Recent progress and prospects in Sasang constitutional medicine: a traditional type of physiome-based treatment.
The history of the constitution perspective in medical care dates back thousands of years and extends from the East to the West. Among the various forms of constitutional medicine, Sasang constitutional medicine (SCM) is a holistic, tailored medical approach that is based on a well-structured theoretical system that includes physiopathological disciplines. Scientific evidence has demonstrated that SCM typology has a constitution-specific basis in anthropometrics, physiological characteristics, disease vulnerability, and genetic origins. Furthermore, the recent rise of systems biology, which requires whole body modeling, uses a state-of-the-art approach in interpreting the holistic spirit of Oriental medicine. This article aims to provide an overview of the recent achievements in SCM research and to discuss how the concept of balance in SCM may contribute to the development of large scale modeling in systems biology.


Fenamates Inhibit Human Sodium Channel Nav1.2 and Protect Glutamate-Induced Injury in SH-SY5Y Cells.
Voltage-gated sodium channels are crucial mediators of neuronal damage in ischemic and excitotoxicity disease models. Fenamates have been reported to have anti-inflammatory properties following a decrease in prostaglandin synthesis. Several researches showed that fenamates appear to be ion channel modulators and potential neuroprotectants. In this study, the neuroprotective effects of tolfenamic acid, flufenamic acid, and mefenamic acid were tested by glutamate-induced injury in SH-SY5Y cells. Following this, fenamates' effects were examined on both the expression level and the function of hNav1.1 and hNav1.2, which were closely associated with neuroprotection, using Western blot and patch clamp. Finally, the effect of fenamates on the expression of apoptosis-related proteins in SH-SY5Y cells was examined. The results showed that both flufenamic acid and mefenamic acid exhibited neuroprotective effects against glutamate-induced injury in SH-SY5Y cells. They inhibited peak currents of both hNav1.1 and hNav1.2. However, fenamates exhibited decreased inhibitory effects on hNav1.1 when compared to hNav1.2. Correspondingly, the inhibitory effect of fenamates was found to be consistent with the level of neuroprotective effects in vitro. Fenamates inhibited glutamate-induced apoptosis through the modulation of the Bcl-2/Bax-dependent cell death pathways. Taken together, Nav1.2 might play a part in fenamates' neuroprotection mechanism. Nav1.2 and NMDAR might take part in the neuroprotection mechanism of the fenamates. The fenamates inhibited glutamate-induced apoptosis through modulation of the Bcl-2/Bax-dependent cell death pathways.


Modulation of antioxidative response in the therapy of hypertension and other cardiovascular diseases.
This paper reviews and compares major approaches and strategies to modulation of antioxidative response in the therapy of hypertension and cardiovascular diseases. There are two major strategies of modulation of antioxidative response in hypertension and cardiovascular diseases: (i) modulation of NO levels by NOS stimulation, increase of NO bioavailability, administration of NO, and NOS gene incorporation; (ii) scavenging of superoxide and suppression of oxidative stress by activation of antioxidant gene expression or by suppression of selected genes by RNA silencing. These strategies are accomplished by several concepts, including (1) delivery of external agents, (2) antioxidant gene therapy and RNA silencing, and (3) combined therapies and approaches. Combined therapies and approches often achieve multiplicative effects and are the most promising attitude in antioxidant-oriented therapy of hypertension and cardiovascular diseases.


Laryngeal chemoreflex: anatomic and physiologic study by use of the superior laryngeal nerve in the piglet.
The laryngeal chemoreflex (LCR) was investigated in 21 piglets (ages 6 to 80 days old) with the use of physiologic and histologic techniques. The central projection of the superior laryngeal nerve (SLN) was determined in 14 animals by use of horseradish peroxidase-wheat germ agglutinin. Ipsilateral labeling of the solitary tract nucleus was seen. The caudal extent of the labeling varied with age. Sensory labeling of the nucleus ambiguus was present bilaterally in three younger animals and unilaterally in older piglets. Bilateral labeling of the nucleus dorsomedialis was seen in all ages. Apneic and cardiovascular response to water stimulation of laryngeal mucosa and the laryngeal adductor reflex (LAR) were examined in 16 piglets. Blunting of the apneic and cardiovascular response was seen after sacrifice of a single SLN. Hypoxia did not significantly affect the LAR or apnea duration in animals with only one intact SLN. A contralateral LAR was found in younger animals. Relevance to the LCR is also discussed.


Brain CB₂ Receptors: Implications for Neuropsychiatric Disorders.
Although previously thought of as the peripheral cannabinoid receptor, it is now accepted that the CB₂ receptor is expressed in the central nervous system on microglia, astrocytes and subpopulations of neurons. Expression of the CB₂ receptor in the brain is significantly lower than that of the CB₁ receptor. Conflicting findings have been reported on the neurological effects of pharmacological agents targeting the CB₂ receptor under normal conditions. Under inflammatory conditions, CB₂ receptor expression in the brain is enhanced and CB2 receptor agonists exhibit potent anti-inflammatory effects. These findings have prompted research into the CB₂ receptor as a possible target for the treatment of neuroinflammatory and neurodegenerative disorders. Neuroinflammatory alterations are also associated with neuropsychiatric disorders and polymorphisms in the CB₂ gene have been reported in depression, eating disorders and schizophrenia. This review will examine the evidence to date for a role of brain CB₂ receptors in neuropsychiatric disorders.


Discovery of an Extended Austinoid Biosynthetic Pathway in Aspergillus calidoustus.
Filamentous fungi produce a wide range of natural products that are commonly used in various industrial contexts (e.g., pharmaceuticals and insecticides). Meroterpenoids are natural products of interest because of their various biological activities. Among the meroterpenoids, there is a group of insecticidal compounds known as the austinoids. These compounds have also been studied because of their intriguing spiro-lactone ring formation along with various modifications. Here, we present an extension of the original austinol/dehydroaustinol biosynthesis pathway from Aspergillus nidulans in the recently identified filamentous fungus Aspergillus calidoustus. Besides the discovery and elucidation of further derivatives, genome mining led to the discovery of new putative biosynthetic genes. The genes involved in the biosynthesis of later austinoid products were characterized, and among them was a second polyketide synthase gene in the A. calidoustus cluster that was unusual because it was a noninterative polyketide synthase producing a diketide. This diketide product was then loaded onto the austinoid backbone, resulting in a new insecticidal derivative, calidodehydroaustin.


Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells.
Under most physiological circumstances, monocytes are excluded from parenchymal CNS tissues. When widespread monocyte entry occurs, their numbers decrease shortly after engraftment in the presence of microglia. However, some disease processes lead to focal and selective loss, or dysfunction, of microglia, and microglial senescence typifies the aged brain. In this regard, the long-term engraftment of monocytes in the microglia-depleted brain remains unknown. Here, we report a model in which a niche for myeloid cells was created through microglia depletion. We show that microglia-depleted brain regions of CD11b-HSVTK transgenic mice are repopulated with new Iba-1-positive cells within 2 wk. The engrafted cells expressed high levels of CD45 and CCR2 and appeared in a wave-like pattern frequently associated with blood vessels, suggesting the engrafted cells were peripheral monocytes. Although two times more numerous and morphologically distinct from resident microglia up to 27 wk after initial engraftment, the overall distribution of the engrafted cells was remarkably similar to that of microglia. Two-photon in vivo imaging revealed that the engrafted myeloid cells extended their processes toward an ATP source and displayed intracellular calcium transients. Moreover, the engrafted cells migrated toward areas of kainic acid-induced neuronal death. These data provide evidence that circulating monocytes have the potential to occupy the adult CNS myeloid niche normally inhabited by microglia and identify a strong homeostatic drive to maintain the myeloid component in the mature brain.


Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo.
Hematopoietic stem cells (HSCs) are first found in the aorta-gonad-mesonephros region and vitelline and umbilical arteries of the midgestation mouse embryo. Runx1 (AML1), the DNA binding subunit of a core binding factor, is required for the emergence and/or subsequent function of HSCs. We show that all HSCs in the embryo express Runx1. Furthermore, HSCs in Runx1(+/-) embryos are heterogeneous and include CD45(+) cells, endothelial cells, and mesenchymal cells. Comparison with wild-type embryos showed that the distribution of HSCs among these various cell populations is sensitive to Runx1 dosage. These data provide the first morphological description of embryonic HSCs and contribute new insight into their cellular origin.


Cranial vault growth in multiple-suture nonsyndromic and syndromic craniosynostosis: a postoperative long-term anthropometric follow-up.
Long-term anthropometric follow-up of cranial vault growth may considerably add valuable information to current literature focusing on treatment strategies for premature multiple-suture craniosynostosis. The aim of this paper was to compare postoperative growth patterns of nonsyndromic and syndromic multiple-suture craniosynostotic children with sex-matched and age-matched children from the typically developing population. Forty-one multiple-suture craniosynostotic patients (19 nonsyndromic and 22 syndromic) were included in this 5-year follow-up. Anthropological data of sex-matched and age-matched normal Swiss children served as a control. A standardized time protocol for anthropometric skull measurements (head circumference and cephalic index) was used. Data were converted into Z-scores for standardized intercenter comparison. All patients showed a marked benefit in cranial vault shape after open skull remodeling. Significant differences in long-term cranial vault growth pattern could be seen between the nonsyndromic and the syndromic groups compared to the control group.


