993) in a sample of 100 Australian women. Consistent with US data, the measure was shown to have high internal consistency. Validity of the instrument was determined by applying self-efficacy theory (Bandura 1982), which predicts that parity should have the largest effect on childbirth self-efficacy, followed by knowledge, then support and finally anxiety. Results revealed that having prior good birth experience and knowledge about childbirth had significant effects on childbirth self-efficacy. A factor analysis was performed to determine whether the original factor structure of this instrument held for Australian women. While outcome expectancies and self-efficacy expectancies emerged as distinct factors, the results showed that Australian women did not differentiate between active and second-stage labour. Rather than the two stages of labour emerging as dimensions of the CBSEI, two externally focused coping strategies were revealed.


Transcriptional response of vaginal epithelial cells to medroxyprogesterone acetate treatment results in decreased barrier integrity.
Medroxyprogesterone acetate (MPA) is a frequently used hormonal contraceptive that has been shown to significantly increase HIV-1 susceptibility by approximately 40 %. However, the underlying mechanism by which this occurs remains unknown. Here, we examined the biological response to MPA by vaginal epithelial cells, the first cells to encounter HIV-1 during sexual transmission, in order to understand the potential mechanism(s) of MPA-mediated increase of HIV-1 infection. Using microarray analysis and in vitro assays, we characterized the response of vaginal epithelial cells, grown in biologically relevant air-liquid interface (ALI) cultures, to physiological levels of female sex hormones, estradiol (E2), progesterone (P4), or MPA. Transcriptional profiling of E2, P4 or MPA-treated vaginal epithelial cells indicated unique transcriptional profiles associated with each hormone. MPA treatment increased transcripts of genes related to cholesterol/sterol synthesis and decreased transcripts related to cell division and cell-cell adhesion, results not seen with E2 or P4 treatments. MPA treatment also resulted in unique gene expression indicative of decreased barrier integrity. Functional assays confirmed that MPA, but not E2 or P4 treatments, resulted in increased epithelial barrier permeability and inhibited cell cycle progression. The effects of MPA on vaginal epithelial cells seen in this study may help explain the increase of HIV-1 infection in women who use MPA as a hormonal contraceptive.


Impact of positive pressure ventilation on mean systemic filling pressure in critically ill patients after death.
Mean systemic filling pressure (Pms) defines the pressure measured in the venous-arterial system when the cardiac output is nil. Its estimation has been proposed in patients with beating hearts by building the venous return curve, using different pairs of right atrial pressure/cardiac output during mechanical ventilation. We raised the hypothesis according to which the Pms is altered by tidal ventilation and positive end-expiratory pressure (PEEP), which would challenge this extrapolation method based on cardiopulmonary interactions. We conducted a two-center, noninterventional, observational, and prospective study, using an arterial and a venous catheter to measure the pressure in the circulatory system at the time of death in critically ill, mechanically ventilated patients with a PEEP. Arterial (Part) and venous pressures (Pra) were recorded in five conditions: at end expiration and end inspiration with and without PEEP and finally once the ventilator was disconnected. Part and Pra did not differ in any experimental conditions. Tidal ventilation increased Pra and Part by 2.4 and 1.9 mmHg, respectively, whereas PEEP increased both values by 1.2 and 1 mmHg, respectively. After disconnection of the ventilator, Pra and Part were 10.0 ± 4.2 and 9.9 ± 4.2 mmHg, respectively. Pms increases during mechanical ventilation, with an effect of tidal ventilation and PEEP. This calls into question the validity of its evaluation in heart-beating patients using cardiopulmonary interactions during mechanical ventilation.NEW & NOTEWORTHY The physiology of the mean systemic filling pressure (Pms) is not well understood in human beings. This study is the first report of a tidal ventilation- and positive end-expiratory pressure-related increase in Pms in critically ill patients. The results challenge the utility and the value estimating Pms in heart-beating patients by reconstruction of the venous return curve using varying inflation pressures.


The effects of nicotinic acid and xanthinol nicotinate on human memory in different categories of age. A double blind study.
The treatment effect of nicotinic acid and xanthinol nicotinate on human memory was compared with placebo in 96 healthy subjects. Forty-three subjects were young (35-45 years), 30 subjects middle aged (55-65 years) and 23 subjects were old aged (75-85 years). Pre- and post-treatment scores were measured on a battery of memory tasks, covering sensory register, short-term memory and long-term memory. The treatment regime was 1 dragee t.i.d. for 8 weeks. The administration of xanthinol nicotinate (500 mg, containing 141.7 mg nicotinic acid), nicotinic acid (141.7 mg) and placebo (lactose) was double-blind. Pre- and post-treatment scores were analysed by means of a multivariate covariance technique, the pre-treatment score serving as covariate. Nicotinic acid treatment resulted in improvement of sensory register and short-term memory, while xanthinol nicotinate improved sensory register, short-term memory and long-term memory. In comparison with placebo, both active compounds yielded improvements of 10-40%, depending on type of task. Treatment effects of nicotinic acid were predominantly found in the young and middle-aged, whereas treatment effects of xanthinol nicotinate were predominantly found in the old. These results are interpreted by the supposed activity of nicotinic acid at the cell membrane, improving neuronal transmission, and of xanthinol nicotinate inside the cell, enhancing cell metabolism and oxygen supply in the brain.


Cognitive evoked potentials to anticipated oesophageal stimulus in humans: quantitative assessment of the cognitive aspects of visceral perception.
Evoked potential studies provide an objective measure of the neural pathways involved with perception. The effects of cognitive factors, such as anticipation or awareness, on evoked potentials are not known. The aim was to compare the evoked potential response to oesophageal stimulation with the cortical activity associated with anticipation of the same stimulus. In 12 healthy men (23.5 +/- 4 years), oesophageal electrical stimulation (15 mA, 0.2 Hz, 0.2 msec) was applied, and the evoked potentials recorded using scalp electrodes. A computerized model of randomly skipped stimuli (4:1 ratio) was used to separately record the evoked potentials associated with stimulation and those associated with an anticipated stimulus. The electrical stimulus represented the nontarget stimulus and the skipped impulse the target (anticipatory) stimulus. This anticipatory evoked potential was also compared to auditory P300 evoked potentials. Reproducible evoked potentials and auditory P300 responses were elicited in all subjects. Anticipatory evoked potentials (peak latency 282.1 +/- 7.9 msec, amplitude 8.2 +/- 0.7 microV, P < 0.05 vs auditory P300 evoked potential) were obtained with the skipped stimulus. This anticipatory evoked potential was located frontocentrally, while the auditory P300 potential was located in the centro-parietal cortex. The anticipatory evoked potential associated with expectation of an oesophageal stimulus, although of similar latency to that of the auditory P300 evoked response, originates from a different cortical location. The recording of cognitive evoked potentials to an expected oesophageal stimulus depends on attention to, and awareness of, the actual stimulus. Anticipatory evoked potentials to GI stimuli may provide an objective electrophysiological tool for the assessment of the cognitive factors associated with visceral perception.


A mathematical model of primary pacemaking cell in SA node of the heart.
Application of voltage-clamp techniques to cardiac primary pacemaker tissue is currently a subject of considerable interest in cardiac electrophysiology. Information regarding the electrical behavior of this type of membrane is by no means complete, yet sufficiently detailed information is available in the literature that would allow the formulation of a reasonably quantitative model to represent the electrical activity of primary pacemaker tissue. In this study the well-known McAllister-Noble-Tsien (MNT) model of the cardiac Purkinje fiber is modified to account for the electrical activity of the primary pacemaking cell (P-cell) of the sinoatrial (SA) node in the heart. Modification is accomplished by appropriately deleting (or inactivating) selected inward- or outward-current channels in the MNT model and adjusting the range of voltage dependence of the various channel-gating variables. Wherever possible, this is accomplished by taking into account voltage-clamp and other electrophysiological data from experiments on the SA node. The resultant model mimics published data quite well and is capable of characterizing the free-running behavior of the primary pacemaker as well as its response to injected currents.


A new model of forelimb ecomorphology for predicting the ancient habitats of fossil turtles.
Various morphological proxies have been used to infer habitat preferences among fossil turtles and their early ancestors, but most are tightly linked to phylogeny, thereby minimizing their predictive power. One particularly widely used model incorporates linear measurements of the forelimb (humerus + ulna + manus), but in addition to the issue of phylogenetic correlation, it does not estimate the likelihood of habitat assignment. Here, we introduce a new model that uses intramanual measurements (digit III metacarpal + non-ungual phalanges + ungual) to statistically estimate habitat likelihood and that has greater predictive strength than prior estimators. Application of the model supports the hypothesis that stem-turtles were primarily terrestrial in nature and recovers the nanhsiungchelyid Basilemys (a fossil crown-group turtle) as having lived primarily on land, despite some prior claims to the contrary.


