Human responses to the geophysical daily, annual and lunar cycles.
Collectively the daily, seasonal, lunar and tidal geophysical cycles regulate much of the temporal biology of life on Earth. The increasing isolation of human societies from these geophysical cycles, as a result of improved living conditions, high-quality nutrition and 24/7 working practices, have led many to believe that human biology functions independently of them. Yet recent studies have highlighted the dominant role that our circadian clock plays in the organisation of 24 hour patterns of behaviour and physiology. Preferred wake and sleep times are to a large extent driven by an endogenous temporal program that uses sunlight as an entraining cue. The alarm clock can drive human activity rhythms but has little direct effect on our endogenous 24 hour physiology. In many situations, our biology and our society appear to be in serious opposition, and the damaging consequences to our health under these circumstances are increasingly recognised. The seasons dominate the lives of non-equatorial species, and until recently, they also had a marked influence on much of human biology. Despite human isolation from seasonal changes in temperature, food and photoperiod in the industrialised nations, the seasons still appear to have a small, but significant, impact upon when individuals are born and many aspects of health. The seasonal changes that modulate our biology, and how these factors might interact with the social and metabolic status of the individual to drive seasonal effects, are still poorly understood. Lunar cycles had, and continue to have, an influence upon human culture, though despite a persistent belief that our mental health and other behaviours are modulated by the phase of the moon, there is no solid evidence that human biology is in any way regulated by the lunar cycle.


Dopamine-oxytocin interactions in penile erection.
Dopamine and oxytocin have established roles in the central regulation of penile erection in rats; however, the neural circuitries involved in a specific erectile context and the interaction between dopamine and oxytocin mechanisms remain to be elucidated. The medial preoptic area (MPOA), supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus may serve as candidate sites because they contain oxytocin cells, receive dopaminergic inputs and have been implicated in mediating masculine sexual behavior. Double immunofluorescence revealed that substantial numbers of oxytocin cells in the MPOA, SON and PVN possess dopamine D(2), D(3) and D(4) receptors. In anaesthetized rats, using intracavernous pressure as a physiological indicator of erection, blockade of lumbosacral oxytocin receptors (UK, 427843) reduced erectile responses to a nonselective dopamine agonist (apomorphine), suggesting that dopamine recruits a paraventriculospinal oxytocin pathway. In conscious males in the absence of a female, penile erection elicited by a D(2)/D(3) (Quinelorane) but not D(4) (PD168077) agonist was associated with activation of medial parvocellular PVN oxytocin cells. In another experiment where males were given full access to a receptive female, a D(4) (L-745870) but not D(2) or D(3) antagonist (L-741626; nafadotride) inhibited penile erection (intromission), and this was correlated with SON magnocellular oxytocin neuron activation. Together, the data suggest dopamine's effects on hypothalamic oxytocin cells during penile erection are context-specific. Dopamine may act via different parvocellular and magnocellular oxytocin subpopulations to elicit erectile responses, depending upon whether intromission is performed. This study demonstrates the potential existence of interaction between central dopamine and oxytocin pathways during penile erection, with the SON and PVN serving as integrative sites.


A systematic review of education and evidence-based practice interventions with health professionals and breast feeding counsellors on duration of breast feeding.
to examine the effects of training, education and practice change interventions with health professionals and lay breast feeding educator/counsellors on duration of breast feeding. this was part of a series of reviews of interventions that affect duration of breast feeding. Full details of methods used, including search strategy, are reported separately. SELECTION CRITERIA FOR INCLUDED STUDIES: randomised controlled trials, non randomised controlled trials with concurrent controls and before after studies (cohort or cross-sectional), undertaken in a developed country, published between 1980 and 2003 in any language. The primary outcome was duration of breast feeding. Secondary and process outcomes, including attitude, knowledge and behaviour change of participants, were included from papers that also reported breast feeding duration outcomes. STUDY-QUALITY ASSESSMENT: inclusion and exclusion criteria were applied, data extracted and study quality assessments made by one reviewer and independently checked by another, with a third reviewer to resolve differences, as recommended by the NHS Centre for Reviews and Dissemination's guidance for reviews. the search identified nine papers. All were before after studies that included the education of health professionals; no studies were identified that related to breast feeding counsellors. In six of the studies, the participants were working with mothers and babies in hospitals (three in the UK, two in Italy and one in France); in three studies, the participants were working in community settings (Canada, Spain and the USA). Two UK studies and two non-UK studies (Spain and USA) involved mothers living in disadvantaged areas. Most interventions aimed to increase knowledge and change professional practice in support of breast feeding. many of the studies reviewed have methodological limitations. Study settings and contexts vary and lack comparability. Evidence from these studies was insufficient to draw conclusions about overall benefit or harm associated with the interventions. From the studies identified, there seems to be no single way that consistently achieves changes in breast feeding duration. From one of the methodologically more robust studies, it seems that UNICEF/WHO Baby Friendly Hospital Initiative (BFI) training might have the potential to influence breast feeding duration. RECOMMENDATIONS FOR FURTHER RESEARCH: further testing of the BFI initiative within a controlled design. Future research into the education of health-care professionals that relates to the support of breast feeding women should have appropriate theoretical underpinning, describe educational programmes and the context of care delivery comprehensively and use standardised time points in the assessment of the effect of interventions. Intermediate outcomes should also be reported, including those related to the effect on education and practice.


Competing theories of multialternative, multiattribute preferential choice.
In accounting for phenomena present in preferential choice experiments, modern models assume a wide array of different mechanisms such as lateral inhibition, leakage, loss aversion, and saliency. These mechanisms create interesting predictions for the dynamics of the deliberation process as well as the aggregate behavior of preferential choice in a variety of contexts. However, the models that embody these different mechanisms are rarely subjected to rigorous quantitative tests of suitability by way of model fitting and evaluation. Recently, complex, stochastic models have been cast aside in favor of simpler approximations, which may or may not capture the data as well. In this article, we use a recently developed method to fit the four extant models of context effects to data from two experiments: one involving consumer goods stimuli, and another involving perceptual stimuli. Our third study investigates the relative merits of the mechanisms currently assumed by the extant models of context effects by testing every possible configuration of mechanism within one overarching model. Across all tasks, our results emphasize the importance of several mechanisms such as lateral inhibition, loss aversion, and pairwise attribute differences, as these mechanisms contribute positively to model performance. Together, our results highlight the notion that mathematical tractability, while certainly a convenient feature of any model, should neither be the primary impetus for model development nor the promoting or demotion of specific model mechanisms. Instead, model fit, balanced with model complexity, should be the greatest burden to bear for any theoretical account of empirical phenomena. (PsycINFO Database Record