Existence of collisional trajectories of Mercury, Mars and Venus with the Earth.
It has been established that, owing to the proximity of a resonance with Jupiter, Mercury's eccentricity can be pumped to values large enough to allow collision with Venus within 5 Gyr (refs 1-3). This conclusion, however, was established either with averaged equations that are not appropriate near the collisions or with non-relativistic models in which the resonance effect is greatly enhanced by a decrease of the perihelion velocity of Mercury. In these previous studies, the Earth's orbit was essentially unaffected. Here we report numerical simulations of the evolution of the Solar System over 5 Gyr, including contributions from the Moon and general relativity. In a set of 2,501 orbits with initial conditions that are in agreement with our present knowledge of the parameters of the Solar System, we found, as in previous studies, that one per cent of the solutions lead to a large increase in Mercury's eccentricity-an increase large enough to allow collisions with Venus or the Sun. More surprisingly, in one of these high-eccentricity solutions, a subsequent decrease in Mercury's eccentricity induces a transfer of angular momentum from the giant planets that destabilizes all the terrestrial planets approximately 3.34 Gyr from now, with possible collisions of Mercury, Mars or Venus with the Earth.


Neurosurgery in Afghanistan during "Operation Enduring Freedom": a 24-month experience.
"Operation Enduring Freedom" is the US war effort in Afghanistan in its global war on terror. One US military neurosurgeon is deployed in support of Operation Enduring Freedom to provide care for both battlefield injuries and humanitarian work. Here, the authors analyze a 24-month neurosurgical caseload experience in Afghanistan. Operative logs were analyzed between October 2007 and September 2009. Operative cases were divided into minor procedures (for example, placement of an intracranial pressure monitor) and major procedures (for example, craniotomy) for both battle injuries and humanitarian work. Battle injuries were defined as injuries sustained by soldiers while in the line of duty or injuries to Afghan civilians from weapons of war. Humanitarian work consisted of providing medical care to Afghans. Six neurosurgeons covering a 24-month period performed 115 minor procedures and 210 major surgical procedures cases. Operations for battlefield injuries included 106 craniotomies, 25 spine surgeries, and 18 miscellaneous surgeries. Humanitarian work included 32 craniotomies (23 for trauma, 3 for tumor, 6 for other reasons, such as cyst fenestration), 27 spine surgeries (12 for degenerative conditions, 9 for trauma, 4 for myelomeningocele closure, and 2 for the treatment of infection), and 2 miscellaneous surgeries. Military neurosurgeons have provided surgical care at rates of 71% (149/210) for battlefield injuries and 29% (61/210) for humanitarian work. Of the operations for battle trauma, 50% (106/210) were cranial and 11% (25/210) spinal surgeries. Fifteen percent (32/210) and 13% (27/210) of operations were for humanitarian cranial and spine procedures, respectively. Overall, military neurosurgeons in Afghanistan are performing life-saving cranial and spine stabilization procedures for battlefield trauma and acting as general neurosurgeons for the Afghan community.


Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods.
The diagnosis of herbal hepatotoxicity or herb induced liver injury (HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation. At the day HILI is suspected in a patient, physicians should start assessing the quality of the used herbal product, optimizing the clinical data for completeness, and applying the Council for International Organizations of Medical Sciences (CIOMS) scale for initial causality assessment. This scale is structured, quantitative, liver specific, and validated for hepatotoxicity cases. Its items provide individual scores, which together yield causality levels of highly probable, probable, possible, unlikely, and excluded. After completion by additional information including raw data, this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation. The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases, compared to numerous other causality assessment methods, which are inferior on various grounds. Among these disputed methods are the Maria and Victorino scale, an insufficiently qualified, shortened version of the CIOMS scale, as well as various liver unspecific methods such as the ad hoc causality approach, the Naranjo scale, the World Health Organization (WHO) method, and the Karch and Lasagna method. An expert panel is required for the Drug Induced Liver Injury Network method, the WHO method, and other approaches based on expert opinion, which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician. In conclusion, HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale, avoiding pitfalls commonly observed with other approaches.


Nasal encephalocele in a child with Beckwith-Wiedemann syndrome.
Beckwith-Wiedemann syndrome (BWS) is a rare congenital syndrome characterized by gigantism, macroglossia, exophthalmos, postpartum hypoglycemia, and multiple midline defects such as omphalocele. The authors describe, to the best of their knowledge, the first case of a child in whom BWS was diagnosed and who was subsequently treated for a nasal encephalocele. Because the authors believe that this feature might not be an incidental finding in patients with BWS, intranasal masses in these patients should be carefully differentiated, as complications might be severe.


An olfactory receptor for food-derived odours promotes male courtship in Drosophila.
Many animals attract mating partners through the release of volatile sex pheromones, which can convey information on the species, gender and receptivity of the sender to induce innate courtship and mating behaviours by the receiver. Male Drosophila melanogaster fruitflies display stereotyped reproductive behaviours towards females, and these behaviours are controlled by the neural circuitry expressing male-specific isoforms of the transcription factor Fruitless (FRU(M)). However, the volatile pheromone ligands, receptors and olfactory sensory neurons (OSNs) that promote male courtship have not been identified in this important model organism. Here we describe a novel courtship function of Ionotropic receptor 84a (IR84a), which is a member of the chemosensory ionotropic glutamate receptor family, in a previously uncharacterized population of FRU(M)-positive OSNs. IR84a-expressing neurons are activated not by fly-derived chemicals but by the aromatic odours phenylacetic acid and phenylacetaldehyde, which are widely found in fruit and other plant tissues that serve as food sources and oviposition sites for drosophilid flies. Mutation of Ir84a abolishes both odour-evoked and spontaneous electrophysiological activity in these neurons and markedly reduces male courtship behaviour. Conversely, male courtship is increased--in an IR84a-dependent manner--in the presence of phenylacetic acid but not in the presence of another fruit odour that does not activate IR84a. Interneurons downstream of IR84a-expressing OSNs innervate a pheromone-processing centre in the brain. Whereas IR84a orthologues and phenylacetic-acid-responsive neurons are present in diverse drosophilid species, IR84a is absent from insects that rely on long-range sex pheromones. Our results suggest a model in which IR84a couples food presence to the activation of the fru(M) courtship circuitry in fruitflies. These findings reveal an unusual but effective evolutionary solution to coordinate feeding and oviposition site selection with reproductive behaviours through a specific sensory pathway.


The Web-Based Osteoarthritis Management Resource My Joint Pain Improves Quality of Care: A Quasi-Experimental Study.
Despite the availability of evidence-based guidelines for conservative treatment of osteoarthritis (OA), management is often confined to the use of analgesics and waiting for eventual total joint replacement. This suggests a gap in knowledge for persons with OA regarding the many different treatments available to them. Our objective was to evaluate outcomes after usage of a Web-based resource called My Joint Pain that contains tailored, evidence-based information and tools aimed to improve self-management of OA on self-management and change in knowledge. A quasi-experimental design was used to evaluate the My Joint Pain website intervention over a 12-month period. The intervention provided participants with general and user-specific information, monthly assessments with validated instruments, and progress-tracking tools. A nationwide convenience sample of 195 participants with self-assessed hip and/or knee OA completed both baseline and 12-month questionnaires (users: n=104; nonusers: n=91). The primary outcome measure was the Health Evaluation Impact Questionnaire (heiQ) to evaluate 8 different domains (health-directed activity, positive and active engagement in life, emotional distress, self-monitoring and insight, constructive attitudes and approaches, skill and technique acquisition, social integration and support, health service navigation) and the secondary outcome measure was the 17-item Osteoarthritis Quality Indicator (OAQI) questionnaire to evaluate the change in appropriateness of care received by participants. Independent t tests were used to compare changes between groups for the heiQ and chi-square tests to identify changes within and between groups from baseline to 12 months for each OAQI item. Baseline demographics between groups were similar for gender (152/195, 77.9% female), age (mean 60, SD 9 years) and body mass index (mean 31.1, SD 6.8 kg/m(2)). With the exception of health service navigation, mean effect sizes from all other heiQ domains showed a positive trend for My Joint Pain users compared to the nonusers, although the differences between groups did not reach statistical significance. Within-group changes also showed improvements among the users of the My Joint Pain website for self-management (absolute change score=15%, P=.03), lifestyle (absolute change score=16%, P=.02), and physical activity (absolute change score=11%, P=.04), with no significant improvements for the nonusers. Following 12 months of exposure to the website, there were significant improvements for users compared to nonusers in self-management (absolute change score 15% vs 2%, P=.001) and weight reduction (absolute change scores 3% vs -6%, P=.03) measured on the OAQI. The My Joint Pain Web resource does not significantly improve overall heiQ, but does improve other important aspects of quality of care in people with hip and/or knee OA. Further work is required to improve engagement with the website and the quality of information delivered in order to provide a greater impact.


Cellular characterization of adipose tissue from various body sites of women.
Adipose tissue is the primary site of estrogen biosynthesis in postmenopausal women. The two main histologic components of adipose tissue are mature adipocytes and fibroblasts. Aromatase P450 expressed in the fibroblast component of adipose tissue is responsible for catalyzing conversion of C19 steroids to estrogens. We previously have demonstrated that in women, aromatase expression in adipose tissue of various body sites increases with age and that aromatase expression in the hip is markedly higher than in the abdomen. To determine whether this age- and regional-dependent variation in aromatase expression is caused by an alteration in the ratio of fibroblasts to mature adipocytes, we collected sc adipose tissue samples from 19 women (age range: 21-93 yr) at the time of autopsy. Using a computerized image analysis system, we determined by morphometry the proportions of adipocytes, fibroblasts, and vascular endothelial cells within histologic sections of adipose tissue from midabdomen, both breasts, and both hips. The percentage of each cell component at each body site was expressed as the mean of triplicate replicates. Statistical analysis of our results did not indicate any correlation between advancing age and fibroblast to adipocyte ratios in the breast, abdomen, or hip. Fibroblast to adipocyte ratios were found to be significantly higher in the breast and abdomen compared with the hip ( P < 0.05). No statistical differences were found between the breast and abdomen. These findings suggest that the increase in aromatase expression with advancing age and the higher aromatase expression in the hip compared with the abdomen in women may be caused by alterations in specific signal transduction mechanisms rather than a simple increase in local adipose fibroblast numbers.