Effects of progressive muscle relaxation training on nociceptive flexion reflex threshold in healthy young adults: a randomized trial.
Although prior studies have demonstrated effects of progressive muscle relaxation (PMR) in reducing self-reported pain, no laboratory studies have examined the effects of PMR on objective indicators of descending modulation of nociception. This randomized controlled study utilized the nociceptive flexion reflex (NFR) to evaluate nociceptive responding among 55 college-age men and women (mean age=19.4+/-1.2 years). Participants completed laboratory assessments of NFR threshold and questionnaires evaluating pain and stress. Participants were then randomly assigned to either a 25-min PMR condition or a no-treatment control condition. Following the brief intervention, participants completed a second NFR procedure and self-report questionnaires. Results indicated a significant time by condition interaction for NFR, with participants in the PMR condition experiencing a significant increase in NFR threshold while participants in the no-treatment condition experienced no change in NFR. Ratings of pain did not change during the study, but PMR participants reported decreased stress following the PMR intervention. This is the first study with a randomized no-treatment control group demonstrating the effect of a brief PMR protocol on descending inhibition of nociception. Results support the efficacy of PMR in reducing nociceptive response and provide further evidence of the utility of behavioral pain management strategies.


p63 in epithelial development.
The epidermis, the outer layer of the skin composed of keratinocytes, is a stratified epithelium that functions as a barrier to protect the organism from dehydration and external insults. The epidermis develops following the action of the transcription factor p63, amember of the p53 family of transcription factors. The Trp63 gene contains two promoters driving the production of distinct proteins, one with an N-terminal transactivation domain (TAp63) and one without (DeltaNp63), although their relative contribution to epidermal development is not clearly established. Trp63 mutations are involved in the pathogenesis of several human diseases, phenotypically characterized by ectodermal dysplasia. In this review, we summarize the current advances that have been made in understanding the role of p63 in epidermal morphogenesis.


The role of protein malnutrition in the pathogenesis of ulcerative "Lazarine" leprosy.
1. Clinical and necropsy observations in lepromatous leprosy associated with severe emaciation and accompanying hypoproteinemia suggest that protein deprivation may be of pathogenic significance in the ulcerative phenomenon that is designated "Lazarine leprosy". 2. An experimental utilizing Wiersung rats infected with Mycobacterium lepraemurium and maintained on a protein-free diet was developed for the purpose of studying the effect of protein starvation on the course of chronic mycobacterial disease similar to lepromatous leprosy with respect to pathogen and host inflammatory response. 3. It was possible to maintain the experimental animals on a protein-free diet for up to 18 weeks of concomitant M. lepraemurium infection. This was long enough for the infection to disseminate to a degree that was evident in control animals only several weeks later. 4. The protein-deprived animals showed decreased inflammatory response to the pathogen, presented more rapid dissemination of the infection and harbored more bacilli per macrophage than did animals similarly infected but maintained on a protein adequate diet. This indicates impairment of native cellular immunity by protein deprivation through decrease in ability of macrophages to inhibit bacillary multiplication. 5. There was no evidence of impairment of macrophage ability to phagocytose the pathogens. 6. Morphologically the increased dissemination of pathogens and decrease in inflammatory response was similar to the increase in number and extent of visceral lesions seen in Lazarine leprosy. Decreased ability to dispose of the infecting bacilli was similar in the two models, human and animal. The animal model does not, as does lepromatous leprosy, involve the skin in the infection. Hence comparable ulcerative phenomena were not replicated in the animals. 7. It is suggested that Lazarine leprosy may result from enhanced lepromatous leprous infection occurring as a result of protein malnutrition. The pathogenic mechanism appears to be impairment of cellular immunity probably enhanced by concomitant impairment of humoral antibody immunity resulting also in decreased resistance to pyogenic and other secondary pathogens. The tissue edema attendant on decreased serum osmotic pressure due to lowering of the serum protein fractions enhances the probability of ulceration.


Potassium transport across basolateral membrane of acinar cells in the perfused rat pancreas.
Efflux and influx of K+ across the basolateral membrane of acinar cells were continuously computed from the change in K+ concentration in the perfusate collected from the portal vein of the isolated perfused rat pancreas. Continuous stimulation with different concentrations of COOH-terminal octapeptide of cholecystokinin (CCK-8) caused characteristic patterns of K+ flux and fluid secretion as follows: 1) stimulation with 10 pM CCK-8 induced a gradual and small increase in K+ influx and sustained fluid secretion; 2) stimulation with 100 pM CCK-8 caused an initial transient K+ efflux followed by a secondary slow K+ influx and sustained fluid secretion; 3) stimulation with 1 nM CCK-8 also induced an initial transient K+ efflux followed by a secondary slow K+ influx, whereas there was only a slight transient increase in fluid secretion. Ouabain abolished the CCK-8-induced K+ influx, but furosemide had little, if any, effect on the CCK-8-induced K+ flux and fluid secretion. Complete replacement of Cl- with equimolar NO3- had little effect on the CCK-8-induced K+ influx. These results suggest that CCK-8 activates not only passive K+ transport but also an ouabain sensitive Na(+)-K+ pump and that the furosemide-sensitive Na(+)-K(+)-2Cl- symport may not play a significant role in CCK-8-induced K+ transport.


[Study on the current status and relationship between psychological capital and compassion fatigue with work engagement of clinical nurses].
Objective: To explore the relationship between clinical nurses' psychological capital, compassion fatigue with work engagement, and analyze the mediating effect of psychological capital between compassion fatigue and work engagement, so as to provide scientific evidence for reducing compassion fatigue and improving work engagement of clinical nurses. Methods: From December 2021 to February 2022, 494 clinical nurses from 7 general hospitals in Sichuan Province were selected for the study using convenience sampling. The General Information Questionnaire, the Compassion Fatigue Short Scale, the Work Engagement Short Scale and the Psychological Capital Questionnaire for Nurses were used to conduct the survey. Pearson correlation was used to analyze the correlation between compassion fatigue, work engagement and psychological capital. And stepwise regression analysis and Bootstrap method were used to analyze the effects of compassion fatigue and psychological capital on work engagement as well as the mediating effect of psychological capital between compassion fatigue and work engagement. Results: Of the 494 clinical nurses, 33 (6.7%) were male and 461 (93.3%) were female, with an average age of (31.47±6.89) years old and an average working years (9.87±7.61) years. The average scores of psychological capital, compassion fatigue and work engagement of clinical nurses were (5.01±0.76), (3.19±2.08) and (4.60±1.37) points, respectively. Compassion fatigue was negatively correlated with psychological capital and work engagement (r=-0.608, -0.580, P<0.001), and work engagement was positively correlated with psychological capital (r=0.771, P<0.001). Compassion fatigue and psychological capital together accounted for 61.3% of the variation in work engagement, with the direct effects on work engagement were -0.206 (95%CI: -0.283--0.138, P<0.001) and 0.677 (95%CI: 0.599-0.744, P=0.001), respectively. Psychological capital partially mediated the relationship between compassion fatigue and work engagement, with a mediating effect of -0.397 (95%CI: -0.456--0.340, P<0.001), accounting for 65.8% of the total effect. Conclusion: The work engagement of clinical nurses is at a high level. Managers should take targeted measures to alleviate the symptoms of clinical nurses' compassion fatigue, improve their psychological capital, and then stabilize and improve their level of work engagement.


Tooth caries classification with quantitative light-induced fluorescence (QLF) images using convolutional neural network for permanent teeth in vivo.
Owing to the remarkable advancements of artificial intelligence (AI) applications, AI-based detection of dental caries is continuously improving. We evaluated the efficacy of the detection of dental caries with quantitative light-induced fluorescence (QLF) images using a convolutional neural network (CNN) model. Overall, 2814 QLF intraoral images were obtained from 606 participants at a dental clinic using Qraypen C® (QC, AIOBIO, Seoul, Republic of Korea) from October 2020 to October 2022. These images included all the types of permanent teeth of which surfaces were smooth or occlusal. Dataset were randomly assigned to the training (56.0%), validation (14.0%), and test (30.0%) subsets of the dataset for caries classification. Moreover, masked images for teeth area were manually prepared to evaluate the segmentation efficacy. To compare diagnostic performance for caries classification according to the types of teeth, the dataset was further classified into the premolar (1,143 images) and molar (1,441 images) groups. As the CNN model, Xception was applied. Using the original QLF images, the performance of the classification algorithm was relatively good showing 83.2% of accuracy, 85.6% of precision, and 86.9% of sensitivity. After applying the segmentation process for the tooth area, all the performance indics including 85.6% of accuracy, 88.9% of precision, and 86.9% of sensitivity were improved. However, the performance indices of each type of teeth (both premolar and molar) were similar to those for all teeth. The application of AI to QLF images for caries classification demonstrated a good performance regardless of teeth type among posterior teeth. Additionally, tooth area segmentation through background elimination from QLF images exhibited a better performance.


The expression of dynein light chain DYNLL1 (LC8-1) is persistently downregulated in glaucomatous rat retinal ganglion cells.
High intraocular pressure induces glaucomatous degeneration of retinal ganglion cells (RGCs). The cellular mechanisms leading to activation of the apoptosis cascade are multidimensional and only partially understood. A small dynein subunit, the light chain DYNLL1 (synonym LC8-1, PIN) has recently been shown to be an important regulator of neuron proteins known to be involved in glaucomatous RGC death including NO synthases, the pro-apoptotic protein Bim and the dynein intermediate chain. Also, DYNLL1 is a regulator of mitochondria anchorage in axons, which is impaired in glaucoma. We investigated expression of DYNLL1 and 2 and its dynein binding partner dynein intermediate chain in a rat model of chronic glaucoma. Laser capture microdissection (LCM) allowed us to collect distinct cell layers and cell bodies from the retina to gain data highly specific for retinal ganglion cells. Glaucoma was induced in 23 rats by laser treatment to the aqueous outflow tract. RNA was extracted from LCM dissected ganglion cell layers (GCL) and 100 pooled RGCs per retina. Expression levels for 1, 2 and 4 week timepoints were analysed by quantitative PCR for DYNLL1 and 2, dynein intermediate chain and GFAP. DYNLL protein abundance in RGCs was quantified in immunostained retina sections. DYNLL gene 1 but not 2 was expressed in RGCs. In the glaucoma model DYNLL1 was strongly and persistently downregulated at all timepoints. DYNLL protein was significantly less abundant at the 4 week timepoint. In contrast, the motorprotein binding partner dynein intermediate chain 1 was more stably expressed. DYNLL2 was upregulated in glia cells at 2 weeks. Expression of DYNLL1, the only form of the dynein light chain expressed in RGCs, is downregulated persistently in glaucoma, while its binding partner dynein IC-1 is unchanged. The specific lack of DYNLL1 could have an impact on the function of their regulatory binding partners and contribute in several ways to neuron dysfunction and apoptosis.