Lag effect of microclimatic conditions on DNA integrity of frozen-thawed bovine sperm.
The objective of this study was to investigate the effect of microclimatic conditions on DNA integrity of bovine sperm. DNA fragmentation of frozen-thawed sperm was analyzed in monthly semen samples of nine AI bulls ejaculating in weekly routine for one year. The extent of DNA fragmentation was determined using the Sperm Chromatin Structure Assay (SCSA™) and quantified by the DNA fragmentation index (DFI) and the percentage of sperm showing high DFI values (%DFI) immediately (0h) and 3h (3h) after thawing. Microclimatic factors (ambient air temperature, relative humidity, dew point) were recorded in hourly intervals throughout the year. Their mean values were calculated for seven different time periods (up to day 56) preceding ejaculation (day 0). DFI (P<0.01) and its relative change between 0h and 3h (P<0.05) were related to the set of microclimatic parameters recorded the last 11 days and from day 49 to 43 prior to ejaculation, respectively. A significant relationship was detected between %DFI and microclimatic parameters of days 35-29 preceding ejaculation (P<0.05), while the degree of change of %DFI from 0h to 3h was related to microclimatic parameters recorded from day 28 to 22 before ejaculation (P<0.05). Dew point and relative humidity appeared to be the strongest and weakest predictors of DNA integrity, respectively. In conclusion, the results of the present study showed a lag effect of microclimate on DNA integrity of frozen-thawed bovine sperm. However, microclimatic parameters of a single time period before ejaculation could not be identified as the source of variation of different SCSA parameters.


Enzyme replacement therapy for mucopolysaccharidosis VI: evaluation of long-term pulmonary function in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase.
Pulmonary function is impaired in untreated mucopolysaccharidosis type VI (MPS VI). Pulmonary function was studied in patients during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB; rhN-acetylgalactosamine 4-sulfatase). Pulmonary function tests prior to and for up to 240 weeks of weekly infusions of rhASB at 1 mg/kg were completed in 56 patients during Phase 1/2, Phase 2, Phase 3 and Phase 3 Extension trials of rhASB and the Survey Study. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and, in a subset of patients, maximum voluntary ventilation (MVV), were analyzed as absolute volume in liters. FEV1 and FVC showed little change from baseline during the first 24 weeks of ERT, but after 96 weeks, these parameters increased over baseline by 11% and 17%, respectively. This positive trend compared with baseline continued beyond 96 weeks of treatment. Improvements from baseline in pulmonary function occurred along with gains in height in the younger group (5.5% change) and in the older patient group (2.4% change) at 96 weeks. Changes in MVV occurred earlier within 24 weeks of treatment to approximately 15% over baseline. Model results based on data from all trials showed significant improvements in the rate of change in pulmonary function during 96 weeks on ERT, whereas little or no improvement was observed for the same time period prior to ERT. Thus, analysis of mean percent change data and longitudinal modeling both indicate that long-term ERT resulted in improvement in pulmonary function in MPS VI patients.


A medical records and data capture and management system for Lassa fever in Sierra Leone: Approach, implementation, and challenges.
Situated in southeastern Sierra Leone, Kenema Government Hospital (KGH) maintains one of the world's only Lassa fever isolation wards and was a strategic Ebola virus disease (EVD) treatment facility during the 2014 EVD outbreak. Since 2006, the Viral Hemorrhagic Fever Consortium (VHFC) has carried out research activities at KGH, capturing clinical and laboratory data for suspected cases of Lassa fever. Here we describe the approach, progress, and challenges in designing and maintaining a data capture and management system (DCMS) at KGH to assist infectious disease researchers in building and sustaining DCMS in low-resource environments. Results on screening patterns and case-fatality rates are provided to illustrate the context and scope of the DCMS covered in this study. A medical records system and DCMS was designed and implemented between 2010 and 2016 linking historical and prospective Lassa fever data sources across KGH Lassa fever units and its peripheral health units. Data were captured using a case report form (CRF) system, enzyme-linked immunosorbent assay (ELISA) plate readers, polymerase chain reaction (PCR) machines, blood chemistry analyzers, and data auditing procedures. Between 2008 and 2016, blood samples for 4,229 suspected Lassa fever cases were screened at KGH, ranging from 219 samples in 2008 to a peak of 760 samples in 2011. Lassa fever case-fatality rates before and following the Ebola outbreak were 65.5% (148/226) and 89.5% (17/19), respectively, suggesting that fewer, but more seriously ill subjects with Lassa fever presented to KGH following the 2014 EVD outbreak (p = .040). DCMS challenges included weak specificity of the Lassa fever suspected case definition, limited capture of patient survival outcome data, internet costs, lapses in internet connectivity, low bandwidth, equipment and software maintenance, lack of computer teaching laboratories, and workload fluctuations due to variable screening activity. DCMS are the backbone of international research efforts and additional literature is needed on the topic for establishing benchmarks and driving goal-based approaches for its advancement in developing countries.


The use of ultrasound to improve practice and reduce complication rates in peripherally inserted central catheter insertions: final report of investigation.
The risk of thrombosis related to peripherally inserted central catheters (PICCs) is a well-known complication. A study was conducted to compare thrombosis rates associated with the old technique of inserting PICCs by visualizing veins in the antecubital fossa, using anatomical landmarks and palpation versus using ultrasound guidance to locate veins in the upper arm. The findings from data collected on 538 patients included a significant decline in the thrombosis rates, as thrombosis decreased from 9.3% with the palpation method to 1.9% with the ultrasound method, and successful PICC placements by registered nurses increased from 76.9% when using the old method to 98.9% when using ultrasound guidance.


Modulation of microsaccades by spatial frequency during object categorization.
The organization of visual processing into a coarse-to-fine information processing based on the spatial frequency properties of the input forms an important facet of the object recognition process. During visual object categorization tasks, microsaccades occur frequently. One potential functional role of these eye movements is to resolve high spatial frequency information. To assess this hypothesis, we examined the rate, amplitude and speed of microsaccades in an object categorization task in which participants viewed object and non-object images and classified them as showing either natural objects, man-made objects or non-objects. Images were presented unfiltered (broadband; BB) or filtered to contain only low (LSF) or high spatial frequency (HSF) information. This allowed us to examine whether microsaccades were modulated independently by the presence of a high-level feature - the presence of an object - and by low-level stimulus characteristics - spatial frequency. We found a bimodal distribution of saccades based on their amplitude, with a split between smaller and larger microsaccades at 0.4° of visual angle. The rate of larger saccades (⩾0.4°) was higher for objects than non-objects, and higher for objects with high spatial frequency content (HSF and BB objects) than for LSF objects. No effects were observed for smaller microsaccades (<0.4°). This is consistent with a role for larger microsaccades in resolving HSF information for object identification, and previous evidence that more microsaccades are directed towards informative image regions.