Effects of body mass index on step count accuracy of physical activity monitors.
Activity monitors are widely used in research, and are currently being used to study physical activity (PA) trends in the US and Canada. The purpose of this study was to determine if body mass index (BMI) affects the step count accuracy of commonly used accelerometer-based activity monitors during treadmill walking. Participants were classified into BMI categories and instructed to walk on a treadmill at 3 different speeds (40, 67, and 94 m·min(-1)) while wearing 4 accelerometer-based activity monitors (ActiGraph GT1M, ActiCal, NL-2000, and StepWatch). There was no significant main effect of BMI on pedometer accuracy. At the slowest speed, all waist-mounted devices significantly underestimated actual steps (P < .001), with the NL-2000 recording the greatest percentage (72%). At the intermediate speed, the ActiGraph was the least accurate, recording only 80% of actual steps. At the fastest speed, all of the activity monitors demonstrated a high level of accuracy. Our data suggest that BMI does not greatly affect the step-counting accuracy of accelerometer-based activity monitors. However, the accuracy of the ActiGraph, ActiCal, and NL-2000 decreases at slower speeds. The ankle-mounted StepWatch was the most accurate device across a wide range of walking speeds.


Interactions between the yeast SM22 homologue Scp1 and actin demonstrate the importance of actin bundling in endocytosis.
The yeast SM22 homologue Scp1 has previously been shown to act as an actin-bundling protein in vitro. In cells, Scp1 localizes to the cortical actin patches that form as part of the invagination process during endocytosis, and its function overlaps with that of the well characterized yeast fimbrin homologue Sac6p. In this work we have used live cell imaging to demonstrate the importance of key residues in the Scp1 actin interface. We have defined two actin binding domains within Scp1 that allow the protein to both bind and bundle actin without the need for dimerization. Green fluorescent protein-tagged mutants of Scp1 also indicate that actin localization does not require the putative phosphorylation site Ser-185 to be functional. Deletion of SCP1 has few discernable effects on cell growth and morphology. However, we reveal that scp1 deletion is compensated for by up-regulation of Sac6. Furthermore, Scp1 levels are increased in the absence of sac6. The presence of compensatory pathways to up-regulate Sac6 or Scp1 levels in the absence of the other suggest that maintenance of sufficient bundling activity is critical within the cell. Analysis of cortical patch assembly and movement during endocytosis reveals a previously undetected role for Scp1 in movement of patches away from the plasma membrane. Additionally, we observe a dramatic increase in patch lifetime in a strain lacking both sac6 and scp1, demonstrating the central role played by actin-bundling proteins in the endocytic process.


Deterioration of Parkinson's disease during hospitalization: survey of 684 patients.
A substantial fraction of Parkinson's disease patients deteriorate during hospitalisation, but the precise proportion and the reasons why have not been studied systematically and the focus has been on surgical wards and on Accident & Emergency departments. We assessed the prevalence and risk factors of deterioration of Parkinson's disease symptoms during hospitalization, including all wards. We invited Parkinson's disease patients from three neurology departments in The Netherlands to answer a standardised questionnaire on general, disease and hospital related issues. Patients who had been hospitalized in the previous year were included and analysed. Possible risk factors for Parkinson's disease deterioration were identified. Proportions were analysed using the Chi-Square test and a logistic regression analysis was performed. Eighteen percent of 684 Parkinson's disease patients had been hospitalized at least once in the last year. Twenty-one percent experienced deterioration of motor symptoms, 33% did have one or more complications and 26% had received incorrect anti-Parkinson's medication. There were no statistically significant differences for these variables between admissions on neurologic or non-neurologic wards and between having surgery or not. Incorrect medication during hospitalization was significantly associated with higher risk (OR 5.8, CI 2.5-13.7) of deterioration, as were having infections (OR 6.7 CI 1.8-24.7). A higher levodopa equivalent dose per day was a significant risk factor for deterioration. When adjusting for different variables, wrong medication distribution was the most important risk factor for deterioration. Incorrect medication and infections are the important risk factors for deterioration of Parkinson's disease patients both for admissions with and without surgery and both for admissions on neurologic and non-neurologic wards. Measures should be taken to improve care and incorporated in guidelines.


The Impact of Acute Loud Noise on the Behavior of Laboratory Birds.
Husbandry procedures and facility settings, such as low-frequency fire alarms, can produce noises in a laboratory environment that cause stress to animals used in research. However, most of the data demonstrating harmful effects that have, consequently, led to adaptations to management, have largely come from laboratory rodents with little known of the impacts on avian behavior and physiology. Here we examined whether exposure to a routine laboratory noise, a low-frequency fire alarm test, induced behavioral changes in laboratory zebra finches (Taeniopygia guttata). Twenty-four breeding pairs of zebra finches were randomly selected and exposed to the low-frequency fire alarm (sounding for 10-20 s) or no noise (control) on separate test days. All birds were filmed before and after the alarm sounded and on a control day (without the alarm). The zebra finches decreased their general activity and increased stationary and social behaviors after exposure to the alarm. Brief exposure to a low-frequency alarm disrupted the birds' behavior for at least 15 min. The induction of this behavioral stress response suggests that low-frequency sound alarms in laboratory facilities have the potential to compromise the welfare of laboratory birds.


Nonassociative learning implementation by a single memristor-based multi-terminal synaptic device.
Animals' survival is dependent on their abilities to adapt to the changing environment by adjusting their behaviours, which is related to the ubiquitous learning behaviour, nonassociative learning. Thus mimicking the indispensable learning behaviour in organisms based on electronic devices is vital to better achieve artificial neural networks and neuromorphic computing. Here a three terminal device consisting of an oxide-based memristor and a NMOS transistor is proposed. The memristor with gradual conductance tuning inherently functions as the synapse between sensor neurons and motor neurons and presents adjustable synaptic plasticity, while the NMOS transistor attached to the memristor is utilized to mimic the modulatory effect of the neuromodulator released by inter neurons. Such a memristor-based multi-terminal device allows the practical implementation of significant nonassociative learning based on a single electronic device. In this study, the experience-induced modification behaviour, both habituation and sensitization, was successfully achieved. The dependence of the nonassociative behavioural response on the strength and interval of presented stimuli was also discussed. The implementation of nonassociative learning offers feasible and experimental advantages for further study on neuromorphic systems based on electronic devices.


Alcohol Consumption, Drinking Patterns, and Cognitive Performance in Young Adults: A Cross-Sectional and Longitudinal Analysis.
Long-term alcohol abuse is associated with poorer cognitive performance. However, the associations between light and moderate drinking and cognitive performance are less clear. We assessed this association via cross-sectional and longitudinal analyses in a sample of 702 Dutch students. At baseline, alcohol consumption was assessed using questionnaires and ecological momentary assessment (EMA) across four weeks ('Wave 1'). Subsequently, cognitive performance, including memory, planning, and reasoning, was assessed at home using six standard cognition tests presented through an online platform. A year later, 436 students completed the four weeks of EMA and online cognitive testing ('Wave 2'). In both waves, there was no association between alcohol consumption and cognitive performance. Further, alcohol consumption during Wave 1 was not related to cognitive performance at Wave 2. In addition, EMA-data-based drinking patterns, which varied widely between persons but were relatively consistent over time within persons, were also not associated with cognitive performance. Post-hoc analyses of cognitive performance revealed higher within-person variance scores (from Wave 1 to Wave 2) than between-person variance scores (both Wave 1 and Wave 2). In conclusion, no association was observed between alcohol consumption and cognitive performance in a large Dutch student sample. However, the online cognitive tests performed at home may not have been sensitive enough to pick up differences in cognitive performance associated with alcohol consumption.


Evaluation of methods for sampling, recovery, and enumeration of bacteria applied to the phylloplane.
Determining the fate and survival of genetically engineered microorganisms released into the environment requires the development and application of accurate and practical methods of detection and enumeration. Several experiments were performed to examine quantitative recovery methods that are commonly used or that have potential applications. In these experiments, Erwinia herbicola and Enterobacter cloacae were applied in greenhouses to Blue Lake bush beans (Phaseolus vulgaris) and Cayuse oats (Avena sativa). Sampling indicated that the variance in bacterial counts among leaves increased over time and that this increase caused an overestimation of the mean population size by bulk leaf samples relative to single leaf samples. An increase in the number of leaves in a bulk sample, above a minimum number, did not significantly reduce the variance between samples. Experiments evaluating recovery methods demonstrated that recovery of bacteria from leaves was significantly better with stomacher blending, than with blending, sonication, or washing and that the recovery efficiency was constant over a range of sample inoculum densities. Delayed processing of leaf samples, by storage in a freezer, did not significantly lower survival and recovery of microorganisms when storage was short term and leaves were not stored in buffer. The drop plate technique for enumeration of bacteria did not significantly differ from the spread plate method. Results of these sampling, recovery, and enumeration experiments indicate a need for increased development and standardization of methods used by researchers as there are significant differences among, and also important limitations to, some of the methods used.