Exploring the link between pholcodine exposure and neuromuscular blocking agent anaphylaxis.
Neuromuscular blocking agents (NMBAs) are the most commonly implicated drugs in IgE-mediated anaphylaxis during anaesthesia that can lead to perioperative morbidity and mortality. The rate of NMBA anaphylaxis shows marked geographical variation in patients who have had no known prior exposure to NMBAs, suggesting that there may be external or environmental factors that contribute to the underlying aetiology and pathophysiology of reactions. Substituted ammonium ions are shared among NMBAs and are therefore thought to be the main allergenic determinant of this class of drugs. Substituted ammonium ions are found in a wide variety of chemical structures, including prescription medications, over-the-counter medications and common household chemicals, such as the quaternary ammonium disinfectants. Epidemiological studies have shown parallels in the consumption of pholcodine, a nonprescription antitussive drug which contains a tertiary ammonium ion, and the incidence of NMBA anaphylaxis. This link has prompted the withdrawal of pholcodine in some countries, with an ensuing fall in the observed rate of NMBA anaphylaxis. While such observations are compelling in their suggestion of a relationship between pholcodine exposure and NMBA hypersensitivity, important questions remain regarding the mechanisms by which pholcodine is able to sensitize against NMBAs and whether there are other, as yet unidentified, agents that can elicit similar hypersensitivity reactions. This review aims to explore the evidence linking pholcodine exposure to NMBA hypersensitivity and discuss the implications for our understanding of the pathophysiology of these reactions.


CLIMATE: Ice, Mud Point to CO2 Role in Glacial Cycle.
The rhythmic stretching of Earth's orbit seems to drive glacial cycles, but how this feeble "orbital variation" could cascade through the climate system of air, land, water, and ice to produce the monstrous climate shifts of the ice ages has remained a mystery. On page 1897 of this issue of Science, a paleoceanographer finds a likely strongman to transmit and enforce the orbital variations' demands: carbon dioxide. Comparing records preserved in deep-sea muds with those in antarctic ice, he finds that orbital variations may muster carbon dioxide into and out of the atmosphere, and the resulting waxing and waning of greenhouse warming may drive the glacial cycle.


Does therapeutic dose of sildenafil citrate treatment lead to central serous chorioretinopathy in patients with erectile dysfunction?
The possible effects of sildenafil citrate administration at therapeutic dosage on visual acuity, color vision, intraocular pressure, macular thickness, macular volume, and central serous chorioretinopathy in patients with erectile dysfunction were evaluated. The study consisted of 43 male patients diagnosed as having erectile dysfunction according to the first five question version of International Index of Erectile Function (IIEF-5). All patients were given sildenafil citrate 50 mg po 2 to 3 times/week for a month. The patients were evaluated at the first week and at the end of the treatment. The macular thickness and volume assessments with optic coherence tomography did not differ significantly in foveal, parafoveal areas, parafoveal superior hemisphere, parafoveal inferior hemisphere, parafoveal temporal, superior, nasal, and inferior quadrants. Central serous chorioretinopathy was not found in any of the patients.


Complications and Surgical Treatment of Breast Augmentation Using Autologous Fat Transfer and Fillers.
Breast augmentation with autologous fat grafting or hyaluronic acid injection requires minimal loss of healthy tissue. With an increasing trend of breast augmentation with these fillers, accompanying complications have also increased. Patients with complications often complain of induration, cyst formation, calcification, and infection, which require surgical treatment. We will discuss these complications and their surgical treatment through our experience of cases. This retrospective study included 20 patients who all required surgical treatment due to breast augmentation complications such as induration, cyst formation, calcification, and infection, and who visited us between May 2007 and June 2018. The patients' ages ranged from 25 to 63, and the mean age was 39.9. The material used for breast augmentation was fat for 17 cases, and hyaluronic acid, paraffin, and silicon for one case each. The results were analyzed through plastic surgeons at our hospital. We performed a zigzag incision in the peri-areola margin to 17 of 18 patients for complications of autologous fat grafting and hyaluronic acid injection. The one excluded patient required an adipo-fascial flap from an inframammary fold incision. For one patient with silicon injection complication and one patient with paraffin injection complication, each required mammary gland resection. A zigzag incision in the peri-areolar margin was useful for treating complications of breast augmentation with autologous fat grafting and hyaluronic acid injection. All cases resulted in inconspicuous fine scars, with high patient satisfaction. However, this incision was insufficient to remove injected silicon and paraffin.


Oxidative mechanisms of poly(carbonate urethane) and poly(ether urethane) biodegradation: in vivo and in vitro correlations.
This study used an in vitro environment that simulated the microenvironment at the adherent cell-material interface to reproduce and accelerate the biodegradation of poly(ether urethane) (PEU) and poly(carbonate urethane) (PCU). Polyurethane films were treated in vitro for 24 days in 20% hydrogen peroxide/0.1 M cobalt chloride solution at 37 degrees C. Characterization with ATR-FTIR and SEM showed soft segment and hard segment degradation consistent with the chemical changes observed after long-term in vivo treatment. Overall, the PCU underwent less degradation and the degraded surface layer was much thinner than PEU. Nevertheless, the results supported a common oxidation mechanism for biodegradation of these polymers. The observed in vitro degradation was inhibited by adding an antioxidant to the polyurethane film. Our findings further support the use of the in vitro H(2)O(2)/CoCl(2) system in evaluating the biostability of polyurethanes under accelerated conditions.


Establishing Apical Patency: To be or not to be?
The apical portion of the root canal is very complex and challenging during endodontic treatment. Root canal preparation and obturation to the apical constriction may provide the best prognosis. Incomplete debridement, foramen transportation, and inadequate seal in the apical portion are considered to be responsible for treatment failure. The technique "apical patency" is considered as a way for maintaining the apical part the free of the debris by recapitulation, using a small K-file through the area of the apical foramen. This term was firstly proposed by Buchanan. In this technique, the smallest diameter file is set 1 mm longer than working length and recapitulated after each instrument to prevent packing of debris in the apical part. Apical patency has been found to be effective in achieving an apical seal with gutta-percha. Teeth prepared with a step back method and with maintained apical patency may show less leakage when obturated with cold lateral condensation technique. Data regarding the effect of apical patency on the healing of periapical tissue are very scarce, and it has been shown that the patency file has detrimental effect on the healing of periapical tissues in animal studies. However, using patency file in endodontic treatment is controversial and further studies are needed. The purpose of this article is to review the effect of using a patency file on the extrusion of root canal contents, the apical seal, postoperative pain, and healing of periapical tissues. Furthermore, the effect of establishing patency on reaching irrigation solutions to the apical portion of the canal and prognosis of root canal treatment are discussed. Keywords: Apical patency, Apical seal, Apical transportation, Postoperative pain, Prognosis.


Anle138b prevents PrP plaque accumulation in Tg(PrP-A116V) mice but does not mitigate clinical disease.
Anle138b is an anti-aggregating compound previously shown to delay the onset of scrapie, a transmissible prion disease, although its in vivo efficacy against other prion disease subtypes has not been fully assessed. TgGSS mice that model Gerstmann-Sträussler-Scheinker disease (GSS) via expression of mouse PrPA116V accumulate PrP amyloid plaques in their brains and develop progressive ataxia leading to death in ~160 days. When allowed to feed on food pellets containing anle138b from weaning until death, the brains of TgGSS mice displayed significant reductions in PrP plaque burden, insoluble PrP, and proteinase K-resistant PrPSc at end stage, compared with TgGSS mice allowed to feed on placebo food pellets. Despite these effects on biological markers of disease, there was no difference in the onset of symptoms or the age at death between the two treatment groups. In contrast, scrapie-inoculated wild-type mice treated with anle138b survived nearly twice as long (254 days) as scrapie-inoculated mice fed placebo (~136 days). They also displayed greater reductions in insoluble and PK-resistant PrPSc than TgGSS mice. Although these results support an anti-aggregating effect of anle138b, the discordance in clinical efficacy noted between the two prion disease models tested underscores the pathophysiological differences between them and highlights the need to consider differences in susceptibilities among prion subtypes when assessing potential therapies for prion diseases.


Addressing health needs of the homeless in Delhi: Standardising on the issues of Street Medicine practice.
Due to barriers in accessing and using healthcare services, a large proportion of the care homeless populations receive comes from informal providers. In Delhi, one such informal programme, called Street Medicine, provides healthcare outreach to homeless communities. Clinical practice guidelines are set to be developed for Street Medicine teams in India and form the object of this research. This study uses a social-ecological model to understand the barriers facing Street Medicine teams and the homeless as they attempt to address the latter's healthcare needs; coupling it with an analytical approach which situates these barriers as the issues within practice through which standardisation can take place. A qualitative inquiry, comprising three months of observations of Street Medicine outreach and interviews with over 30 key informants, was conducted between April and July 2018. The analysis identified novel barriers to addressing the needs of homeless individuals, which bely a deficit between the design of health and social care systems and the agency homeless individuals possess within this system to influence their health outcomes. These barriers - which include user-dependent technological inscriptions, collaborating with untargeted providers and the distinct health needs of homeless individuals - are the entry points for standardising, or opening up, Street Medicine practices .