Human exposure to endocrine disrupters: standardisation of a marker of estrogenic exposure in adipose tissue.
In many epidemiological studies based on the direct measurement of exposure to organochlorines, the chemicals of concern are determined directly from adipose tissue samples. Although the measurement of all possible organochlorines, their metabolites, isomers and congeners may be desirable, it is expensive and time-consuming and many chemicals with hormonal activity may not yet have been identified. Testing systems are therefore required to screen for estrogenicity and to identify appropriate biomarkers of human exposure. To address this issue, we developed and standardised a method to assess the total estrogenic xenobiotic burden in human adipose tissue. The method extracts and separates the more lipophilic xenoestrogens from ovarian estrogens, with a subsequent bioassay determination of the cumulative effect of the xenoestrogens. It was applied to 400 women, using 200 mg of adipose tissue: 65% of samples showed measurable estrogenicity in the fraction where most non-polar xenoestrogens eluted, and 76% of fractions where ovarian estrogens eluted were positive for estrogenicity. Residues of 16 organochlorine pesticides were determined. No correlation was found between pesticide content and estrogenicity of the samples. The high percentage of positive samples suggests that the method is sensitive enough to be used as a biomarker of human exposure to estrogenic xenobiotics and can be applied in epidemiological studies.


Topographic anatomy of the superior labial artery for dermal filler injection.
The superior labial artery, which is a branch of the facial artery, supplies the upper lip area. The aim of this study was to determine the distribution pattern of the superior labial artery and provide precise topographic information of the artery for dermal filler injection. Sixty hemifaces from 18 Korean and 18 Thai cadavers were used for this study. The various distribution patterns of the superior labial artery were classified according to its relationship with the facial artery. The course of the superior labial artery was classified into four types: type I (56.7 percent), in which the artery and the alar branch both arise directly and independently from the facial artery; type II (21.7 percent), in which the superior labial artery branches off from the facial artery and then gives off an alar branch; type III (15.0 percent), in which it is the terminal branch of the facial artery; and type IV (6.7 percent), in which the artery is absent. The origin of the superior labial artery was located 12.1 ± 3.1 mm (mean ± SD) lateral and at a variable angle of 42.8 ± 26.9 degrees relative to the mouth corner. The superior labial artery proceeded from the origin of the artery located within a 1.5-cm-side square superolateral to the mouth corner as running along the vermilion border of the upper lip to the facial sagittal midline at a depth of 3 mm. Thus, clinicians should be careful when injecting dermal filler into this area.


Arbitrary phasing technique for two-dimensional coherent laser array based on an active segmented mirror.
We introduce a novel (to the best of our knowledge) phasing technique for a coherent laser array. We have accomplished arbitrary phasing in the interval 0-π. A seven-channel laser array experiment is built for verification. A custom-made beam arraying structure is designed to arrange beamlets into a two-dimensional hexagonal array. In the phase-locking loop, the wavefront sensing is performed interferometrically. An active segmented mirror is used for phasing, and the control signals are generated by the proportional control algorithm. In experiment, all the beamlets have been properly phased, and the experiment of inertia-free beam steering has been accomplished.


Homozygosity for a missense variant in COMP gene associated with severe pseudoachondroplasia.
The phenotypic spectrum associated with heterozygous mutations in cartilage oligomeric matrix protein gene (COMP) range from a mild form of multiple epiphyseal dysplasia (MED) to pseudoachondroplasia (PSACH). However, the phenotypic effect from biallelic COMP variants is unclear. We investigated a large consanguineous Pakistani family with a severe form of PSACH in 2 individuals. Another 14 family members presented with a mild PSACH phenotype similar to MED. Using exome sequencing and subsequent segregation analysis, we identified homozygosity for a COMP missense variant [c.1423G>A; p.(D475N)] in the 2 severely affected individuals, whereas family members with the mild PSACH phenotype were heterozygous. Our observations show for the first time that a biallelic COMP variant may be associated with pronounced and widespread skeletal malformations suggesting an additive effect of the 2 mutated alleles.


The switch process in manic-depressive psychosis.
Bipolar manic-depressive illness is a chronic disease in which patients experience recurrent episodes of mania and depression. Patients often change from a nonverbal, retarded depression of many months' duration to a hyperactive, psychotic, manic condition during the switch. The time required for the switch from depression into mania varies from 5 minutes to a couple of days. Just before it happens, pateints experience marked insomnia and decreased rapid eye movement sleep. It is hypothesized that specific changes in brain monoamine metabolism precede the switch. Alterations in neurotransmitter metabolites, as measured in urine and cerebrospinal fluid, may precede and accompany it. The switch into mania can be precipitated by environmental stresses or by drugs that act by increasing functional brain monoamines. Drugs that reverse the manic state all share the common property of affecting biogenic amines. The switch into mania is viewed in the context of a longitudinal cyclic process and may be further studied with specific pharmacologic agents that block drug-induced maniclike states in man.


The role of interleukin-2 in memory CD8 cell differentiation.
The current literature on the role of interleukin (IL)-2 in memory CD8+ T-cell differentiation indicates a significant contribution of IL-2 during primary and also secondary expansion of CD8+ T cells. IL-2 seems to be responsible for optimal expansion and generation of effector functions following primary antigenic challenge. As the magnitude of T-cell expansion determines the numbers of memory CD8+ T cells surviving after pathogen elimination, these event influence memory cell generation. Moreover, during the contraction phase of an immune respons where most antigen-specific CD8+ T cells disappear by apoptosis, IL-2 signals are able to rescu CD8+ T cells from cell death and provide a durable increase in memory CD8+ T-cell counts. At the memory stage, CD8+ T-cell frequencies can be boosted by administration of exogenous IL-2 Significantly, only CD8+ T cells that have received IL-2 signals during initial priming are able t mediate efficient secondary expansion following renewed antigenic challenge. Thus, IL-2 signals during different phases of an immune response are key in optimizing CD8+ T-cell functions, thereby affecting both primary and secondary responses of these T cells.


Light nondegenerate squarks at the LHC.
Experimental bounds on squarks of the first two generations assume their masses to be eightfold degenerate and consequently constrain them to be heavier than ∼1.4 TeV when the gluino is lighter than 2.5 TeV. The assumption of squark-mass universality is neither a direct consequence of minimal flavor violation (MFV), which allows for splittings within squark generations, nor a prediction of supersymmetric alignment models, which allow for splittings between generations. We reinterpret a recent CMS multijet plus missing energy search allowing for deviations from U(2) universality and find significantly weakened squark bounds: A 400 GeV second-generation squark singlet is allowed, even with exclusive decays to a massless neutralino, and, in an MFV scenario, the down-type squark singlets can be as light as 600 GeV, provided the up-type singlets are pushed up to 1.8 TeV, for a 1.5 TeV gluino and decoupled doublet squarks.