Emergency general surgery in a low-middle income health care setting: Determinants of outcomes.
Emergency general surgery (EGS) has emerged as an important component of frontline operative care. Efforts in high-income settings have described its burden but have yet to consider low- and middle-income health care settings in which emergent conditions represent a high proportion of operative need. The objective of this study was to describe the disease spectrum of EGS conditions and associated factors among patients presenting in a low-middle income context. March 2009-April 2014 discharge data from a university teaching hospital in South Asia were obtained for patients (≥16 years) with primary International Classification of Diseases, 9(th) revision, Clinical Modification diagnosis codes consistent with an EGS condition as defined by the American Association for the Surgery of Trauma. Outcomes included in-hospital mortality and occurrence of ≥1 major complication(s). Multivariable analyses were performed, adjusting for differences in demographic and case-mix factors. A total of 13,893 discharge records corresponded to EGS conditions. Average age was 47.2 years (±16.8, standard deviation), with a male preponderance (59.9%). The majority presented with admitting diagnoses of biliary disease (20.2%), followed by soft-tissue disorders (15.7%), hernias (14.9%), and colorectal disease (14.3%). Rates of death and complications were 2.7% and 6.6%, respectively; increasing age was an independent predictor of both. Patients in need of resuscitation (n = 225) had the greatest rates of mortality (72.9%) and complications (94.2%). This study takes an important step toward quantifying outcomes and complications of EGS, providing one of the first assessments of EGS conditions using American Association for the Surgery of Trauma definitions in a low-middle income health care setting. Further efforts in varied settings are needed to promote representative benchmarking worldwide.


Polarization-entangled Bell states generation based on birefringence in high nonlinear microstructure fiber at 1.5 microm.
Polarization-entangled photon pair generation based on two scalar scattering processes of the vector four- photon scattering has been demonstrated experimentally in high nonlinear microstructure fiber with birefringence. By controlling pump polarization state, polarization-entangled Bell states can be realized. It provides a simple way to realize efficient and compact fiber-based polarization-entangled photon pair sources.


The preferences of adult outpatients in medical or dental care settings for giving saliva, urine or blood for clinical testing.
The design of new diagnostic tests would benefit from knowing patients' preferences for the collection of bodily fluids. These preferences, however, are unknown. The authors assessed patients' preferences for the collection of saliva, urine and blood as diagnostic fluids. The authors handed out surveys adult outpatients who sought treatment at two medical care sites and one dental care site at a medical center regarding the comfort, convenience and ease of collection of saliva, urine and blood for diagnostic testing. A total of 413 surveys were completed. Subjects regarded the donation of saliva as more comfortable and convenient than that of blood or urine at the doctor's (physician's or dentist's) office, and they reported that saliva and urine are easiest to collect at home compared with blood. Male subjects and subjects who had ever donated saliva were more likely to perceive saliva donation in the doctor's office favorably. Subjects at all care sites regarded the donation of saliva as more comfortable and convenient than that of blood or urine; however, subjects at the dental care site perceived saliva donation more favorably than did subjects at the medical care sites. In addition, respondents said they were more willing to participate in research and medical testing if it required saliva donation rather than urine or blood collection. In terms of convenience and comfort, saliva compared well with blood and urine as a diagnostic fluid for clinical and research testing. Patients who sought care at both medical and dental sites shared these perceptions. Given strong patient preferences, saliva may be the fluid of choice for the development and implementation of patient-centered diagnostic tests in research and practice.


The Anti-cancer Activity of Vernonia divaricata Sw against Leukaemia, Breast and Prostate Cancers In Vitro.
Vernonia divaricata is one of five endemic Vernonia species of Jamaica. The ethno-medicinal uses of other species have been established, however, scientific validation of this species has not yet been done and as such this paper is aimed at identifying the anti-cancer activity of V divaricata against leukaemia, breast and prostate cancer cell lines. Leaves and stems of V divaricata were dried and milled into powder. The crude hexane and methanol extracts of the leaves and stems were obtained and bio-assayed using WST-1 cell proliferation assay against leukaemia, breast and prostate cancer cell lines. The crude hexane and methanol extracts of V divaricata were able to significantly retard the growth of the MCF-7 (breast), HL-60 (leukaemia) and the PC-3 (prostate) cancer cell lines. The crude methanol extract of the stem was the strongest, exhibiting anti-proliferation activity with IC50 values of 10.14, 12.63 and 9.894 µg/ml for the HL-60, MCF-7 and PC-3 cancer cell lines, respectively, with the most potent toward prostate cancer. The medicinal use of V divaricata as an anti-cancer agent was corroborated as the crude hexane and methanol extracts demonstrated potent anti-proliferation activity and as such hold potential for further research and development into a drug to prevent or treat various cancers.


What mechanism of niche segregation allows the coexistence of sympatric sibling rhinolophid bats?
Our purpose was to assess how pairs of sibling horseshoe bats coexists when their morphology and echolocation are almost identical. We collected data on echolocation, wing morphology, diet, and habitat use of sympatric Rhinolophus mehelyi and R. euryale. We compared our results with literature data collected in allopatry with similar protocols and at the same time of the year (breeding season). Echolocation frequencies recorded in sympatry for R. mehelyi (mean = 106.8 kHz) and R. euryale (105.1 kHz) were similar to those reported in allopatry (R. mehelyi 105-111 kHz; R. euryale 101-109 kHz). Wing parameters were larger in R. mehelyi than R. euryale for both sympatric and allopatric conditions. Moths constitute the bulk of the diet of both species in sympatry and allopatry, with minor variation in the amounts of other prey. There were no inter-specific differences in the use of foraging habitats in allopatry in terms of structural complexity, however we found inter-specific differences between sympatric populations: R. mehelyi foraged in less complex habitats. The subtle inter-specific differences in echolocation frequency seems to be unlikely to facilitate dietary niche partitioning; overall divergences observed in diet may be explained as a consequence of differential prey availability among foraging habitats. Inter-specific differences in the use of foraging habitats in sympatry seems to be the main dimension for niche partitioning between R. mehelyi and R. euryale, probably due to letter differences in wing morphology. Coexistence between sympatric sibling horseshoe bats is likely allowed by a displacement in spatial niche dimension, presumably due to the wing morphology of each species, and shifts the niche domains that minimise competition. Effective measures for conservation of sibling/similar horseshoe bats should guarantee structural diversity of foraging habitats.


Cancer in human immunodeficiency virus-infected children: a case series from the Children's Cancer Group and the National Cancer Institute.
To describe the spectrum of malignancies in human immunodeficiency virus (HIV)-infected children and the clinical outcome of patients with these tumors. We retrospectively surveyed the Children's Cancer Group (CCG) and the National Cancer Institute (NCI) for cases of cancer that occurred between July 1982 and February 1997 in children who were HIV seropositive before or at the time of cancer diagnosis. We used Kaplan-Meier survivorship curves, hazard function estimates, and Cox proportional hazards models to evaluate survival. Sixty-four children (39 boys, 25 girls) with 65 tumors were reported. Thirty-seven children (58%) acquired HIV infection vertically (median age at cancer diagnosis, 4.3 years); 22 children (34%) acquired HIV through transfusion of blood or blood products (median age at cancer diagnosis, 13.4 years). Forty-two children (65%) had non-Hodgkin's lymphoma (NHL). Eleven children (17%) had leiomyosarcomas (or leiomyomas), which are otherwise exceptionally rare in children. Other malignancies included acute leukemia (five children), Kaposi's sarcoma (KS; three children), Hodgkin's disease (two children), vaginal carcinoma in situ (one child), and tracheal neuroendocrine carcinoma (one child). Median survival after NHL diagnosis was 6 months (range, 1 day to 89 months) and after leiomyosarcoma was 12 months (range, 10 days to 19 months). The average monthly death rate after NHL diagnosis was 12% in the first 6 months, which decreased to about 2% thereafter. In contrast, the monthly death rate after leiomyosarcoma diagnosis increased from 5% in the first 6 months to about 20% thereafter. After NHL, leiomyosarcoma is the second leading cancer in children with HIV infection. Both cancers have high mortality rates; improved outcome for NHL, in particular, may depend on earlier diagnosis and therapy.


Automatic analysis of quantitative NMR data of pharmaceutical compound libraries.
In drug discovery, chemical library compounds are usually dissolved in DMSO at a certain concentration and then distributed to biologists for target screening. Quantitative (1)H NMR (qNMR) is the preferred method for the determination of the actual concentrations of compounds because the relative single proton peak areas of two chemical species represent the relative molar concentrations of the two compounds, that is, the compound of interest and a calibrant. Thus, an analyte concentration can be determined using a calibration compound at a known concentration. One particularly time-consuming step in the qNMR analysis of compound libraries is the manual integration of peaks. In this report is presented an automated method for performing this task without prior knowledge of compound structures and by using an external calibration spectrum. The script for automated integration is fast and adaptable to large-scale data sets, eliminating the need for manual integration in ~80% of the cases.


A functional interplay between intein and extein sequences in protein splicing compensates for the essential block B histidine.
Inteins remove themselves from a precursor protein by protein splicing. Due to the concomitant structural changes of the host protein, this self-processing reaction has enabled many applications in protein biotechnology and chemical biology. We show that the evolved M86 mutant of the Ssp DnaB intein displays a significantly improved tolerance towards non-native amino acids at the N-terminally flanking (-1) extein position compared to the parent intein, in the form of both an artificially trans-splicing split intein and the cis-splicing mini-intein. Surprisingly, side chains with increased steric bulk compared to the native Gly(-1) residue, including d-amino acids, were found to compensate for the essential block B histidine in His73Ala mutants in the initial N-S acyl shift of the protein splicing pathway. In the case of the M86 intein, large (-1) side chains can even rescue protein splicing activity as a whole. With the comparison of three crystal structures, namely of the M86 intein as well as of its Gly(-1)Phe and Gly(-1)Phe/His73Ala mutants, our data supports a model in which the intein's active site can exert a strain by varying mechanisms on the different angles of the scissile bond at the extein-intein junction to effect a ground-state destabilization. The compensatory mechanism of the block B histidine is the first example for the direct functional role of an extein residue in protein splicing. It sheds new light on the extein-intein interplay and on possible consequences of their co-evolution as well as on the laboratory engineering of improved inteins.