A Versatile, Incubator-Compatible, Monolithic GaN Photonic Chipscope for Label-Free Monitoring of Live Cell Activities.
The ability to quantitatively monitor various cellular activities is critical for understanding their biological functions and the therapeutic response of cells to drugs. Unfortunately, existing approaches such as fluorescent staining and impedance-based methods are often hindered by their multiple time-consuming preparation steps, sophisticated labeling procedures, and complicated apparatus. The cost-effective, monolithic gallium nitride (GaN) photonic chip has been demonstrated as an ultrasensitive and ultracompact optical refractometer in a previous work, but it has never been applied to cell studies. Here, for the first time, the so-called GaN chipscope is proposed to quantitatively monitor the progression of different intracellular processes in a label-free manner. Specifically, the GaN-based monolithic chip enables not only a photoelectric readout of cellular/subcellular refractive index changes but also the direct imaging of cellular/subcellular ultrastructural features using a customized differential interference contrast (DIC) microscope. The miniaturized chipscope adopts an ultracompact design, which can be readily mounted with conventional cell culture dishes and placed inside standard cell incubators for real-time observation of cell activities. As a proof-of-concept demonstration, its applications are explored in 1) cell adhesion dynamics monitoring, 2) drug screening, and 3) cell differentiation studies, highlighting its potential in broad fundamental cell biology studies as well as in clinical applications.


Alteration of choroidal vascular structure in diabetic retinopathy.
The aim of this study was to analyse choroidal structures in normal patients and patients with diabetes with various severities of diabetic retinopathy (DR). This is a retrospective observation case control study. Three hundred and forty-two diabetic eyes, and age-matched 112 eyes without diabetes mellitus (DM) were enrolled in this study. Patients with DM were classified into no DR, mild/moderate non-proliferative DR (mNPDR), severe NPDR and proliferative DR (PDR). Patients with DM were further divided into two groups based on information regarding systemic DM treatment situation: DM-treated and untreated groups. Central choroidal thickness (CCT), and total choroidal area (TCA), luminal area (LA) and stromal area (SA) were determined using enhanced depth imaging optical coherence tomography and a binarisation method, respectively. The ratio of LA in the TCA was defined as L/C ratio. The haemoglobin A1c (HbA1c) value was significantly higher in the DM-untreated than in the DM-treated subjects. L/C ratio was significantly lower in all the diabetic eyes than control eyes (p<0.05). TCA, LA, L/C ratio and CCT were significantly greater in the DM-untreated than treated group (each p<0.05). In the DM-untreated group, TCA and LAs (p<0.05) and L/C ratio (p<0.01) were significantly lower in mNPDR subjects than normal controls (p<0.05). PDR in the DM-untreated group showed significantly larger SA and LA, and greater CCT than normal controls (each p<0.05). These results suggest that choroidal vasculature was initially involved at an early DR, whereas thickened LA and SA were noted in advanced DR.


Dopamine electrophysiology of ventral pallidal/substantia innominata neurons: comparison with the dorsal globus pallidus.
The ventral pallidum/substantia innominata (VP/SI) is an infracommissural extension of the dorsal globus pallidus (GP). Functional studies suggest that the VP/SI is indirectly influenced by dopamine (DA) via inputs from dopaminoceptive regions. However, recent anatomical evidence indicates a direct dopaminergic projection to the VP/SI, but the physiologic and pharmacologic consequences of this input have not been evaluated. Thus, the present study was designed to electrophysiologically characterize VP/SI neuronal responses to i.v. administered apomorphine (APO) and microiontophoretically applied DA. Because of similarities in circuitry and morphology, VP/SI responses were compared to those obtained from the GP. Single neurons recorded in vivo from rat VP/SI and GP exhibited similar electrophysiologic characteristics. The majority of the 50 neurons tested with APO demonstrated a dose-related increase in firing rate, with equivalent maximum responses and equivalent doses that produced half-maximal responding (ED50) for the two brain areas. APO generally was antagonized by haloperidol, indicating that the agonist was acting at dopaminergic receptors to produce the observed rate changes. From 212 neurons tested, it was determined that microiontophoretically applied DA altered neuronal firing throughout both regions. However, more DA-sensitive neurons were encountered in the GP than the VP/SI (75% vs. 42%, respectively). DA-induced rate increases and decreases were observed, with rate suppression occurring most frequently. The maximum response and the current that produced half-maximal responding were comparable for the two regions for both response directions. Systemic administration of antagonists revealed that pallidal responses to dopamine likely involve both the D1 and D2 receptor subtypes. These studies 1) demonstrate that the VP/SI is a functionally important dopaminoceptive brain region, and (2) confirm previous work regarding dopaminergic regulation of the GP. The similarities in pharmacologic profiles of responses by GP and VP/SI neurons to dopaminergic agents likely reflect comparable circuitries for the two regions. The differential responding to systemically administered DA agonists and locally applied DA implies that a combination of direct and indirect influences ultimately determines the impact that an activated dopaminergic system has on pallidal brain regions.


Long-term results of coronary surgery with endoscopic vein harvesting.
In this study, we aimed to evaluate early and longterm outcomes of both isolated or concomitant coronary artery bypass grafting with the endoscopic vein harvesting technique. Between November 2012 and May 2017, a total of 324 patients (259 males, 65 females; mean age: 63.2±9.8 years; range, 36 to 91 years) who underwent coronary artery bypass grafting, with or without concomitant procedures, using the endoscopic vein harvesting technique were retrospectively analyzed. Early postoperative outcomes and long-term follow-up data of the patients, such as cardiovascular or cerebral events, cardiac reinterventions, and the images of coronary angiography were recorded. Median logistic EuroSCORE and in hospital mortality was 3.99 (0.8-81) vs. 0 .9% f or i solated c oronary surgery and 13.34 (1.5-76.4) vs. 1.5% for concomitant procedures. The long-term data could be obtained in 288 patients with a median of 59.6 (7-90) months of follow-up. During this period, 22 (7.6%) patients underwent coronary angiography for control or treatment, 12 (4.2%) patients needed revascularization, and none of the patients underwent redo coronary surgery. Our study results suggest that the endoscopic vein harvesting technique during coronary artery bypass grafting is safe in experienced hands.


Cancer stem cell biomarkers and related signaling pathways.
Cancer stem cells (CSCs) represent a distinct subset of neoplastic cells characterized by their heightened capacity for tumorigenesis. These cells are implicated in the facilitation of cancer metastasis, recurrence, and resistance to conventional therapeutic interventions. Extensive scientific research has been devoted to the identification of biomarkers and the elucidation of molecular mechanisms in order to improve targeted therapeutic approaches. Accurate identification of cancer stem cells based on biomarkers can provide a theoretical basis for drug combinations of malignant tumors. Targeted biomarker-based therapies also offer a silver lining for patients with advanced malignancies. This review aims comprehensively to consolidate the latest findings on CSCs biomarkers, targeted agents as well as biomarkers associated signaling pathways in well-established cancer types, thereby contributing to improved prognostic outcomes.


Dendritic Cell-Mediated Cross-Priming by a Bispecific Neutralizing Antibody Boosts Cytotoxic T Cell Responses and Protects Mice against SARS-CoV-2.
Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS-CoV-2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross-priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT , are first generated by grafting an anti-RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo-EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high-avidity neutralizing interaction. Then, by C-terminal fusion of an anti-DNGR-1 scFv to TNT , the bispecific trimerbody TNT DNGR-1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross-priming. Therapeutic administration of TNT DNGR-1, but not TNT , protects K18-hACE2 mice from a lethal SARS-CoV-2 infection, boosting virus-specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus-neutralizing antibody activity and demonstrate the therapeutic potential of the Fc-free strategy that can be used advantageously to provide both immediate and long-term protection against SARS-CoV-2 and other viral infections.


Recombining sequence recombination in normal kappa-chain-expressing B cells.
Recombining sequence (RS) recombination is a DNA rearrangement that deletes one or two C kappa alleles in a large proportion of lambda-expressing B cells. Since its discovery, this recombination has been suggested to play a role in activating lambda gene rearrangements. A model involving a positive signal generated by RS recombination seems to be excluded, but another model that is still under consideration proposes that RS recombination removes DNA sequences within the kappa locus that would interfere with lambda gene assembly. Using PCR assays, we have found that kappa-expressing cells account for the majority of RS rearrangements in mouse spleen. RS rearrangements were also detected by Southern blot in kappa-secreting hybridomas. Quantification of rearrangements indicates that approximately 12% of kappa cells bear an RS recombination. From this finding, we infer that once a cell has performed an RS recombination on one kappa allele, it has a 3 times higher probability of rearranging functionally its other kappa allele rather than one of the lambda genes. These data call into question the role of RS recombination in the switch from kappa to lambda and suggest another function for this nonproductive rearrangement.


[Questioning of relatives--potentials for the internal quality management in institutions caring for the elderly].
The German care quality assurance law ("Pflege-Qualitätssicherungs-Gesetz", PQsG) calls for internal quality management in residential care facilities. Empirical surveys with residents, their relatives and employees are essential to get transparency and to assess the quality of service. Within the scope of the present study more than 1400 relatives of residents of 31 residential care institutions were surveyed. Therefore in preliminary studies a questionnaire for the relatives was developed, which collects data concerning quality aspects on various aspects (for example care, staff, medical care, cooperation with relatives). On the average, relatives judged the quality of the institutions as good. The overall mean of 2.2 (scale values between 1.8 ["administration/management"] and 2.5 ["care"]) reveals a positive aspect, but there is substantial variation between institutions. Empirical surveys are important tools for internal quality management. Among other things, their results can be used as input for specific quality circle work and thus for continuous improvement. Used continually in the sense of a routine-monitoring system, surveys can also serve to evaluate quality management procedures.