Acousto-optic interaction with the use of cylindrical ultrasonic waves in the laser cavity.
In this paper, acousto-optic interaction between laser light and cylindrical airborne ultrasound in both He-Ne laser and argon-ion laser cavities is considered. The modulation properties of these acousto-optic systems were studied. The schlieren technique has been used to visualize a cylindrical ultrasonic wave generated in the air by radial vibration of a cylindrical piezoelectric shell. It was revealed that acoustic nonlinear effects together with acoustic absorption appear in the vicinity of the axis, where the ultrasound is focused. The observed waveforms of ultrasonic wave correspond to the curves of modulation of laser light.


N-Heterocyclic carbene (NHC)-modulated Pd/Cu cocatalyzed three-component synthesis of 2,6-diarylquinolines.
Two new NHC adducts of cyclopalladated ferrocenylpyrazine complexes 1-2 have been prepared and characterized. An efficient NHC-modulated Pd/Cu cocatalyzed three-component coupling reaction for the synthesis of 2,6-diarylquinolines from aminobenzyl alcohols, aryl ketones, and arylboronic acids in air is described. The reaction involves oxidation, cyclization and Suzuki reactions. The luminescence of the resulting arylquinolines 3-30 was also investigated.


Adjustable sling for the treatment of post-prostatectomy urinary incontinence: systematic review and meta-analysis.
Urinary incontinence after prostatectomy has a significant negative impact on the quality of life of the patient. The surgical treatment includes several models of male slings, such as adjustable slings. The objective of this study was to evaluate the effectiveness and safety of adjustable sling in the treatment of post-prostatectomy urinary incontinence. This is a systematic review of literature. The following electronic databases were searched until January 2018: PubMed®, Embase, CENTRAL and LILACS. The keywords used in the search strategies were: "prostatectomy" [Mesh], "urinary incontinence" [Mesh] and "suburethral slings" [Mesh]. Randomized clinical trials and observational studies, with or without Control Group, and follow-up of more than 12 months were included. Only one randomized study with high risk of bias was included and it concluded the effectiveness equivalence between adjustable and non-adjustable slings. All other studies were cases series with patients of varying levels of incontinence intensity and history of pelvic radiation therapy and previous surgeries. The meta-analysis for 0 pad in 24 hours demonstrated an effectiveness of 53%. For the 0 to 1 pad test in 24 hours, the meta-analysis resulted in an effectiveness of 69%. Risk factors for surgery failure include prior radiation, severity of post-prostatectomy urinary incontinence, and previous surgeries. The meta-analysis of the extrusion rate was 9.8% and the most commonly reported adverse effects were pain and local infection. Evidence of low quality indicates that adjustable slings are effective for treating post-prostatectomy urinary incontinence, with frequency of adverse events similar to the surgical option considered gold standard (the artificial urinary sphincter implant).


Paclitaxel as neoadjuvant therapy for high grade angiosarcoma of the spleen: a brief report and literature review.
Splenic angiosarcoma is a rare tumor with only a few cases reported in the literature. Surgical resection offers the best chance of cure for this aggressive neoplasm but is often precluded by infiltration of the tumor to surrounding critical structures. We report a case of a locally advanced angiosarcoma rendered operable by treatment with Paclitaxel monotherapy. A 69 year old female presented with a high grade splenic angiosarcoma, considered inoperable due to the extent of local spread. She received three cycles of single agent Paclitaxel and underwent a successful resection of the tumor. Chemotherapy options for splenic angiosarcoma are not well studied. Paclitaxel as monotherapy is a useful therapeutic option in down staging tumors, facilitating surgical resection and merits further study in clinical trials.


Effects of metal compounds with distinct physicochemical properties on iron homeostasis and antibacterial activity in the lungs: chromium and vanadium.
In situ reactions of metal ions or their compounds are important mechanisms by which particles alter lung immune responses. The authors hypothesized that major determinants of the immunomodulatory effect of any metal include its redox behavior/properties, oxidation state, and/or solubility, and that the toxicities arising from differences in physicochemical parameters are manifest, in part, via differential shifts in lung iron (Fe) homeostasis. To test the hypotheses, immunomodulatory potentials for both pentavalent vanadium (VV; as soluble metavanadate or insoluble vanadium pentoxide) and hexavalent chromium (CrVI; as soluble sodium chromate or insoluble calcium chromate) were quantified in rats after inhalation (5h/day for 5 days) of each at 100 microg metal/m3. Differences in effects on local bacterial resistance between the two VV, and between each CrVI, agents suggested that solubility might be a determinant of in situ immunotoxicity. For the soluble forms, VV had a greater impact on resistance than CrVI, indicating that redox behavior/properties was likely also a determinant. The soluble VV agent was the strongest immunomodulant. Regarding Fe homeostasis, both VV agents had dramatic effects on airway Fe levels. Both also impacted local immune/airway epithelial cell Fe levels in that there were significant increases in production of select cytokines/chemokines whose genes are subject to regulation by HIF-1 (whose intracellular longevity is related to cell Fe status). Our findings contribute to a better understanding of the role that metal compound properties play in respiratory disease pathogenesis and provide a rationale for differing pulmonary immunotoxicities of commonly encountered ambient metal pollutants.


Is Pilates an effective rehabilitation tool? A systematic review.
Pilates is a system of exercise focusing upon controlled movement, stretching and breathing. Pilates is popular today not only for physical fitness but also for rehabilitation programs. This paper is a review of the literature on the effectiveness of Pilates as a rehabilitation tool in a wide range of conditions in an adult population. A systematic literature review was carried out according to the PRISMA guidelines. Electronic databases were searched for cohort studies or randomised controlled trials (RCTs), and inclusion and exclusion criteria were applied. The final RCTs were assessed using the PEDro and CONSORT 2010 checklists. Twenty-three studies, published between 2005 and 2016, met the inclusion criteria. These papers assessed the efficacy of Pilates in the rehabilitation of low back pain, ankylosing spondylitis, multiple sclerosis, post-menopausal osteoporosis, non-structural scoliosis, hypertension and chronic neck pain. Nineteen papers found Pilates to be more effective than the control or comparator group at improving outcomes including pain and disability levels. When assessed using the CONSORT and PEDro scales, the quality of the papers varied, with more falling toward the upper end of the scale. The majority of the clinical trials in the last five years into the use of Pilates as a rehabilitation tool have found it to be effective in achieving desired outcomes, particularly in the area of reducing pain and disability. It indicates the need for further research in these many areas, and especially into the benefits of particular Pilates exercises in the rehabilitation of specific conditions.