Updates on the Systemic Treatment of Advanced Non-melanoma Skin Cancer.
Non-melanoma skin cancers (NMSCs), which represent a diverse group of cutaneous malignancies, are the most common forms of human neoplasia. The incidence of these diseases is increasing due to a number of factors, including that of increasing human lifespans. The majority of NMSCs are basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC), with the remainder being various rare skin cancers, including extramammary Paget's disease (EMPD), Merkel cell carcinoma (MCC), and several skin adnexal carcinomas. Of these, MCC usually shows aggressive behavior with a high mortality rate. On the other hand, BCC, cSCC, EMPD, and skin adnexal tumors usually show an indolent clinical course and metastasize only rarely. Nevertheless, the metastatic forms of these tumors commonly lead to poor patient outcome. A definitive management strategy for the treatment of advanced NMSC has not been established, mainly due to their rarity and lack of reliable information based on well-controlled randomized trials. Chemotherapeutic regimens for treatment of these diseases have been mainly based on the observations of isolated, small case series or clinical trials with a limited numbers of patients. However, accumulating evidence regarding their pathobiological backgrounds as well as recent advances in molecular biotechnology have facilitated the development of novel drugs for treatment of these diseases. Over the past decade, the U.S. Food and Drug Administration has approved several molecular targeting therapies, including Hedgehog inhibitors for BCC, monoclonal antibodies targeting anti-programmed death ligand-1 and anti- programmed cell death 1 (PD-1) for MCC, and anti-PD-1 for cSCC. Here, we review their clinical utility and discuss updated systemic treatment strategies for advanced NMSC.


Unplanned readmissions and survival following brain tumor surgery.
Research on readmissions has been influenced by efforts to reduce hospital cost and avoid penalties stipulated by the Centers for Medicare and Medicaid Services. Less emphasis has been placed on understanding these readmissions and their impact on patient outcomes. This study 1) delineates reasons for readmission, 2) explores factors associated with readmissions, and 3) describes their impact on the survival of glioblastoma patients. The authors conducted a retrospective review of 362 cases involving patients with glioblastoma undergoing biopsy or tumor resection at their institution between 2003 and 2011. Reasons for re-hospitalization were characterized according to whether or not they were related to surgery and considered preventable. Multivariate analyses were conducted to identify the effect of readmission on survival and determine factors associated with re-hospitalizations. Twenty-seven (7.5%) of 362 patients experienced unplanned readmissions within 30 days of surgery. Six patients (22.2%) were readmitted by Day 7, 14 (51.9%) by Day 14, and 20 (74.1%) by Day 21. Neurological, infectious, and thromboembolic complications were leading reasons for readmission, accounting for, respectively, 37.0%, 29.6%, and 22.2% of unplanned readmissions. Twenty-one (77.8%) of the 27 readmissions were related to surgery and 19 (70.4%) were preventable. The adjusted hazard ratio of mortality associated with a readmission was 2.03 (95% CI 1.3-3.1). Higher-functioning patients (OR 0.96, 95% CI 0.9-1.0) and patients discharged home (OR 0.21, 95% CI 0.1-0.6) were less likely to get readmitted. An overwhelming fraction of documented unplanned readmissions were considered preventable and related to surgery. Patients who were readmitted to the hospital within 30 days of surgery had twice the risk of mortality compared with patients who were not readmitted.


Chlamydia trachomatis: genome sequence analysis of lymphogranuloma venereum isolates.
Chlamydia trachomatis is the most common cause of sexually transmitted infections in the UK, a statistic that is also reflected globally. There are three biovariants of C. trachomatis: trachoma (serotypes A-C) and two sexually transmitted pathovars; serotypes D-K and lymphogranuloma venereum (LGV). Trachoma isolates and the sexually transmitted serotypes D-K are noninvasive, whereas the LGV strains are invasive, causing a disseminating infection of the local draining lymph nodes. Genome sequences are available for single isolates from the trachoma (serotype A) and sexually transmitted (serotype D) biotypes. We sequenced two isolates from the remaining biotype, LGV, a long-term laboratory passaged strain and the recent "epidemic" LGV isolate-causing proctitis. Although the genome of the LGV strain shows no additional genes that could account for the differences in disease outcome, we found evidence of functional gene loss and identified regions of heightened sequence variation that have previously been shown to be important sites for interstrain recombination. We have used new sequencing technologies to show that the recent clinical LGV isolate causing proctitis is unlikely to be a newly emerged strain but is most probably an old strain with relatively new clinical manifestations.


Group treatments for sensitive health care problems: a randomised controlled trial of group versus individual physiotherapy sessions for female urinary incontinence.
The aim was to compare effectiveness of group versus individual sessions of physiotherapy in terms of symptoms, quality of life, and costs, and to investigate the effect of patient preference on uptake and outcome of treatment. A pragmatic, multi-centre randomised controlled trial in five British National Health Service physiotherapy departments. 174 women with stress and/or urge incontinence were randomised to receive treatment from a physiotherapist delivered in a group or individual setting over three weekly sessions. Outcome were measured as Symptom Severity Index; Incontinence-related Quality of Life questionnaire; National Health Service costs, and out of pocket expenses. The majority of women expressed no preference (55%) or preference for individual treatment (36%). Treatment attendance was good, with similar attendance with both service delivery models. Overall, there were no statistically significant differences in symptom severity or quality of life outcomes between the models. Over 85% of women reported a subjective benefit of treatment, with a slightly higher rating in the individual compared with the group setting. When all health care costs were considered, average cost per patient was lower for group sessions (Mean cost difference 52.91 pounds 95%, confidence interval ( 25.82 pounds- 80.00 pounds)). Indications are that whilst some women may have an initial preference for individual treatment, there are no substantial differences in the symptom, quality of life outcomes or non-attendance. Because of the significant difference in mean cost, group treatment is recommended. ISRCTN 16772662.


An Integrated Microfluidic Platform for Quantifying Drug Permeation across Biomimetic Vesicle Membranes.
The low membrane permeability of candidate drug molecules is a major challenge in drug development, and insufficient permeability is one reason for the failure of antibiotic treatment against bacteria. Quantifying drug transport across specific pathways in living systems is challenging because one typically lacks knowledge of the exact lipidome and proteome of the individual cells under investigation. Here, we quantify drug permeability across biomimetic liposome membranes, with comprehensive control over membrane composition. We integrate the microfluidic octanol-assisted liposome assembly platform with an optofluidic transport assay to create a complete microfluidic total analysis system for quantifying drug permeability. Our system enables us to form liposomes with charged lipids mimicking the negative charge of bacterial membranes at physiological pH and salt concentrations, which proved difficult with previous liposome formation techniques. Furthermore, the microfluidic technique yields an order of magnitude more liposomes per experiment than previous assays. We demonstrate the feasibility of the assay by determining the permeability coefficient of norfloxacin and ciprofloxacin across biomimetic liposomes.


The impact of relationship quality on life satisfaction and well-being in dementia caregiving dyads: findings from the IDEAL study.
Objectives: The quality of the relationship between people with dementia and their informal caregiver maybe an important determinant of life satisfaction and well-being for both members of the dyad. Taking a dyadic perspective, the aim of this study was to examine whether self- and partner-rated relationship quality influences life satisfaction and well-being for both people with dementia and their caregivers.Design and methods: Using data from 1283 dyads in the Improving the Experience of Dementia and Enhancing Active Life (IDEAL) cohort, we examined the impact of current relationship quality on life satisfaction and well-being in dementia caregiving dyads. Data were analysed using the Actor-Partner Interdependence Model (APIM) framework.Results: Self-rated relationship quality was associated with own life satisfaction and well-being for both people with dementia and caregivers. Partner-rated relationship quality did not influence own life satisfaction or well-being for either member of the dyad.Conclusion: This study is the first to use the APIM framework to explore the dyadic associations between relationship quality and life satisfaction and well-being in a large cohort of dementia caregiving dyads. The obtained findings suggest that the individual perception of the quality of the caregiving relationship held by each member of the caregiving dyad is an important factor for that member's life satisfaction and well-being, while the partner's perception of relationship quality is not. The findings highlight the importance of considering the individual perspective of both the person with dementia and the caregiver and enabling each to maintain positive perceptions of relationship quality.


Up by upwest: Is slope like north?
Terrain slope can be used to encode the location of a goal. However, this directional information may be encoded using a conceptual north (i.e., invariantly with respect to the environment), or in an observer-relative fashion (i.e., varying depending on the direction one faces when learning the goal). This study examines which representation is used, whether the sensory modality in which slope is encoded (visual, kinaesthetic, or both) influences representations, and whether use of slope varies for men and women. In a square room, with a sloped floor explicitly pointed out as the only useful cue, participants encoded the corner in which a goal was hidden. Without direct sensory access to slope cues, participants used a dial to point to the goal. For each trial, the goal was hidden uphill or downhill, and the participants were informed whether they faced uphill or downhill when pointing. In support of observer-relative representations, participants pointed more accurately and quickly when facing concordantly with the hiding position. There was no effect of sensory modality, providing support for functional equivalence. Sex did not interact with the findings on modality or reference frame, but spatial measures correlated with success on the slope task differently for each sex.


Statistical test for tolerability of effects of an antifungal biocontrol strain on fungal communities in three arable soils.
A statistical method was developed to test for equivalence of microbial communities analysed by next-generation sequencing of amplicons. The test uses Bray-Curtis distances between the microbial community structures and is based on a two-sample jackknife procedure. This approach was applied to investigate putative effects of the antifungal biocontrol strain RU47 on fungal communities in three arable soils which were analysed by high-throughput ITS amplicon sequencing. Two contrasting workflows to produce abundance tables of operational taxonomic units from sequence data were applied. For both, the developed test indicated highly significant equivalence of the fungal communities with or without previous exposure to RU47 for all soil types, with reference to fungal community differences in conjunction with field site or cropping history. However, minor effects of RU47 on fungal communities were statistically significant using highly sensitive multivariate tests. Nearly all fungal taxa responding to RU47 increased in relative abundance indicating the absence of ecotoxicological effects. Use of the developed equivalence test is not restricted to evaluate effects on soil microbial communities by inoculants for biocontrol, bioremediation or other purposes, but could also be applied for biosafety assessment of compounds like pesticides, or genetically engineered plants.