Immunological aspects of mammary involution.
Frequency of new intramammary infection is greatest during early involution, decreases during middle stages, and then increases prepartum. Penetrability of the teat canal, antibacterial properties of keratin, bacterial adherence, and epithelial sensitivity to toxins play a role in resistance. Leukocytes phagocytose bacteria and regulate expression of immune mechanisms, although their function is compromised during certain stages of involution. These cells increase to millions per milliliter as involution progresses and then decrease prepartum. Macrophages predominate in lacteal secretions, followed by lymphocytes and neutrophils. Lactoferrin, a major whey protein and iron chelator, is also associated with resistance to infection during the nonlactating period and may have immunomodulatory properties. Lacteal immunoglobulins increase throughout involution peaking prepartum and function by opsonizing bacteria, neutralizing toxins, and preventing bacterial adherence. Immunoglobulins are derived from blood or are produced locally by plasma cells present in the subepithelial mammary stroma. Plasma cells, lymphoid cells, and other protective leukocytes present in teat end tissues accumulate during infection and concentrations increase in response to local antigenic stimulation. Various aspects of the mammary immune system are compromised during periods of functional transition. Thus, vaccination, immunostimulation, accelerated involution, and intramammary devices are some methods now being tested to amplify local immunity and protect the gland from bacterial infection.


Spreading speeds as slowest wave speeds for cooperative systems.
It is well known that in many scalar models for the spread of a fitter phenotype or species into the territory of a less fit one, the asymptotic spreading speed can be characterized as the lowest speed of a suitable family of traveling waves of the model. Despite a general belief that multi-species (vector) models have the same property, we are unaware of any proof to support this belief. The present work establishes this result for a class of multi-species model of a kind studied by Lui [Biological growth and spread modeled by systems of recursions. I: Mathematical theory, Math. Biosci. 93 (1989) 269] and generalized by the authors [Weinberger et al., Analysis of the linear conjecture for spread in cooperative models, J. Math. Biol. 45 (2002) 183; Lewis et al., Spreading speeds and the linear conjecture for two-species competition models, J. Math. Biol. 45 (2002) 219]. Lui showed the existence of a single spreading speed c(*) for all species. For the systems in the two aforementioned studies by the authors, which include related continuous-time models such as reaction-diffusion systems, as well as some standard competition models, it sometimes happens that different species spread at different rates, so that there are a slowest speed c(*) and a fastest speed c(f)(*). It is shown here that, for a large class of such multi-species systems, the slowest spreading speed c(*) is always characterized as the slowest speed of a class of traveling wave solutions.


Familial resemblance for hostility: the National Heart, Lung, and Blood Institute Family Heart Study.
The purpose of this study was to examine whether several aspects of hostility as measured by the Cook-Medley Hostility Scale (ie, aggressive responding, hostile affect, cynicism, and overall hostility score) were determined in part by family factors (ie, genes and/or familial environments). Analyses were based on 680 European-American families (2525 individuals) from the NHLBI Family Heart Study (FHS), a population-based study of genetic and nongenetic determinants of CHD, atherosclerosis, and cardiovascular risk factors. The influence of family relationships, age, and education on the variation in each of the four hostility scores were estimated. Significant familial resemblance in all hostility scores was found, accounting for 42% of the variance in total hostility, 30% in cynicism, 38% in aggressive responding, and 18% in hostile affect. Very little of this resemblance could be explained by similarities in education. Familial resemblance for cynicism was solely due to significant parent-offspring and sibling correlations (ie, no spouse resemblance), suggesting the possibility of genetic influences. Gender and generation differences were also evident in the familial correlations. Hostility aggregates in families. Both family environmental and genetic sources of resemblance are suggested for hostility.


[Biological evaluation of an infant food based on soybean, rice and banana].
An infant food, a mixture of soy, rice and banana was biologically evaluated in three studies carried out in Sprague-Dawley rats. In the first assay, the caloric supplementation and milk protein complementation effect on the nutritive value of the product was studied. Results indicated that an equal nutritive value as that of milk is obtained when 50% of the vegetable protein is replaced by animal protein. The fact that caloric supplementation does not exert any positive effect on the nutritive value of the infant food, under the conditions of the study, was also confirmed. In the second assay, the effect of amino acid (lysine and methionine) supplementation was evaluated. Results revealed a significant improvement of the product quality with lysine supplementation, a finding that implies thermal protein damage caused by industrial processing. In the third study, whole milk supplementation effect at the levels that the product could be offered in school lunch programs and Nutrition and Education Centers was investigated. Such values, as determined, correspond to 343 to 655 ml of fluid milk per 100 g of the cereal product. It was also found that milk complements and improves the nutritive value of the product at equal statistical (P less than 0.05) values as those of milk.


[Isolation and characterization of an evolutionary precursor of human monoamine oxidases A and B].
An interesting flavoprotein-type monoamine oxidase (MAO) was recently isolated from Aspergillus niger and cloned by Schilling and Lerch (1995a,b) The properties of this MAO, as well as a substantial part of its amino acid sequence resemble those of both MAO A and B from higher animals, raising the possibility that it may be an evolutionary precursor of these mitochondrial enzymes. It differs from MAO A and B in several respect, however, including the fact that it is soluble and of peroxisomal localization and that the FAD is non-covalently attached. We have overexpressed the fungal enzyme (MAO-N) in Escherichia coli, isolated it for the first time in pure form, and, in collaboration with Dr. Elena Sablin, crystallized it. Since several of the observations of previous workers on MAO-N could not be reproduced and seem to be erroneous, we have reexamined its, substrate specificity, interaction with reversible and irreversible inhibitors and other catalytic and molecular properties. MAO-N has a considerably higher turnover number on many aliphatic and aromatic amines than either form of the mammalian enzyme. Some aspects of the substrate specificity resemble those of MAO B, while others are similar to MAO A, including biphasic kinetics in double reciprocal plots. Contrary to the report of Schilling and Lerch (1995a), however, the fungal enzyme does not oxidize serotonin, norepinephrine, dopamine or other biogenic amines. MAO-N is irreversibly inhibited by stoichiometric amounts of both (-)deprenyl and clorgyline in a mechanism-based reaction, forming flavocyanine adducts with N(5) of the FAD, like the mammalian enzymes, but inactivation is much faster with clorgyline than deprenyl, suggesting again a closer resemblance to MAO A than B. The dissociation constants for a large number of reversible competitive inhibitors have been determined for MAO-N and comparison with similar values for MAO A and B again pointed to a much greater similarity to the former than the latter. Experiments designed to change the linkage of the FAD to covalent form by site-directed mutagenesis and to dissociate.


Studies on bound trans-4-hydroxy-L-proline in sandal (Santalum album L.).
1. trans-4-Hydroxy-l-proline was found to occur in the bound state in the leaves of sandal (Santalum album L.), in which large amounts of free cis-4-hydroxy-l-proline are also present. 2. Bound trans-4-hydroxy-l-proline was present, associated mainly with a ;wall' fraction and a ;soluble' fraction roughly in equal proportions. 3. Bound proline is present only in small amounts in the ;soluble' fraction but is mostly associated with the ;wall' fraction and the other sedimented fractions. 4. In the free amino acid fraction more than 98% of the hydroxyproline had the cis-configuration, whereas in the ;wall' and ;soluble' fractions more than 90% of the bound hydroxyproline was in the trans-configuration. 5. Various extraction procedures indicated heterogeneity of the hydroxyproline-containing components. Hot 5% (w/v) trichloroacetic acid extracts about 25% of hydroxyproline and m-NaOH extracts an additional 25%. 6. Incorporation of [(14)C]proline into the bound hydroxyproline was demonstrated. The hydroxyproline component of the ;soluble' fraction does not appear to be the precursor of that of the ;wall' fraction.


#AbortionChangesYou: A Case Study to Understand the Communicative Tensions in Women's Medication Abortion Narratives.
One out of four women in the United States will have an abortion by age 45. While abortion rates are steadily declining in the United States, the rate of medication abortions continues to increase, with 39% of all abortions being medication abortions. Our study is one of the first to analyze women's narratives after having had a medication abortion. Using relational dialectics theory, we conducted a case study of the nonpartisan website, Abortion Changes You. Our contrapuntal analysis rendered four sites of dialectical tension found across women's blog posts: only choice vs. other alternatives, unprepared vs. knowledgeable, relief vs. regret, and silence vs. openness. Each site of struggle characterized a different noteworthy moment within a woman's medication abortion experience: the decision, the medication abortion process, identity after abortion, and managing the stigmatizing silence before and after the abortion. We discuss theoretical and practical implications about how the larger politicized discourses prevalent within the abortion debate impact the liminality of women who are contemplating a medication abortion and affect their own narrative construction about the medication abortion experience.


Nonparametric methods for doubly robust estimation of continuous treatment effects.
Continuous treatments (e.g., doses) arise often in practice, but many available causal effect estimators are limited by either requiring parametric models for the effect curve, or by not allowing doubly robust covariate adjustment. We develop a novel kernel smoothing approach that requires only mild smoothness assumptions on the effect curve, and still allows for misspecification of either the treatment density or outcome regression. We derive asymptotic properties and give a procedure for data-driven bandwidth selection. The methods are illustrated via simulation and in a study of the effect of nurse staffing on hospital readmissions penalties.