More severe white matter changes in the elderly with jugular venous reflux.
The etiology of age-related white matter changes is unclear. Cerebral white matter changes on magnetic resonance imaging (MRI) and progressive dementia have been reported in patients with dural arteriovenous fistulas of the sigmoid sinus. The frequency of jugular venous reflux, which mimics a dural arteriovenous fistula, significantly increases with age. We investigated whether jugular venous reflux was associated with the severity of age-related white matter changes in 97 persons (aged 55-90 years, mean [standard deviation]: 75.77 [8.19] years; 55 men) from a medical center memory clinic. MRI (1.5T) and the semiquantitative Scheltens scale were used to investigate the severity of white matter changes. Subjects were classified into 3 groups (no, mild, and severe jugular venous reflux) by duplex ultrasonography. Subjects with severe jugular venous reflux had more severe age-related white matter changes in occipital subcortical, thalamus, pontine, and summed infratentorial regions compared with subjects with no jugular venous reflux (all corrected p < 0.0166), especially subjects aged ≥75 years (corrected p < 0.0166 in occipital subcortical; corrected p < 0.0001 in pontine and summed infratentorial regions). In subjects ≥75 years, we further noted that the whole brain age-related white matter changes rating scores were higher in the severe jugular venous reflux group than the no and mild jugular venous reflux groups (corrected p < 0.0166). People with severe jugular venous reflux exhibit more severe age-related white matter changes, especially in caudal brain regions. We also demonstrate age-dependent jugular venous reflux effects on the severity of age-related white matter changes. These findings may provide new clues into the pathophysiology of age-related white matter changes.


Splenic abscess due to chronic melioidosis in a patient previously misdiagnosed as tuberculosis.
Melioidosis is endemic in Southeast Asia and Northern Australia. Sporadic cases have been reported from many parts of the world where it has an epidemic potential with high-rate fatality cases. In non-endemic areas, melioidosis may be misdiagnosed with common diseases and this may prove fatal. Sporadic cases of melioidosis are mistaken for tuberculosis in India. We report a case of splenic abscess due to chronic melioidosis who was earlier misdiagnosed as tuberculosis and underwent anti-tuberculosis therapy. Following treatment of melioidosis his symptoms subsided. This case is reported because of the rarity of the disease and to highlight the importance of looking for melioidosis in patients with splenic abscess even in non-endemic areas.


Comparison of ribotyping, arbitrarily primed PCR, and pulsed-field gel electrophoresis for molecular typing of Listeria monocytogenes.
Fifty-one clinical isolates of Listeria monocytogenes (15 isolates from two outbreaks and 36 epidemiologically unrelated isolates) were typed by conventional serotyping, ribotyping (RT), pulsed-field gel electrophoresis (PFGE), and arbitrarily primed PCR (AP-PCR). Serotyping was unable to distinguish between related and unrelated strains of L. monocytogenes. Each of the three molecular methods showed excellent typeability and reproducibility. Restriction with EcoRI and PvuII gave 16 and 23 RT patterns, respectively. Restriction with ApaI or SmaI generated 22 and 26 PFGE profiles, respectively. ApaI profiles were easier to interpret, with 10 to 15 bands each, while SmaI profiles had 15 to 20 bands each. AP-PCR with two different primers yielded 29 and 31 randomly amplified polymorphic DNA patterns, respectively. Strains from the same outbreak shared concordant patterns by each of the three methods. Of the three techniques evaluated, RT was the least discriminating and could not distinguish between strains from the two outbreaks. The abilities of AP-PCR and PFGE to differentiate between strains were comparable. However, AP-PCR was more rapid and easier to perform. We conclude that the DNA profiles generated by either AP-PCR or PFGE can be used to differentiate outbreak strains from epidemiologically unrelated strains and to clearly identify unrelated strains as being distinct from one another. We recommend that at least two independent primers be used for AP-PCR typing in order to improve its discriminatory power.


Changes in fatty acid composition and distribution of N-3 fatty acids in goat tissues fed different levels of whole linseed.
The effects of feeding different levels of whole linseed on fatty acid (FA) composition of muscles and adipose tissues of goat were investigated. Twenty-four Crossed Boer bucks were assigned randomly into three treatment diets: L0, L10, or L20, containing 0%, 10%, or 20% whole linseed, respectively. The goats were slaughtered after 110 days of feeding. Samples from the longissimus dorsi, supraspinatus, semitendinosus, and subcutaneous fat (SF) and perirenal fat (PF) were taken for FA analyses. In muscles, the average increments in α-linolenic (ALA) and total n-3 PUFA were 6.48 and 3.4, and 11.48 and 4.78 for L10 and L20, respectively. In the adipose tissues, the increments in ALA and total n-3 PUFA were 3.07- and 6.92-fold and 3.00- and 7.54-fold in SF and PF for L10 and L20, respectively. The n-6 : n-3 ratio of the muscles was decreased from up to 8.86 in L0 to 2 or less in L10 and L20. The PUFA : SFA ratio was increased in all the tissues of L20 compared to L0. It is concluded that both inclusion levels (10% and 20%) of whole linseed in goat diets resulted in producing meat highly enriched with n-3 PUFA with desirable n-6 : n-3 ratio.


Simultaneous quantitation of multiple classes of organohalogen compounds in fish oils with direct sample introduction comprehensive two-dimensional gas chromatography and time-of-flight mass spectrometry.
We successfully optimized an analytical method using gel permeation chromatography followed by direct sample introduction comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry to quantify multiple groups of targeted persistent organic pollutants and halogenated natural products (HNPs) simultaneously in fish oil samples. This new method has a wider analytical scope than the traditional approach to use multiple methods to cover each class of compounds. Our analysis revealed that the relatively more volatile and lighter organic compounds, such as polychlorinated biphenyls (PCBs), organochlorine pesticides, and other smaller organohalogen compounds, were still present in two brands of "PCB-free" cod liver oils, albeit at much lower levels than in an untreated commercial sample. Moreover, the less volatile organic compounds, such as polybrominated diphenyl ethers and brominated HNPs, were detected at similar levels in all three cod liver oils. This suggests that the commercial molecular distillation treatment used for removal of organic/inorganic toxic contaminants is only effective for the lighter organic contaminants.


An implementation of a spike-response model with escape noise using an avalanche diode.
This paper introduces a novel probabilistic spike-response model through the combination of avalanche diode-generated Poisson distributed noise, and a standard exponential decay-based spike-response curve. The noise source, which is derived from a 0.35-μm single-photon avalanche diode (kept in the dark), was tested experimentally to verify its characteristics, before being combined with a field-programmable gate-array implementation of a spike-response model. This simple model was then analyzed, and shown to reproduce seven of eight behaviors recorded during an extensive study of the ventral medial hypothalamic (VMH) region of the brain. It is thought that many of the cell types found within the VMH are fed from a tonic noise synaptic input, where the patterns generated are a product of their spike response and not their interconnection. This paper shows how this tonic noise source can be modelled, and due to the independent nature of the noise sources, provides an avenue for the exploration of networks of noise-fueled neurons, which play a significant role in pattern generation within the brain.