Asian American women in California: a pooled analysis of predictors for breast and cervical cancer screening.
We examined patterns of cervical and breast cancer screening among Asian American women in California and assessed their screening trends over time. We pooled weighted data from 5 cycles of the California Health Interview Survey (2001, 2003, 2005, 2007, 2009) to examine breast and cervical cancer screening trends and predictors among 6 Asian nationalities. We calculated descriptive statistics, bivariate associations, multivariate logistic regressions, predictive margins, and 95% confidence intervals. Multivariate analyses indicated that Papanicolaou test rates did not significantly change over time (77.9% in 2001 vs 81.2% in 2007), but mammography receipt increased among Asian American women overall (75.6% in 2001 vs 81.8% in 2009). Length of time in the United States was associated with increased breast and cervical cancer screening among all nationalities. Sociodemographic and health care access factors had varied effects, with education and insurance coverage significantly predicting screening for certain groups. Overall, we observed striking variation by nationality. Our results underscore the need for intervention and policy efforts that are targeted to specific Asian nationalities, recent immigrants, and individuals without health care access to increase screening rates among Asian women in California.


Bite and kick injuries in horses: prevalence, risk factors and prevention.
Studies on the prevalence and predisposing factors of bite and kick injuries in horses have not been reported in a population-based data sample. To investigate the prevalence of bite and kick injuries in horses and associated risk factors in a representative sample of horses in Switzerland. A questionnaire on the incidence of disease and injury, which included the frequency of bite and kick injuries and their association with breed, housing, use and feeding regime, was sent to 2559 horse owners randomly selected throughout Switzerland. The data of 2912 horses with 897 disorders diagnosed by a veterinarian were analysed. There were 231 injuries, 50 (21.6%) caused by a bite or kick from another horse; this number corresponded to 5.6% of all diseases and injuries and concerned only 1.7% of all the horses evaluated. Warmblood, Thoroughbred and Arabian horses had a 4.3 times higher risk of bite or kick injuries than horses of other breeds. Eighteen per cent of injuries were associated with a change in housing management and occurred regardless of whether horses were kept in groups permanently or sporadically. A stable group hierarchy and a housing system that provides adequate space and is adapted to horse-specific behaviour are important factors in prevention and kick and bite injuries.


Supplementation with a lecithin-based delivery form of Boswellia serrata extract (Casperome®) controls symptoms of mild irritable bowel syndrome.
Irritable Bowel Syndrome (IBS) is a chronic, gastrointestinal disorder in which abdominal pain or discomfort is associated with defecation or changes in bowel habits. Its multifactorial pathophysiology leads to a variety of available treatments, mainly aimed at controlling symptoms. The management of IBS patients could be optimized by individualized strategies, including non-pharmaceutical approaches. In this study, we evaluated the efficacy and safety of a novel delivery form of Boswellia serrata extracts (BSE) (Casperome®) in patients with IBS. 71 otherwise healthy subjects with idiopathic IBS were recruited. Participants were assigned to the following management strategies: hyoscine butylbromide; papaverine hydrochloride + A. belladonna extract; supplementation with Casperome®. Predominant IBS symptoms were evaluated at inclusion and at the end of the observational period (4 weeks). The numbers of subjects who needed rescue medication or medical attention/hospital admission were recorded. Adverse events were also evaluated. In all groups, the IBS symptoms investigated, namely abdominal pain, altered bowel movements, meteorism and cramps improved during the observational period. Of note, the number of subjects who needed medical attention significantly decreased only in Casperome®-supplemented group. In addition, Casperome® supplementation was related to a lower incidence of side effects (mainly stypsis). This preliminary study suggests that Casperome® supplementation could represent a promising alternative approach to manage symptoms associated with IBS in otherwise healthy subjects.


Histopathologic comparison of the subsets of lupus erythematosus.
A recent study by Bangert et al suggests that there are quantitative histologic differences that distinguish discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). Utilizing criteria proposed by these authors, we examined 77 biopsy specimens from 63 patients with various forms of lupus erythematosus, but we were unable to predict the correct clinical subset. Using the clinical diagnosis of DLE as a positive reference standard, the sensitivity and specificity for the overall pathologic diagnosis of DLE were 55% and 42%, respectively. Statistically significant histologic factors favoring the diagnosis of DLE over SCLE in the present study were pilosebaceous atrophy, hyperkeratosis, parakeratosis, basement membrane thickening around the follicles, subepidermal edema, and vascular ectasia. These histologic variables were entered into a forward stepwise multivariate regression analysis to determine distinct predictors of DLE vs SCLE. This analysis showed that pilosebaceous atrophy was the only distinct significant predictor of DLE vs SCLE. These results suggest that the histologic differentiation of clinically defined DLE and SCLE cannot be established from the histologic features examined.


Mapping multiple QTL using linkage disequilibrium and linkage analysis information and multitrait data.
A multi-locus QTL mapping method is presented, which combines linkage and linkage disequilibrium (LD) information and uses multitrait data. The method assumed a putative QTL at the midpoint of each marker bracket. Whether the putative QTL had an effect or not was sampled using Markov chain Monte Carlo (MCMC) methods. The method was tested in dairy cattle data on chromosome 14 where the DGAT1 gene was known to be segregating. The DGAT1 gene was mapped to a region of 0.04 cM, and the effects of the gene were accurately estimated. The fitting of multiple QTL gave a much sharper indication of the QTL position than a single QTL model using multitrait data, probably because the multi-locus QTL mapping reduced the carry over effect of the large DGAT1 gene to adjacent putative QTL positions. This suggests that the method could detect secondary QTL that would, in single point analyses, remain hidden under the broad peak of the dominant QTL. However, no indications for a second QTL affecting dairy traits were found on chromosome 14.


Collagen type III content of the long head of the biceps tendon as an indicator of glenohumeral arthritis.
Tendonosis is characterized by an increase in collagen type III relative to collagen type I, but the precise ratio of collagen type I to collagen type III in pathologic shoulder tendons has not been reported. A tendon continuously bathed in an OA synovial environment may exhibit histomorphologic differences as compared to those from shoulders with a preserved articular surface. The purpose of this study was to evaluate the biochemical and histological differences in the proximal portion of the long head of the biceps tendon (LHBT) from a non-arthritic versus an arthritic glenohumeral joint. Sixteen patients undergoing shoulder surgery were prospectively enrolled in the study. Group-1 consisted of patients with glenohumeral OA and Group-2 consisted of patients without OA. The LHBT was tenodesed and excised tendon was fixed, embedded, sectioned (5 µm), deparaffinized, and used for histology (H&E and Masson trichrome staining) and immunofluorescence analysis to determine levels of collagen III, MMP-1, MMP-9, TIMP-1, and TIMP-2. Compared to the patients without arthritis, group-1 exhibited significant inflammation with extracellular matrix disorganization and significantly higher (P < 0.05) collagen III, MMP-2, and MMP-9 levels. No considerable difference in collagen I was observed between the two groups. TIMP-1 and TIMP-2 were completely absent in both the groups. The level of collagen subtypes varied markedly between LHBT tendons from patients with and without OA. Increased collagen III in the LHBT is associated with glenohumeral arthritis. Measuring collagen type in the LHBT may serve as a useful metric in the diagnosis and treatment of musculoskeletal pathology.


Fabrication and characterization of nanomaterial-based sensors using dielectrophoresis.
Dielectrophoresis (DEP) is an electrokinetic motion of dielectrically polarized materials in nonuniform electric fields. DEP has been successfully applied to manipulation of nanomaterials including carbon nanotubes (CNTs), metallic nanoparticles, and semiconducting nanowires. Under positive DEP force, which attracts nanomaterials toward the higher field region, nanomaterials are trapped in the electrode gap and automatically establish good electrical connections between them and the external measuring circuit. This feature allows us a fast, simple, and low-cost fabrication of nanomaterial-based sensors based on a bottom-up approach. This paper first presents a theoretical background of DEP phenomena and then reviews recent works of the present author, which were aimed to develop nanomaterial-based sensors, such as a CNT gas sensor and a ZnO nanowire photosensor, using DEP fabrication technique. It is also demonstrated that DEP technique enables self-formation of interfaces between various nanomaterials, which can be also applicable as novel sensing transducers.


The effect of centre of mass location on sagittal plane moments around the centre of mass in trotting horses.
The diagonal limb support pattern at trot provides pitch and roll stability, but little is known about the control of moments about the centre of mass (COM) in horses. Correct COM location is critical in the calculation of pitching moments. The objectives were to determine the effect of COM location on pitching moments in trotting horses and explore how COM location could influence balance. Kinematic (120 Hz) and GRF (4 force plates, 960 Hz) data were collected at trot from three trials of eight horses. The position of the COM was determined from the weighted summation of the segmental COMs and this was then manipulated cranially and caudally to test the model. Sagittal-plane moments around the COM were calculated for each manipulation of the model and their relationship determined using reduced major axis regression. Over the stride, the moments must sum to zero to prevent accumulation of rotational motion. This was found when the weight on the forelimbs in standing was 58.7% ± 3% (mean ± 95% C.I.), which corresponded closely to the COP ratio in standing. Moments were typically nose-up at foot strike changing to nose-down prior to midstance, and then reversing to nose-up in late stance. Mean moments were larger in the hindlimbs and more sensitive to COM location changes. Divergence of the COM from the COP creating a vertical force moment arm prior to midstance may assist the hindlimb in relation to propulsive effort. A similar effect is seen in the forelimb during single limb support.