Cannibalism in the Madagascan dinosaur Majungatholus atopus.
Many lines of evidence have been brought to bear on the question of theropod feeding ecology, including functional and physiological considerations, morphological constraints, taphonomic associations, and telling--although rare--indications of direct ingestion. Tooth marks of theropods, although rarely described and generally left unassigned to a particular taxon, can provide unique clues into predator-prey interaction, and can also yield insights into the extent of carcass utilization. Here we describe a sample of tooth-marked dinosaur bone recovered from three well-documented localities in the Upper Cretaceous Maevarano Formation of Madagascar that provides insights into the feeding ecology of the abelisaurid theropod Majungatholus atopus. Intensely tooth-marked elements from multiple individuals show that Majungatholus defleshed dinosaur carcasses. Furthermore, Majungatholus clearly fed upon the remains of not only sauropods, but also conspecifics, and thus was a cannibal. Cannibalism is a common ecological strategy among extant carnivores, but until now the evidence in relation to carnivorous dinosaurs has been sparse and anecdotal.


Osteoblast-specific Krm2 overexpression and Lrp5 deficiency have different effects on fracture healing in mice.
The canonical Wnt/β-catenin pathway plays a key role in the regulation of bone remodeling in mice and humans. Two transmembrane proteins that are involved in decreasing the activity of this pathway by binding to extracellular antagonists, such as Dickkopf 1 (Dkk1), are the low-density lipoprotein receptor related protein 5 (Lrp5) and Kremen 2 (Krm2). Lrp 5 deficiency (Lrp5-/-) as well as osteoblast-specific overexpression of Krm2 in mice (Col1a1-Krm2) result in severe osteoporosis occurring at young age. In this study, we analyzed the influence of Lrp5 deficiency and osteoblast-specific overexpression of Krm2 on fracture healing in mice using flexible and semi-rigid fracture fixation. We demonstrated that fracture healing was highly impaired in both mouse genotypes, but that impairment was more severe in Col1a1-Krm2 than in Lrp5-/- mice and particularly evident in mice in which the more flexible fixation was used. Bone formation was more reduced in Col1a1-Krm2 than in Lrp5-/- mice, whereas osteoclast number was similarly increased in both genotypes in comparison with wild-type mice. Using microarray analysis we identified reduced expression of genes mainly involved in osteogenesis that seemed to be responsible for the observed stronger impairment of healing in Col1a1-Krm2 mice. In line with these findings, we detected decreased expression of sphingomyelin phosphodiesterase 3 (Smpd3) and less active β-catenin in the calli of Col1a1-Krm2 mice. Since Krm2 seems to play a significant role in regulating bone formation during fracture healing, antagonizing KRM2 might be a therapeutic option to improve fracture healing under compromised conditions, such as osteoporosis.


Evaluating viral interference between infectious bronchitis virus and Newcastle disease virus vaccine strains using quantitative reverse transcription-polymerase chain reaction.
The potential for infectious bronchitis virus (IBV) and Newcastle disease virus (NDV) replication interference was evaluated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Fourteen-day-old broiler chickens were inoculated via eyedrop with live commercial vaccine strains of IBV and NDV alone or in combination to directly evaluate IBV and NDV replication in the trachea at 1, 3, and 5 days after vaccination. Commercial NDV vaccine strains used were B1, VG/GA, and C2. The vaccine strains of IBV tested were Massachusetts (Mass) and Arkansas (Ark). The NDV + Mass vaccines used were commercially manufactured combined products. The NDV + Ark vaccines used were commercial vaccines manufactured as single entity products that were administered by eyedrop to opposite eyes of each chicken. As measured by qRT-PCR, the replication of NDV strains B1, VG/GA, and C2 did not interfere with the growth of IBV Mass and Ark strain vaccines in the combined vaccine treatment groups. Combination vaccinations using B1 and VG/GA did not interfere with IBV immunity based on challenge or serum antibody production. In the C2 + Mass vaccination trial, IBV immunity after challenge was reduced, but it did not seem to be a result of reduced Mass vaccine growth or the ability of the Mass vaccine to induce serum IBV antibody. In contrast, the replication of IBV strains Mass and Ark interfered with the growth of NDV strains B1, VG/GA, and C2 as measured by qRT-PCR. However, interference with NDV replication was not reflected in a reduction in Newcastle disease challenge of immunity findings when combination Mass + NDV products manufactured by vaccine companies were tested. Moreover, NDV immunity was not compromised in two of three trials using single entity vaccines of NDV and Ark IBV vaccines manufactured separately but administered simultaneously. However, in one trial, NDV immunity was decreased where a NDV single entity product (C2) was given with an IBV single entity Ark vaccine. This finding emphasizes the importance of using manufactured combination vaccines whenever possible to avoid potential interference.


Host-guest luminescent materials based on highly emissive species loaded into versatile sol-gel hosts.
Sol-gel chemistry has been extensively employed to produce several classes of materials (e.g. nanoparticles, thin films, fibers, gels, glasses and ceramic powders) with desired easily-controllable morphological, crystallographic and mechanical properties. In particular, the methodology can be explored for the development of optical supramolecular materials with interesting properties for light-emitting devices, chemical and biological sensing, biomarking and targeting, among many others. To this end, the strategies usually adopted consist of embedding a luminescent guest species into normally non-emissive sol-gel host materials, resulting in optical systems that preserve both the guest's photophysical characteristics and the host's mechanical and morphological properties. This concise review provides insights into the development of promising new host-guest optical materials based on versatile sol-gel hosts (i.e. mesoporous MCM-41 nanoparticles, mesoporous sodium-aluminosilicate glasses and other mesoporous matrices for sensors) and highly luminescent guests (i.e. organic dyes, d6 complexes and lanthanide complexes), mostly focusing on the findings from our group and similar findings in the literature of the past decade.


Analysis of 500 bone marrow transplants from unrelated donors (UR-BMT) facilitated by the Japan Marrow Donor Program: confirmation of UR-BMT as a standard therapy for patients with leukemia and aplastic anemia.
In December 1991, the Japan Marrow Donor Program (JMDP) was established with the cooperation of the Japanese Red Cross and Japan Marrow Donor Foundation under the auspices of the Ministry of Health and Welfare in Japan. By December 1998, 122365 HLA-A,B typed volunteer marrow donors and 7207 patients had been cumulatively registered in the JMDP. The results of HLA-matching between donors and patients revealed that 5684 out of 7207 (78.9%) patients could have at least one HLA-A,B,DR serologically matched donor. Among these matched pairs, 1829 unrelated bone marrow transplants (UR-BMT) were performed. The initial 500 UR-BMT transplanted from January 1993 to October 1995 were analyzed as of July 1998. Engraftment was achieved in 95% of cases. Probability of the occurrence of grade III and IV acute GVHD was 18.4%. The rate of disease-free survival (DFS) of the patients who had standard-risk leukemia and did not suffer from grade III or IV acute GVHD (n = 154) was 60-71% and the rate of survival of patients with aplastic anemia was 56%. It can be stated that UR-BMT is a modality of treatment which is as effective as related BMT if the occurrence of grade III or IV acute GVHD is predicted and prevented.


Significant inhibition of TRAIL-mediated fibroblast-like synovial cell apoptosis by IFN-gamma through JAK/STAT pathway by translational regulation.
The pathway of interferon-gamma (IFN-gamma)-induced suppression in tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) was investigated. rTRAIL triggered FLS apoptosis in a type II cell death manner, whereas IFN-gamma pretreatment significantly inhibited TRAIL-mediated apoptosis. As disruption of mitochondrial transmembrane potential (DeltaPsim), Leu-Glu-His-Asp ase (IETD ase) activity, and the appearance of hypodiploid DNA + cells were markedly suppressed in IFN-gamma-treated FLS in response to TRAIL, IFN-gamma-induced suppression was supposed to achieve at upstream of caspase-8. IFN-gamma rapidly phosphorylated signal transducers and activators of transcription 1 (STAT1), STAT3, and STAT6 as well as ERK, whereas enhanced neither phosphorylation of Akt nor nuclear translocation of nuclear factor kappaB (NF-kappaB) p65. Janus kinase (JAK)-induced phosphorylation of STAT1/3/6, which acts at translational regulation, seemed to be crucial because chemical inhibition of JAK as well as cycloheximide (CHX) abolished both the phosphorylation of STAT1/3/6 and the IFN-gamma-induced inhibitory effect. Although ERK was phosphorylated through IFN-gamma, chemical inhibition of ERK by PD98059 did not abolish the IFN-gamma-induced inhibitory effect. The authors tried to determine the responsible molecules; however, expression of TRAIL receptors; pro-caspase-3/-8/-9; Fas-associated death domain protein (FADD); tumor necrosis factor receptor 1-associated death domain protein (TRADD); silencer of death domain (SODD); FLICE inhibitory protein (FLIP); and Bcl-2, Bcl-xL, and Bax in FLS was not modulated by IFN-gamma. Although the authors have not yet clarified the precise mechanism, these data suggest that IFN-gamma/JAK/STAT pathway, which is supposed to be activated in inflammatory rheumatoid arthritis (RA) synovial tissues, contributes to form apoptosis resistance phenotype of the cells in situ, leading to a marked increase in cellularity of synovial cells.


Female rats are smarter than males: influence of test, oestrogen receptor subtypes and glutamate.
Interest in the influence of sex hormones within the central nervous system is a rapidly expanding area of research. A considerable amount of evidence has recently been obtained to support an important role of the gonadal steroids in cognitive processing. Not only are distinct and complementary behavioural phenotypes evident for each gender, in the case of the female but they are also reliant upon hormonal status. Gender influences and hormonal status are thus paramount and should encourage the development of more hypothesis-driven research strategies to understand gender differences in both normal behaviour and where this is altered in neuropsychiatric disorders.