Bronchoscopic modalities to diagnose sarcoidosis.
Several studies have investigated different bronchoscopic techniques to obtain tissue diagnosis in patients with suspected sarcoidosis when the diagnosis cannot be based on clinicoradiographic findings alone. In this review, we will describe the most recent and relevant evidence from different bronchoscopic modalities to diagnose sarcoidosis. Despite multiple available bronchoscopic modalities to procure tissue samples to diagnose sarcoidosis, the vast majority of evidence favors endobronchial ultrasound transbronchial needle aspiration to diagnose Scadding stages 1 and 2 sarcoidosis. Transbronchial lung cryobiopsy is a new technique that is mainly used to aid in the diagnosis of undifferentiated interstitial lung disease; however, we will discuss its potential use in sarcoidosis. This review illustrates the limited information about the different bronchoscopic techniques to aid in the diagnosis of pulmonary sarcoidosis. However, it demonstrates that the combination of available bronchoscopic techniques increases the diagnostic yield for suspected sarcoidosis.


Affective reactions to visually masked stimuli within a virtual environment.
Within perceptual psychology, visual masking describes a process whereby the presentation of one image, the mask, affects the conscious perception of another, the target. Given the right conditions the target can effectively be rendered invisible. There is a dearth of research into the effects of visually masked stimuli within virtual environments, particularly with regard to affect psychology. Of the two studies presented here, the first study was used to establish the efficacy of visual masking using three dimensional, masked objects. Usually, mask and target stimuli are co-planar, with no internal depth disparity. This study found that visual masking is possible within a virtual space using target objects with internal depth disparity. The second study investigated affect driven, choice reactions to three dimensional, masked facial expressions. This study also found an effect, specifically an unconscious bias to navigate away from angry, masked faces and towards smiling, masked expressions. These two studies form a foundation for a wider project: using visual masking within a virtual environment for mood induction, primarily as a cybertherapeutic aid.


Spin-orbit effects on the (119)Sn magnetic-shielding tensor in solids: a ZORA/DFT investigation.
Periodic-boundary and cluster calculations of the magnetic-shielding tensors of (119)Sn sites in various co-ordination and stereochemical environments are reported. The results indicate a significant difference between the predicted NMR chemical shifts for tin(ii) sites that exhibit stereochemically-active lone pairs and tin(iv) sites that do not have stereochemically-active lone pairs. The predicted magnetic shieldings determined either with the cluster model treated with the ZORA/Scalar Hamiltonian or with the GIPAW formalism are dependent on the oxidation state and the co-ordination geometry of the tin atom. The inclusion of relativistic effects at the spin-orbit level removes systematic differences in computed magnetic-shielding parameters between tin sites of differing stereochemistries, and brings computed NMR shielding parameters into significant agreement with experimentally-determined chemical-shift principal values. Slight improvement in agreement with experiment is noted in calculations using hybrid exchange-correlation functionals.


Impact of Adverse Childhood Experiences on Psychotic-Like Symptoms and Stress Reactivity in Daily Life in Nonclinical Young Adults.
There is increasing interest in elucidating the association of different childhood adversities with psychosis-spectrum symptoms as well as the mechanistic processes involved. This study used experience sampling methodology to examine (i) associations of a range of childhood adversities with psychosis symptom domains in daily life; (ii) whether associations of abuse and neglect with symptoms are consistent across self-report and interview methods of trauma assessment; and (iii) the role of different adversities in moderating affective, psychotic-like, and paranoid reactivity to situational and social stressors. A total of 206 nonclinical young adults were administered self-report and interview measures to assess childhood abuse, neglect, bullying, losses, and general traumatic events. Participants received personal digital assistants that signaled them randomly eight times daily for one week to complete questionnaires about current experiences, including symptoms, affect, and stress. Self-reported and interview-based abuse and neglect were associated with psychotic-like and paranoid symptoms, whereas only self-reported neglect was associated with negative-like symptoms. Bullying was associated with psychotic-like symptoms. Losses and general traumatic events were not directly associated with any of the symptom domains. All the childhood adversities were associated with stress reactivity in daily life. Interpersonal adversities (abuse, neglect, bullying, and losses) moderated psychotic-like and/or paranoid reactivity to situational and social stressors, whereas general traumatic events moderated psychotic-like reactivity to situational stress. Also, different interpersonal adversities exacerbated psychotic-like and/or paranoid symptoms in response to distinct social stressors. The present study provides a unique examination of how childhood adversities impact the expression of spectrum symptoms in the real world and lends support to the notion that stress reactivity is a mechanism implicated in the experience of reality distortion in individuals exposed to childhood trauma. Investigating the interplay between childhood experience and current context is relevant for uncovering potential pathways to the extended psychosis phenotype.


Gambling-Related Problems as a Mediator Between Treatment and Mental Health with At-Risk College Student Gamblers.
Disordered gambling has been linked to increased negative affect, and some promising treatments have been shown to be effective at reducing gambling behaviors and related problems (Larimer et al. in Addiction 107:1148-1158, 2012). The current study seeks to expand upon the findings of Larimer et al. (Addiction 107:1148-1158, 2012) by examining the relationship between gambling-related problems and mental health symptoms in college students. Specifically, the three-group design tested the effects of two brief interventions for gambling—an individual, in-person personalized feedback intervention (PFI) delivered using motivational interviewing and group-based cognitive behavioral therapy, versus assessment only on mood outcomes. The mediating effect of gambling-related problems on mood was also explored. Participants (N = 141; 65% men; 60% Caucasian, 28% Asian) were at-risk college student gamblers [South Oaks Gambling Screen (Lesieur and Blume in Am J Psychiatry 144:1184-1188, 1987) ≥3], assessed at baseline and 6-month follow-up. Gambling problems were assessed using the Gambling Problems Index (Neighbors et al. in J Gamb Stud 18:339-360, 2002). Mental health symptoms were assessed using the depression, anxiety, and hostility subscales of the Brief Symptom Inventory (Derogatis in Brief Symptom Inventory (BSI): administration, scoring, and procedures manual, National Computer Systems, Inc., Minneapolis, 1993). Results revealed that the PFI condition differentially reduced negative mood, and that reductions in gambling-related problems partially mediated this effect. Implications for intervention for comorbid mood and gambling disorders are discussed.