Cellular requirements for the generation of primary cell-mediated lympholysis responses to Qa-1 antigens.
Mixed leukocyte cultures (MLC) between NZB responder spleen cells and Qa-1-disparate stimulator spleen cells were employed to determine the cellular requirements for the generation of primary anti-Qa-1 cell-mediated lympholysis (CML) responses. Although primary anti-Qa-1 cytotoxic lymphocytes (CTL) were generated during H-2-homologous stimulation, anti-Qa-1 CTL were not detectable from MLC in which the stimulators were H-2 allogeneic. Anti-Qa-1 CTL also were not generated from MLC in which the stimulators were semiallogeneic. Thus, H-2 identity between responder and stimulator cells was not sufficient to permit the generation of primary anti-Qa-1 CTL when H-2 disparity was also present. The capacity for H-2 disparity to prevent anti-Qa-1 CML responses was further demonstrated in MLC containing both H-2-allogeneic and H-2-homologous stimulator cells. Therefore, in subsequent studies we employed NZB responders and H-2-homologous, Qa-1-disparate stimulators. When various subpopulations of stimulator cells were studied for their ability to induce anti-Qa-1 CTL, nylon wool-adherent cells were found to be potent stimulators, but nylon wool-nonadherent cells were not. Furthermore, depletion of macrophages from the stimulator population abrogated the generation of anti-Qa-1 CML responses, despite the presence of responder macrophages in the culture. In contrast, all fractionated subpopulations stimulated anti-H-2 CML responses. When macrophage-enriched cells were used as stimulators, anti-Qa-1 CTL could be generated with approximately 80-fold fewer stimulator cells than when unfractionated splenocytes were used as stimulators. These findings indicated that stimulator macrophages were essential for the generation of primary anti-Qa-1 CTL. Direct evidence for macrophage expression of Qa-1-antigens was obtained by using a Qa-1b-specific CTL clone. These studies provide i) the first evidence for Qa-1 expression on macrophages, ii) a basis for comparison of the cellular interactions necessary to generate CTL against H-2K/D-encoded vs Qa-1-encoded class 1 antigens, and iii) a model for investigating the mechanisms responsible for the immunodominance of H-2K/D alloantigens.


MASTL is the human orthologue of Greatwall kinase that facilitates mitotic entry, anaphase and cytokinesis.
Greatwall (Gwl) was originally discovered in Drosophila as an essential kinase for correct chromosome condensation and mitotic progression. In Xenopus, Gwl may influence the positive-feedback loop that directs cyclin B1-Cdk1 activation and the mitotic state by inhibiting the phosphatase PP 2A. Here, we describe the human orthologue of Gwl called microtubule-associated serine/threonine kinase-like (MASTL). We found that MASTL localizes to the nucleus in interphase and re-localizes in part to centrosomes in mitosis, when it is active. Cells strongly depleted of MASTL by RNAi delay in G(2) phase and reveal slow chromosome condensation. MASTL RNAi cells that enter and progress through mitosis often fail to completely separate their sister chromatids in anaphase. This causes chromatin to be trapped in the cleavage furrow, which may lead to the formation of 4N G(1) cells by cytokinesis failure. Further, our experiments indicate that MASTL supports the phosphorylation state of mitotic phospho-proteins downstream of cyclin B1-Cdk1, including the APC/C. Cyclin B1 destruction is incomplete when mitotic cells that are strongly depleted of MASTL exit mitosis. We propose that MASTL enhances cyclin B1-Cdk1-dependent mitotic phosphorylation events, directing mitotic entry, anaphase and cytokinesis in human cells.


Resolving Evolutionary Relationships in Closely Related Species with Whole-Genome Sequencing Data.
Using genetic data to resolve the evolutionary relationships of species is of major interest in evolutionary and systematic biology. However, reconstructing the sequence of speciation events, the so-called species tree, in closely related and potentially hybridizing species is very challenging. Processes such as incomplete lineage sorting and interspecific gene flow result in local gene genealogies that differ in their topology from the species tree, and analyses of few loci with a single sequence per species are likely to produce conflicting or even misleading results. To study these phenomena on a full phylogenomic scale, we use whole-genome sequence data from 200 individuals of four black-and-white flycatcher species with so far unresolved phylogenetic relationships to infer gene tree topologies and visualize genome-wide patterns of gene tree incongruence. Using phylogenetic analysis in nonoverlapping 10-kb windows, we show that gene tree topologies are extremely diverse and change on a very small physical scale. Moreover, we find strong evidence for gene flow among flycatcher species, with distinct patterns of reduced introgression on the Z chromosome. To resolve species relationships on the background of widespread gene tree incongruence, we used four complementary coalescent-based methods for species tree reconstruction, including complex modeling approaches that incorporate post-divergence gene flow among species. This allowed us to infer the most likely species tree with high confidence. Based on this finding, we show that regions of reduced effective population size, which have been suggested as particularly useful for species tree inference, can produce positively misleading species tree topologies. Our findings disclose the pitfalls of using loci potentially under selection as phylogenetic markers and highlight the potential of modeling approaches to disentangle species relationships in systems with large effective population sizes and post-divergence gene flow.


2016 Guidelines for the management of thyroid storm from The Japan Thyroid Association and Japan Endocrine Society (First edition).
Thyroid storm is an endocrine emergency which is characterized by multiple organ failure due to severe thyrotoxicosis, often associated with triggering illnesses. Early suspicion, prompt diagnosis and intensive treatment will improve survival in thyroid storm patients. Because of its rarity and high mortality, prospective intervention studies for the treatment of thyroid storm are difficult to carry out. We, the Japan Thyroid Association and Japan Endocrine Society taskforce committee, previously developed new diagnostic criteria and conducted nationwide surveys for thyroid storm in Japan. Detailed analyses of clinical data from 356 patients revealed that the mortality in Japan was still high (∼11%) and that multiple organ failure and acute heart failure were common causes of death. In addition, multimodal treatment with antithyroid drugs, inorganic iodide, corticosteroids and beta-adrenergic antagonists has been suggested to improve mortality of these patients. Based on the evidence obtained by nationwide surveys and additional literature searches, we herein established clinical guidelines for the management of thyroid storm. The present guideline includes 15 recommendations for the treatment of thyrotoxicosis and organ failure in the central nervous system, cardiovascular system, and hepato-gastrointestinal tract, admission criteria for the intensive care unit, and prognostic evaluation. We also proposed preventive approaches to thyroid storm, roles of definitive therapy, and future prospective trial plans for the treatment of thyroid storm. We hope that this guideline will be useful for many physicians all over the world as well as in Japan in the management of thyroid storm and the improvement of its outcome.


Evidence for transmission of Plasmodium vivax among a duffy antigen negative population in Western Kenya.
We present evidence that a parasite with characteristics of Plasmodium vivax is being transmitted among Duffy blood group-negative inhabitants of Kenya. Thirty-two of 4,901 Anopheles gambiae and An. funestus (0.65%) collected in Nyanza Province were ELISA positive for the P. vivax circumsporozoite protein VK 247. All positives were found late in the rainy season, when An. funestus predominated, and disproportionately many were found at a single village. A P. vivax specific sequence of the SSU rRNA gene was amplified from three of six ELISA-positive mosquitoes. Erythrocytes from 31 children, including 9 microscopically diagnosed as infected with P. vivax, were negative by flow cytometry for the Fy3 or Fy6 epitopes, which indicate Duffy blood group expression. A DNA fragment specific for the C terminus of the gene for P. vivax merozoite surface protein 1 (MSP-1) was amplified from the blood of four of these children and subsequently sequenced from two.


Changes in the gut microbiome and fermentation products concurrent with enhanced longevity in acarbose-treated mice.
Treatment with the α-glucosidase inhibitor acarbose increases median lifespan by approximately 20% in male mice and 5% in females. This longevity extension differs from dietary restriction based on a number of features, including the relatively small effects on weight and the sex-specificity of the lifespan effect. By inhibiting host digestion, acarbose increases the flux of starch to the lower digestive system, resulting in changes to the gut microbiota and their fermentation products. Given the documented health benefits of short-chain fatty acids (SCFAs), the dominant products of starch fermentation by gut bacteria, this secondary effect of acarbose could contribute to increased longevity in mice. To explore this hypothesis, we compared the fecal microbiome of mice treated with acarbose to control mice at three independent study sites. Microbial communities and the concentrations of SCFAs in the feces of mice treated with acarbose were notably different from those of control mice. At all three study sites, the bloom of a single bacterial taxon was the most obvious response to acarbose treatment. The blooming populations were classified to the largely uncultured Bacteroidales family Muribaculaceae and were the same taxonomic unit at two of the three sites. Propionate concentrations in feces were consistently elevated in treated mice, while the concentrations of acetate and butyrate reflected a dependence on study site. Across all samples, Muribaculaceae abundance was strongly correlated with propionate and community composition was an important predictor of SCFA concentrations. Cox proportional hazards regression showed that the fecal concentrations of acetate, butyrate, and propionate were, together, predictive of mouse longevity even while controlling for sex, site, and acarbose. We observed a correlation between fecal SCFAs and lifespan in mice, suggesting a role of the gut microbiota in the longevity-enhancing properties of acarbose. Treatment modulated the taxonomic composition and fermentation products of the gut microbiome, while the site-dependence of the responses illustrate the challenges facing reproducibility and interpretation in microbiome studies. These results motivate future studies exploring manipulation of the gut microbial community and its fermentation products for increased longevity, testing causal roles of SCFAs in the observed effects of acarbose.