Detection of cardiac geometry via difference intensity of echocardiogram images.
Echocardiogram is an ultrasound image of the heart that demonstrates the size, motion and composition of cardiac structures and is also used to diagnose various abnormalities of the heart including abnormal chamber size, shape and congenital heart disease. Echocardiography provides important morphological and functional details of the heart. Most of the presented automatic cardiac disease recognition systems that use echocardiograms based on defective anatomical region detection. In this paper we present a simple technique for cardiac geometry detection via echocardiogram images which conquer these borders and exploits cues from cardiac structure. To demonstrate the effectiveness of this technique, we present results for cardiac geometry detection through difference intensity of echocardiogram images. We have developed a simple program code for the prediction of cardiac geometry using difference intensity of echocardiogram images. With this code, users can generate node or point for detection of cardiac geometry as ventricle and atrium in size, shape and location.


[Method of evaluating occupational suitability to precision work].
An original method concurrent with functional system of occupational activities assessed occupational ability to highly precise work (watch assembling). Female assemblers with noticeable ability to this work, if compared to those with the diminished ability, demonstrate better occupational achievements, better functional state, lower fatigue at work, however presenting no differences in ophthalmologic and psychophysiologic criteria. The authors designed and put into practice a method based on timing of notably delicate movements and on psychologic criteria of durability to monotonous work.


4-Bromodiphenyl Ether Causes Adrenal Gland Dysfunction in Rats during Puberty.
Polybrominated diphenyl ethers (PBDEs) are a group of flame retardants with two or more bromines attached. They are endocrine disruptors. PBDEs photodegrade into 4-bromodiphenyl ether (BDE3). Whether BDE3 impairs adrenal cortical cell function during postnatal development still remains unknown. The aim of the current study was to investigate the influence of BDE3 on adrenal cortical cell function. Sprague-Dawley rats (35 days of age, male) were orally administered with BDE3 (0, 50, 100, and 200 mg/kg/day body weight) for 21 days. BDE3 significantly increased serum aldosterone and corticosterone levels at 200 mg/kg without affecting adrenocorticotropic hormone level. Further study showed that BDE3 up-regulated Cyp11b1 at 100 and 200 mg/kg and Scarb1, Star, Cyp11b2, Cyp21, and Nr5a1 mRNA levels in the 200 mg/kg group. BDE3 also decreased the phosphorylation of AMP-activated protein kinase (AMPK) at 200 mg/kg and increased PGC-1α and phosphorylated cyclic AMP-responsive element-binding protein (CREB)/CREB at 200 mg/kg. Taken together, these findings demonstrate that BDE3 stimulates adrenal cell function likely through decreasing phosphorylation of AMPK and increasing phosphorylation of CREB.


Theranostics through Utilizing Cherenkov Radiation of Radioisotope Zr-89 with a Nanocomposite Combination of TiO2 and MnO2.
Cherenkov radiation (CR) derived from the decay of diagnostic and therapeutic radionuclides is currently being studied by the scientific community to determine if these emissions can be harnessed for cancer detection and therapy. While Cherenkov luminescence imaging (CLI) has been studied in the preclinical and clinical settings, Cherenkov radiation-induced cancer therapy (CRICT) is a relatively new area of research that harnesses the emitted photons to kill cancer cells through free radical generation and DNA damage. Nanoparticles seem well suited for developing a theranostic platform that would allow researchers to visualize therapy delivery and also generate the reactive oxygen species necessary to kill cancer cells. Herein, we report the preparation of an 89Zr-TiO2-MnO2 nanocomposite that incorporates transferrin onto the nanoparticle surface to enhance cancer cell growth inhibition. The incorporation of the positron emission tomography (PET) radioisotope 89Zr (half-life: 3.3 days) allowed for the detection of the nanoparticle using PET and for the creation of Cherenkov emissions that interacted with the nanoparticle surface to generate free radicals for therapy delivery. After preparation, these systems were observed to be stable in various media and provided excellent tumor growth control after being intratumorally injected into mice bearing CT-26 tumors. These results demonstrate that a therapeutically efficient CRICT platform can be generated using commercially available and affordable materials.


The Biology of Bone Metastasis.
Bone metastasis, or the development of secondary tumors within the bone of cancer patients, is a debilitating and incurable disease. Despite its morbidity, the biology of bone metastasis represents one of the most complex and intriguing of all oncogenic processes. This complexity derives from the intricately organized bone microenvironment in which the various stages of hematopoiesis, osteogenesis, and osteolysis are jointly regulated but spatially restricted. Disseminated tumor cells (DTCs) from various common malignancies such as breast, prostate, lung, and kidney cancers or myeloma are uniquely primed to subvert these endogenous bone stromal elements to grow into pathological osteolytic or osteoblastic lesions. This colonization process can be separated into three key steps: seeding, dormancy, and outgrowth. Targeting the processes of dormancy and initial outgrowth offers the most therapeutic promise. Here, we discuss the concepts of the bone metastasis niche, from controlling tumor-cell survival to growth into clinically detectable disease.


Hospital stay in patients admitted for acute bipolar manic episodes prescribed quetiapine immediate or extended release: a retrospective non-interventional cohort study (HOME).
Bipolar manic episodes often require hospital admission to ensure patient safety. The antipsychotic quetiapine is a common treatment for bipolar mania and is available in immediate release (IR) and extended release (XR) formulations; however, outcomes in patients receiving these different formulations have not been directly compared in an acute hospital setting. We conducted a multinational, observational, retrospective cohort study to describe and compare hospital stay in patients admitted for an acute bipolar manic episode treated with quetiapine IR or XR from 1 October 2009-1 October 2010. The primary outcome measure was comparison of length of stay (LOS) using zero-truncated negative binomial regression. In total, 1230 patients were included (659 in the IR cohort; 571 in the XR cohort). The median LOS (interquartile range) was 18.0 days (12.0, 28.0) in the IR cohort and 20.0 days (12.0, 34.0) in the XR cohort, respectively. LOS was not significantly associated with quetiapine formulation irrespective of whether or not clinical characteristics were taken into account (p = 0.820 and p = 0.386, respectively). Overall, 84.2% and 84.4% of patients in the IR and XR cohorts, respectively, had not previously used quetiapine; of these patients, 78.7% and 68.9% received one total daily dose, and 14.4% and 23.9% received dose titration. Over half of patients received antipsychotic monotherapy (53.1% and 58.3% in the IR and XR cohorts, respectively) and most received a daily quetiapine dose ≥ 400 mg (64.9% and 71.8%, respectively, for quetiapine monotherapy and 59.9% and 80.3%, respectively, for combination treatment). As a secondary outcome, multivariate analysis was used to identify other factors that affect LOS. Factors associated with a longer hospital stay included public funding versus private, maximum number of new medications administered, did not receive lithium and did not receive anxiolytics, sedatives/hypnotics (all p < 0.0001). Factors associated with a shorter hospital stay included presence of drug/alcohol abuse, living accompanied and having a psychiatric medical history (all p < 0.05). LOS was not found to be associated with quetiapine formulation. However, most patients received only one total daily dose of quetiapine without dose titration, which was unexpected and contrary to current recommendations. NCT01239589.


A Novel Circular RNA circPTCD3 Promotes Breast Cancer Progression Through Sponging miR-198.
Circular RNAs (circRNAs), a new type of non-coding RNA, have been demonstrated to play critical roles in the progression of various of malignant cancers. However, the function of circRNAs in breast cancer is not clearly understood. qPCR was used to evaluate the gene expression. Function studies including MTT, transwell, wound healing and colony formation assay were performed to evaluate the function of circPTCD3 in breast cancer. Luciferase and RNA pull-down assays were used to verify the interaction between circPTCD3 and miR-198. The xenograft model was established to evaluate the function of circPTCD3 in vivo. In the present study, we identified a novel circRNA termed as circPTCD3 which was indicated to be significantly up-regulated in breast cancer tissues and cell lines. The results revealed that ectopic expression of circPTCD3 promoted the cell proliferation, migration and colony formation ability of breast cancer cells. Constantly, silencing of circPTCD3 inhibited those of breast cancer cells. Furthermore, we identified that circPTCD3 was able to target miR-198 in breast cancer cell. miR-198 has the function of inhibiting proliferation and migration of breast cancer cells which can be reversed by circPTCD3. Taken together, our findings for the first time identified a novel circRNA (circPTCD3) and revealed its oncogenic role in breast cancer. Mechanically, we reported that circPTCD3 served as a competing endogenous RNA (ceRNA) to sponge miR-198. These findings provide insights into breast cancer progression and also potential new targets for diagnosis or treatment of breast cancer.


Management of a Severe Degloving Injury With a Type 2 Open Tibia Fracture Using Negative Pressure Wound Therapy With Instillation and Dwell Time.
Severe lower extremity trauma cases are challenging for most orthopedic surgeons if a degloving injury with open fracture is associated, especially in the elderly population. The management of the soft tissue is essential for bone union and reduction of infection. The authors present the case of an 87-year-old female admitted to their department after a road accident in which she sustained an open fracture of the distal tibia classified as Gustilo-Anderson Type II, a closed fracture of the lateral malleoli, and a degloving of the posterior and lateral aspect of the left leg. After antibiotic delivery, she underwent surgical debridement and wound irrigation, 5 hours after the accident. The avulsed skin flap was conserved, the fracture of the lateral malleoli was fixed using the minimally invasive plate osteosynthesis technique, and an external fixation was applied for the distal tibia fracture. After 1 week, the necrotic skin flap and muscle were excised, and negative pressure wound therapy with instillation and dwell time (NPWTi-d) was applied for 9 days. Once granulation tissue with healthy wound edges was obtained, a split-thickness skin graft was used to provide total coverage. After 8 weeks, external fixation was replaced by a plaster cast. Eight weeks later, all wounds and fractures were healed, and the patient was able to return to their daily activities. The authors' main goal was achieved: preserving the architecture of the leg, achieving bone union, and avoiding infection. A large part of this good result comes back to NPWTi-d, a promising treatment that grants clinical benefit for the patient and surgeon. Additional research and larger prospective studies are required before giving a strict recommendation.