Staff injuries from patient attack: five years' data.
We report on five years' experience of staff injuries from patient attack in a large state hospital. In 1984 to 1988, with a total of 6,225 staff person-years of exposure, 209 employees suffered 236 injuries from patient attack. Ward nursing staff sustained 185 of the injuries (5.7 injuries per hundred person-years), professional staff 17 (rate = 2.3), psychiatric technician trainees 27 (rate = 6.2), and nonclinical staff 7 (rate = 0.4). The annual rate of injury by attack was 50 percent higher among male nursing staff (6.9 injuries per hundred) than among females (4.5). The annual rate of injury by attack was slightly higher among psychiatrists (6.0 per hundred person-years) than among nursing staff. Two three-hour peak periods for injury from patient attack were identified: 8:00 am to 10:59 am and 4:00 pm to 6:59 pm. These six hours accounted for half the injuries. We observed more injuries on Mondays and Tuesdays (42.5 per day), compared with the rest of the week (30.4 per day). No difference in staff injuries was noted between Wednesday-Thursday-Friday and weekend days; 74 percent of staff injuries from attack occurred on the victim's own ward; 70.7 percent of injuries from patient attack were head injuries.


Microbial specialists in below-grade foundation walls in Scandinavia.
Below-grade foundation walls are often exposed to excessive moisture by water infiltration, condensation, leakage, or lack of ventilation. Microbial growth in these structures depends largely on environmental factors, elapsed time, and the type of building materials and construction setup. The ecological preferences of Actinomycetes (Actinobacteria) and the molds Ascotricha chartarum, Myxotrichum chartarum (Ascomycota), Geomyces pannorum, and Monocillium sp. (Hyphomycetes) have been addressed based on analyses of 1764 samples collected in below-grade spaces during the period of 2001-2012. Our results show a significant correlation between these taxa and moist foundation walls as ecological niches. Substrate preference was the strongest predictor of taxa distribution within the wall, but the taxa's physiological needs, together with gradients of abiotic factors within the wall structure, also played a role. Our study describes for the first time how the wall environment affects microbial growth.


Tumefactive demyelination-to cracks the nut without cracking the pot.
A 45-year-old female recently detected diabetic, admitted with difficulty in walking, irrelevant talk and urinary incontinence for 3 weeks and deviation of angle of mouth to left. Examination revealed pallor, delusional thoughts, right upper motor neuron facial weakness, ataxia. CT brain revealed bulky hyperdense lesion in corpus callosum and subsequently MRI of the brain revealed T2-hyperintense lesions involving genu and body of corpus callosum with restricted diffusion, and MR spectroscopy revealed reduced uptake of choline. Possibilities considered were infiltrative glioma of corpus callosum, demyelination and central nervous system lymphoma. As the patient and relatives were not willing to allow stereotactic biopsy, she was started on steroids. Her neurological deficits started improving and 1 month later repeat MRI brain showed a drastic reduction in the size of the lesion. Her neurological condition disappeared and is doing well.


Lentiviral vectors and gene therapy.
Gene therapy is a novel method under investigation for the treatment of genetic, metabolic and neurologic diseases, cancer and AIDS. The primary goal of gene therapy is to deliver a specific gene to a pre-determined target cell, and to direct expression of such a gene in a manner which will result in a therapeutic effect. Retroviral vectors have the ability to integrate in the host cell DNA irreversibly and therefore, are suitable vectors for permanent genetic modification of cells. Retrovirus-mediated gene transfer has been limited, however, by the inability of onco-retroviruses to productively infect non-dividing cells. Lentiviruses are unique among retroviruses because of their ability to infect target cells independently of their proliferation status. This chapter presents an up-to-date description of available lentiviral vectors, including vector design, applications to disease treatment and safety considerations. In addition, general aspects of the biology of lentiviruses with relevance to vector development will be discussed.


More than a Mentor: Leonard Darwin's Contribution to the Assimilation of Mendelism into Eugenics and Darwinism.
This article discusses the contribution to evolutionary theory of Leonard Darwin (1850-1943), the eighth child of Charles Darwin. By analysing the correspondence Leonard Darwin maintained with Ronald Aylmer Fisher in conjunction with an assessment of his books and other written works between the 1910s and 1930s, this article argues for a more prominent role played by him than the previously recognised in the literature as an informal mentor of Fisher. The paper discusses Leonard's efforts to amalgamate Mendelism with both Eugenics and Darwinism in order for the first to base their policies on new scientific developments and to help the second in finding a target for natural selection. Without a formal qualification in biological sciences and as such mistrusted by some "formal" scientists, Leonard Darwin engaged with key themes of Darwinism such as mimicry, the role of mutations on speciation and the process of genetic variability, arriving at important conclusions concerning the usefulness of Mendelian genetics for his father's theory.


Identification of Alzheimer's disease using a convolutional neural network model based on T1-weighted magnetic resonance imaging.
The classification of Alzheimer's disease (AD) using deep learning methods has shown promising results, but successful application in clinical settings requires a combination of high accuracy, short processing time, and generalizability to various populations. In this study, we developed a convolutional neural network (CNN)-based AD classification algorithm using magnetic resonance imaging (MRI) scans from AD patients and age/gender-matched cognitively normal controls from two populations that differ in ethnicity and education level. These populations come from the Seoul National University Bundang Hospital (SNUBH) and Alzheimer's Disease Neuroimaging Initiative (ADNI). For each population, we trained CNNs on five subsets using coronal slices of T1-weighted images that cover the medial temporal lobe. We evaluated the models on validation subsets from both the same population (within-dataset validation) and other population (between-dataset validation). Our models achieved average areas under the curves of 0.91-0.94 for within-dataset validation and 0.88-0.89 for between-dataset validation. The mean processing time per person was 23-24 s. The within-dataset and between-dataset performances were comparable between the ADNI-derived and SNUBH-derived models. These results demonstrate the generalizability of our models to different patients with different ethnicities and education levels, as well as their potential for deployment as fast and accurate diagnostic support tools for AD.


Dietary protein is important in the practical management of prediabetes and type 2 diabetes.
Many misconceptions surround the role of dietary protein in the management of diabetes. Although dietary recommendations for managing diabetes have changed greatly over the centuries, recommended protein intake has remained relatively constant. Currently, recommendations for protein intake are based on individual assessment and the consideration of other health issues and implications, such as the extent of glycemic control, the presence of kidney disease, overweight and obesity, and the age of the patient. Two common misconceptions about dietary protein in diabetes management are that a certain amount of the protein consumed is converted into blood glucose and that consuming too much protein can lead to diabetic kidney disease. These misconceptions have been disproven. For many people with type 2 diabetes, aiming for 20-30% of total energy intake as protein is the goal. Exceptions may be for those individuals with impaired renal function. A protein intake of this amount can be beneficial by improving glycemic control, aiding in satiety and preservation of lean body mass during weight loss in those with both diabetes and prediabetes, and providing for the increased protein requirements of the older adult. Health care providers should discuss the role of dietary protein with their patients, reinforce sources of protein in the diet, and use simple but effective teaching tools, such as the plate method, to convey important nutrition messages. In addition, health care providers should recognize that persons with diabetes are attempting to manage many other aspects of their diabetes, including blood glucose monitoring, physical activity, taking of medication, risk reduction, and problem solving.