Human resources for health in southeast Asia: shortages, distributional challenges, and international trade in health services.
In this paper, we address the issues of shortage and maldistribution of health personnel in southeast Asia in the context of the international trade in health services. Although there is no shortage of health workers in the region overall, when analysed separately, five low-income countries have some deficit. All countries in southeast Asia face problems of maldistribution of health workers, and rural areas are often understaffed. Despite a high capacity for medical and nursing training in both public and private facilities, there is weak coordination between production of health workers and capacity for employment. Regional experiences and policy responses to address these challenges can be used to inform future policy in the region and elsewhere. A distinctive feature of southeast Asia is its engagement in international trade in health services. Singapore and Malaysia import health workers to meet domestic demand and to provide services to international patients. Thailand attracts many foreign patients for health services. This situation has resulted in the so-called brain drain of highly specialised staff from public medical schools to the private hospitals. The Philippines and Indonesia are the main exporters of doctors and nurses in the region. Agreements about mutual recognition of professional qualifications for three groups of health workers under the Association of Southeast Asian Nations Framework Agreement on Services could result in increased movement within the region in the future. To ensure that vital human resources for health are available to meet the needs of the populations that they serve, migration management and retention strategies need to be integrated into ongoing efforts to strengthen health systems in southeast Asia. There is also a need for improved dialogue between the health and trade sectors on how to balance economic opportunities associated with trade in health services with domestic health needs and equity issues.


City structure, obesity, and environmental justice: an integrated analysis of physical and social barriers to walkable streets and park access.
Local parks and walkable neighborhoods are commonly cited as elements of the urban environment that promote physical activity and reduce obesity risk. When those vulnerable to obesity-related diseases live in neighborhoods without these qualities, it works against environmental justice goals that aim for a fair distribution of amenities. We use geographic information systems (GIS) to evaluate the relationship between the distribution of populations vulnerable to obesity and proximity to parks and walkable street networks in Phoenix, Arizona, USA. Though previous studies have used GIS to assess the distribution of access to opportunities for physical activity, none have analyzed access to both parks and walkable resources at once. Neither have they included data that reflects findings on a smaller scale indicating that perceptions of resource quality, safety, and cultural relevance also affect physical activity levels. We include these safety and quality factors in our study through statistical data on traffic fatalities, crime rates and park size. We find that, counter to predictions, subpopulations generally considered vulnerable to obesity (and environmental injustices more generally) are more likely to live in walkable neighborhoods and have better walking access to neighborhood parks than other groups in Phoenix. However, crime is highest in walkable neighborhoods with large Latino/a and African-American populations and parks are smaller in areas populated by Latino/as. Given the higher prevalence of obesity and related diseases in lower income and minority populations in Phoenix, the results suggest that benefits of built environments may be offset by social characteristics. Our most consistent finding indicates a strong negative relationship between the percentage of the population under 18 years of age living in an area and the likelihood that the structure of the built environment supports physical activity. Children under 18 are significantly underrepresented in regions deemed highly walkable and those with access to parks.


Multicriterion cross-entropy minimization approach to positron emission tomographic imaging.
A multicriterion cross-entropy minimization approach to positron emission tomographic (PET) imaging is described. An unexplored multicriterion cross-entropy optimization algorithm based on weighted-sum scalarization is used to solve this problem. The efficacy of the algorithm is compared with that of the single-criterion optimization algorithm and the convolution backprojection method for image reconstruction from computer-generated projection data and Siemens PET scanner data. The algorithms described have been implemented on a PIII/686 microcomputer.


Perceptions and experiences of blood pressure self-monitoring during hypertensive pregnancy: A qualitative analysis of women's and clinicians' experiences in the OPTIMUM-BP trial.
Self-monitoring of blood pressure (BP) has been shown to be effective at improving BP control in the general population. The OPTIMUM-BP feasibility study was a prospective randomised controlled trial of self-monitoring of BP (SMBP) during hypertensive pregnancy. To explore experiences, perceptions, and use of the OPTIMUM-BP self-monitoring intervention. Qualitative study within the OPTIMUM-BP feasibility trial. Semi-structured interviews with a purposive sample of pregnant women with chronic hypertension (n = 24) and their clinicians (n = 8) as well as 38 ethnographic observations of antenatal visits. Women found self-monitoring of BP feasible and acceptable and were highly motivated and pro-active in their monitoring, reporting greater control and knowledge of BP and reassurance. Women's persistence with SMBP was driven by a perceived need to safeguard the pregnancy, particularly among those taking antihypertensive medication. Clinicians also described the intervention as acceptable, though BP variability could cause uncertainty. Clinicians used different heuristics to integrate home and clinic readings. Observations suggested close working relationships between women and clinicians were key for confident integration of self-monitoring. Self-monitoring of BP was acceptable both to pregnant women with hypertension and their clinicians. More research is needed to understand BP variability within pregnancy to help interpret and integrate home BP readings for improved BP management. Clinical pathways that use BP self-monitoring should aim to maintain the continuity of care and relationships that are valued and appear pivotal for the confident and safe use of self-monitoring in pregnancy.


Conformations of Human Telomeric G-Quadruplex Studied Using a Nucleotide-Independent Nitroxide Label.
Guanine-rich oligonucleotides can form a unique G-quadruplex (GQ) structure with stacking units of four guanine bases organized in a plane through Hoogsteen bonding. GQ structures have been detected in vivo and shown to exert their roles in maintaining genome integrity and regulating gene expression. Understanding GQ conformation is important for understanding its inherent biological role and for devising strategies to control and manipulate functions based on targeting GQ. Although a number of biophysical methods have been used to investigate structure and dynamics of GQs, our understanding is far from complete. As such, this work explores the use of the site-directed spin labeling technique, complemented by molecular dynamics simulations, for investigating GQ conformations. A nucleotide-independent nitroxide label (R5), which has been previously applied for probing conformations of noncoding RNA and DNA duplexes, is attached to multiple sites in a 22-nucleotide DNA strand derived from the human telomeric sequence (hTel-22) that is known to form GQ. The R5 labels are shown to minimally impact GQ folding, and inter-R5 distances measured using double electron-electron resonance spectroscopy are shown to adequately distinguish the different topological conformations of hTel-22 and report variations in their occupancies in response to changes of the environment variables such as salt, crowding agent, and small molecule ligand. The work demonstrates that the R5 label is able to probe GQ conformation and establishes the base for using R5 to study more complex sequences, such as those that may potentially form multimeric GQs in long telomeric repeats.


Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors.
We evaluated the feasibility and efficacy of a reduced-intensity conditioning (RIC) regimen of fludarabine and melphalan to achieve rapid complete donor chimerism after allogeneic stem cell transplantation (SCT) in patients with metastatic solid tumors. Between January 1999 and January 2003, 8 patients with metastatic breast cancer (BC) and 15 with metastatic renal cell carcinoma (RCC) underwent allogeneic SCT after an RIC regimen of 5 days of fludarabine and 2 days of melphalan. Filgrastim-mobilized stem cells from HLA-identical related or unrelated donors were infused. Prophylaxis for graft-versus-host disease (GVHD) consisted of tacrolimus and methotrexate. All 22 evaluable patients had 100% donor chimerism at day 30 and at all measurement times thereafter. One patient died 19 days after SCT. Nine patients (39%) had grades II to IV acute GVHD and 10 patients (43%) had chronic GVHD. Five patients (22%) died of nonrelapse treatment-related complications. Treatment-related disease response was seen in 10 patients (45%), with 3 complete responses, 2 partial responses, and 5 minor responses. Fludarabine-melphalan is a feasible and effective RIC regimen for allogeneic SCT in metastatic BC and RCC. It induces rapid complete donor chimerism without the need for donor lymphocyte infusion. Tumor regression associated with GVHD is consistent with graft-versus-tumor effect.


Volumetrics relate to the development of depression after traumatic brain injury.
Previous research suggests that many people who sustain a traumatic brain injury (TBI), even of the mild form, will develop major depression (MD). We previously reported white matter integrity differences between those who did and did not develop MD after mild TBI. In this current paper, we aimed to investigate whether there were also volumetric differences between these groups, as suggested by previous volumetric studies in mild TBI populations. A sample of TBI-with-MD subjects (N=14), TBI-without-MD subjects (N=12), MD-without-TBI (N=26) and control subjects (no TBI or MD, N=23), received structural MRI brain scans. T1-weighted data were analysed using the Freesurfer software package which produces automated volumetric results. The findings of this study indicate that (1) TBI patients who develop MD have reduced volume in temporal, parietal and lingual regions compared to TBI patients who do not develop MD, and (2) MD patients with a history of TBI have decreased volume in the temporal region compared to those who had MD but without a history of TBI. We also found that more severe MD in those with TBI-with-MD significantly correlated with reduced volume in anterior cingulate, temporal lobe and insula. These findings suggest that volumetric reduction to specific regions, including parietal, temporal and occipital lobes, after a mild TBI may underlie the susceptibility of these patients developing major depression, in addition to altered white matter integrity.


Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study.
Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Tumor tissues from patients treated with pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab and chemotherapy in patients with PDAC would be safe and effective. A phase Ib single-arm study enrolled patients with PDAC who progressed after first-line treatment. Patients received pelareorep, pembrolizumab, and either 5-fluorouracil, gemcitabine, or irinotecan until disease progression or unacceptable toxicity. Study objectives included safety and dose-limiting toxicities, tumor response, evaluation for reovirus replication, and immune analysis in peripheral blood and tumor biopsies. Eleven patients were enrolled. Disease control was achieved in three of the 10 efficacy-evaluable patients. One patient achieved partial response for 17.4 months. Two additional patients achieved stable disease, lasting 9 and 4 months, respectively. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed the creation of new T-cell clones during treatment. High peripheral clonality and changes in the expression of immune genes were observed in patients with clinical benefit. Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy. Further evaluation of pelareorep and anti-PD-1 therapy is ongoing in follow-up studies. This research highlights the potential utility of several pretreatment and on-treatment biomarkers for pelareorep therapy warranting further investigation.