A quick fix?
Recommendations from the National Institute for Health and Clinical Excellence say more people with high cholesterol levels should be prescribed statins. But some professionals have reservations. Currently 2 million people in England and Wales take statins. This figure will rise to 3.3 million with the change in threshold for statin treatment. The threshold for considering statin use has changed from a 30 per cent ten-year risk of developing cardiovascular disease to a 20 per cent or more risk. Statins in low dosage are available over the counter.


A digital dissection of two teleost fishes: comparative functional anatomy of the cranial musculoskeletal system in pike (Esox lucius) and eel (Anguilla anguilla).
Advances in X-ray computed tomography (CT) have led to a rise in the use of non-destructive imaging methods in comparative anatomy. Among these is contrast-enhanced CT scanning, which employs chemical stains to visualize soft tissues. Specimens may then be 'digitally dissected', producing detailed, three-dimensional digital reconstructions of the soft- and hard-tissue anatomy, allowing examination of anatomical structures in situ and making accurate measurements (lengths, volumes, etc.). Here, we apply this technique to two species of teleost fish, providing one of the first comprehensive three-dimensional (3D) descriptions of teleost cranial soft tissue and quantifying differences in muscle anatomy that may be related to differences in feeding ecology. Two species with different feeding ecologies were stained, scanned and imaged to create digital 3D musculoskeletal reconstructions: Esox lucius (Northern Pike), predominantly a suction feeder; and Anguilla anguilla (European eel), which captures prey predominantly by biting. Muscle cross-sectional areas were calculated and compared between taxa, focusing on muscles that serve important roles in feeding. The adductor mandibulae complex - used in biting - was larger in Esox than Anguilla relative to head size. However, the overall architecture of the adductor mandibulae was also very different between the two species, with that of Anguilla better optimized for delivering forceful bites. Levator arcus palatini and sternohyoideus - which are used in suction feeding - are larger in Esox, whereas the levator operculi is larger in Anguilla. Therefore, differences in the size of functionally important muscles do not necessarily correlate neatly with presumed differences in feeding mode.


Beyond Heritability: Twin Studies in Behavioral Research.
The heritability of human behavioral traits is now well established, due in large measure to classical twin studies. We see little need for further studies of the heritability of individual traits in behavioral science, but the twin study is far from having outlived its usefulness. The existence of pervasive familial influences on behavior means that selection bias is always a concern in any study of the causal effects of environmental circumstances. Twin samples continue to provide new opportunities to identify causal effects with appropriate genetic and shared environmental controls. We discuss environmental studies of discordant twin pairs and twin studies of genetic and environmental transactions in this context.


Ablative Therapy for Oligometastatic Non-Small Cell Lung Cancer.
The oligometastatic state represents a distinct entity among those with metastatic disease and consists of patients with metastases limited in number and location, representing an intermediate state between locally confined and widely metastatic cancer. Although similar, "oligorecurrence" (limited number of metachronous metastases under conditions of a controlled primary lesion) and "oligoprogressive" (disease progression at a limited number of sites with disease controlled at other disease sites) states are distinct entities. In non-small cell lung cancer (NSCLC), the oligometastatic state is relatively common, with 20% to 50% of patients having oligometastatic disease at diagnosis. This subgroup of patients when receiving ablative therapy, such as surgery or stereotactic body radiation radiotherapy, can obtain markedly long progression-free and overall survival. The role of radical treatment for intracranial oligometastases is well established. Fewer data exist regarding radical treatment of extracranial metastases in lung cancer; however, retrospective series using surgery or stereotactic body radiotherapy for extracranial oligometastatic disease in NSCLC have shown excellent local control, with a suggestion of improvement in progression-free survival. In the present report, we have reviewed the data on the treatment of brain metastases in oligometastatic NSCLC and the results of ablative treatment of extracranial sites. Recently, the first randomized trial comparing ablative treatment versus control in oligometastatic disease was reported, and those data are reviewed in the context of smaller series. Finally, areas of controversy are discussed and a therapeutic approach for patients with oligometastatic disease is proposed.


Tailored biosynthesis of polyhydroxyalkanoates in chemostat cultures.
Polyhydroxyalkanoates (PHAs) are accumulated intracellularly by many bacteria and serve as a carbon and energy storage compound. PHAs are polyesters of high molecular weight and can be isolated by solvent extraction and precipitation in antisolvents. The material properties of PHAs are of great interest due to the inherent biodegradability and excellent biocompatibility. To date, more than 150 different PHA monomers have been described in literature and it has been found that the monomeric unit composition significantly influences the physico-chemical properties of PHAs. The monomer composition may be controlled to some extent by the choice of the PHA production strain but also by the cultivation conditions and the carbon substrate/PHA precursor supply. In previous studies, it has been shown that the most reproducible production method of PHA is the chemostat cultivation of suitable bacteria under multiple nutrient limited growth conditions. This chapter is dedicated to provide step-by step instructions to produce PHAs in a chemostat culture and specifically describes how the composition of PHA copolymers can be tailored during biosynthesis, as well as a set of analytical tools and methods to characterize PHAs.


The cost of treatment failure: resource use and costs incurred by hepatitis C virus genotype 1-infected patients who do or do not achieve sustained virological response to therapy.
Chronic hepatitis C virus (HCV) infection places a considerable economic burden on health services. Cost-effectiveness analyses of antiviral treatment for patients with chronic HCV infection are dependent on assumptions about cost reductions following sustained virological response (SVR) to therapy. This study quantified the medium-term difference in health resource usage and costs depending on treatment outcome. Retrospective chart review of patients with HCV genotype 1 infection who had received at least 2 months pegylated interferon and ribavirin therapy, with known treatment outcome was conducted. Disease status was categorized as chronic hepatitis, cirrhosis or decompensated liver disease. Health resource use was documented for each patient in each disease state. Unit costs were from the NHS 'Payment by Results' database and the British National Formulary. One hundred and ninety three patients (108 SVR, 85 non-SVR) with mean follow-up of 3.5 (SVR) and 4.9 (non-SVR) years were enrolled. No SVR patient progressed to a more severe liver disease state. Annual transition rates for non-SVR patients were 7.4% (chronic hepatitis to cirrhosis) and 4.9% (cirrhosis to decompensated liver disease). By extrapolation of modelled data over a 5-year post-treatment period, failure of patients with chronic hepatitis to achieve SVR was associated with a 13-fold increase (roughly £2300) in costs, whilst for patients who were retreated, the increase was 56-fold, equating to more than £10 000. Achievement of an SVR has significant effects on health service usage and costs. This work provides real-life data for future cost-effectiveness analyses related to the treatment for chronic HCV infection.


A comparison of NT-proBNP and albuminuria for predicting cardiac events in patients with diabetes mellitus.
Cardiovascular events are the most relevant events in patients with diabetes mellitus. We aimed to compare the predictive values of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the state-of-the-art marker, albuminuria, for cardiac events in diabetic patients. In this prospective observational study we recruited 1071 patients with diabetes mellitus. NT-proBNP and albuminuria ⊟ defined as a urinary albumin/creatinine ratio >30 mg/g were measured at baseline. Patients were followed during a mean observation period of 33.1 months. A total of 103 patients reached the defined endpoint (unplanned hospitalization due to a cardiac event or death). The mean duration of diabetes was 15 ± 12 years and the mean HbA(1c) was 7.5 ± 3.1%. At baseline, 23.7% of the patients presented with albuminuria and 36.6% had plasma NT-proBNP values >125 pg/ml. Multiple Cox regression analysis including age, gender, duration of diabetes HbA(1c), albuminuria, and lnNT-proBNP revealed that lnNT-proBNP (hazard ratio 2.314; 95% CI 1.914-2.798, p < 0.001) was a better predictor than albuminuria (HR 1.544; 95% CI 1.007-2.368, p = 0.047) or age (HR 1.030; 95% CI 1.008-1.053, p = 0.007). Calculating different Cox-models with (A) albuminuria, (B) NT-proBNP, or (C) both in the model revealed that the C-index was best if NT-proBNP was entered in the model (C-index for A 0.735, for B 0.809, and for C 0.786). Kaplan-Meier analysis demonstrated that albuminuria does not add substantial information if NT-proBNP is entered into the model. NT-proBNP was superior to albuminuria for predicting cardiac events.


Neural substrates of parallel devaluation-sensitive and devaluation-insensitive Pavlovian learning in humans.
We aim to differentiate the brain regions involved in the learning and encoding of Pavlovian associations sensitive to changes in outcome value from those that are not sensitive to such changes by combining a learning task with outcome devaluation, eye-tracking, and functional magnetic resonance imaging in humans. Contrary to theoretical expectation, voxels correlating with reward prediction errors in the ventral striatum and subgenual cingulate appear to be sensitive to devaluation. Moreover, regions encoding state prediction errors appear to be devaluation insensitive. We can also distinguish regions encoding predictions about outcome taste identity from predictions about expected spatial location. Regions encoding predictions about taste identity seem devaluation sensitive while those encoding predictions about an outcome's spatial location seem devaluation insensitive. These findings suggest the existence of multiple and distinct associative mechanisms in the brain and help identify putative neural correlates for the parallel expression of both devaluation sensitive and insensitive conditioned behaviors.