Primary structure and possible origin of the non-glycosylated basic proline-rich protein of human submandibular/sublingual saliva.
Human submandibular/sublingual saliva contains one non-glycosylated basic proline-rich protein whereas parotid saliva contains multiple such components. The submandibular protein has a primary structure identical with the C-terminal segment [TZ] of the human parotid acidic proline-rich proteins that contain 150 amino acid residues (Mr 16,000). Northern-blot analyses of human parotid and submandibular glands revealed that mRNAs containing the HaeIII repeat sequence typical for acidic proline-rich proteins are expressed in both of these salivary glands whereas mRNAs for non-glycosylated basic proline-rich proteins containing a typical BstN1 repeat sequence are expressed in the parotid but not in the submandibular gland. Products of translation in vitro of mRNAs from human parotid and submandibular glands were also examined. Two immunoprecipitable bands with Mr 29,000 and 28,000 were obtained by translation of both parotid and submandibular mRNA. In the presence of microsomal membranes these proteins gave rise to proteins electrophoretically identical with the secreted acidic proline-rich proteins of Mr 16,000. These proteins were cleaved by kallikrein, giving rise to proteins with electrophoretic mobilities identical with those of a smaller acidic proline-rich protein with Mr 11,000 and peptide TZ. Additional immunoprecipitable bands with Mr ranging from 35,000 to 46,000 were seen when parotid mRNA was used for translation in vitro, and are believed to be precursors of the basic proline-rich proteins encoded by the BstN1 repeat type mRNA. Neither these bands nor a separate precursor for the basic non-glycosylated proline-rich protein was detected when submandibular mRNA was used for translation in vitro. It is suggested that the non-glycosylated basic proline-rich protein present in human submandibular saliva arises by cleavage of acidic proline-rich proteins.


Aldose reductase is involved in the development of murine diet-induced nonalcoholic steatohepatitis.
Hepatic aldose reductase (AR) expression is known to be induced in liver diseases, including hepatitis and hepatocellular carcinoma. However, the role of AR in the development of these diseases remains unclear. We performed this current study to determine whether and how AR might be involved in the development of diet-induced nonalcoholic steatohepatitis. Our results showed that the level of AR protein expression was significantly higher in db/db mice fed the methionine-choline-deficient (MCD) diet than in mice fed the control diet. In parallel with the elevation in AR, steatohepatitis was observed in MCD diet-fed mice, and this diet-induced steatohepatitis was significantly attenuated by lentiviral-mediated knock-down of the AR gene. This suppressive effect of AR knock-down was associated with repressed levels of serum alanine aminotransferase and hepatic lipoperoxides, reduced mRNA and protein expression of hepatic cytochrome P450 2E1 (CYP2E1), and decreased mRNA expression of pro-inflammatory tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Moreover, AR-induced elevations on the level of CYP2E1 expression, reactive oxygen species, mRNA expression of TNF-α and IL-6 were confirmed in AML12 hepatocytes. Further, lentiviral-mediated knock-down of AR ameliorated MCD diet-induced collagen deposition in the livers of db/db mice. With the improvement in liver fibrosis, the mRNA levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metalloproteinase-2 (MMP-2), two genes involved in hepatic fibrogenesis, were found to be significantly suppressed, while TIMP-2 and MMP-13 were unaffected. Together these data indicate that inhibition of AR alleviates the MCD diet-induced liver inflammation and fibrosis in db/db mice, probably through dampening CYP2E1 mediated-oxidative stress and ameliorating the expression of pro-inflammatory cytokines.


[History of psychiatric legislation in Italy].
The different models of mental illness which have followed one another in Italian psychiatry have been linked to the history of psychiatric legislation and its various attempts at reform. The first law of the newly United State which unified legislations and former procedures, whose prevalent psychiatric theories were those that referred to degeneration, was the law 36/1904 that set up the asylums. Accordingly psychiatric praxis was focused on social protection and custody, given that the mentally ill was seen as incurable; Fascism added the inmate's obligation to be enrolled in the judicial register. Afterwards numerous attempts to reform the psychiatric legislation were made that eventually gave rise to law 431/1968 which paved the way to territorial psychiatry. Law 180/1978 changed the organization of Italian psychiatry abolishing asylums and the concept of dangerousness, including psychiatry in the National Health Service but adopting an idea of mental illness as simply social unease.


Investigation of the effect of epicardial adipose tissue thickness on cardiac conduction system in children with type 1 diabetes mellitus.
Objectives Investigation of the association between epicardial adipose tissue thickness (EATT) and P-wave dispersion (Pd), QT dispersion (QTd), corrected QT dispersion (QTcd) and Tp-e interval in children with Type 1 Diabetes Mellitus (T1DM) was aimed. Methods Forty-one children with T1DM and 41 age- and gender-matched healthy children were included in the study. Demographical characteristics of all cases were examined. In echocardiography; in addition to conventional echocardiographic measurements, end-systolic EATT was measured from right ventricular free wall. In electrocardiogram; Pd, QTd, QTcd and Tp-e interval durations, as well as Tp-e/QT and Tp-e/QTc ratios were calculated. Correlation values between EATT and electrocardiographic parameters were also noted. Results Mean age of the patient group was determined to be 12.43 ± 3.04 years and that of the control group was determined to be 12.08 ± 2.56 years. There was no significant difference between the groups in regard to age, gender, body weight, height and body mass index. In the patient group; EATT, Pd, QTd, QTcd and Tp-e interval were determined to be significantly higher compared to the control group. In the patient group, no significant correlation was determined between EATT and Pd, QTd, QTcd and Tp-e. However, when both patient and control groups were evaluated together, a statistically significant positive correlation was determined between EATT and Pd, QTd, QTcd and Tp-e. Conclusions In children with T1DM, an increase in epicardial adipose tissue thickness and in risk of cardiac arrhythmias has been demonstrated. To reveal the possible unfavorable effects of EATT on cardiac conduction system in T1DM patients needs further studies.


Biased attentional processing of food cues and modification in obese individuals.
This paper reports two experiments designed to investigate and modify biased attentional processing of food cues in obesity. Experiment 1: Experiment 1 used a dot probe task to show a food-related attentional bias in 58 obese women, relative to a comparison sample of normal weight controls. Experiment 2: Experiment 2 examined whether this bias can be modified. Using a modified dot probe task, 96 obese women were trained to attend to, or to avoid, food pictures. Attentional bias for food increased in the attend group, and decreased in the avoid group. The attentional retraining effects generalized to an independent measure of biased information processing, such that participants in the avoid group produced relatively fewer food than animal words on a subsequent word stem completion task than those in the attend group. The results extend the application of attentional bias modification from anxiety and addiction to obesity. They also offer potential scope for tackling pathological (over)eating.


Diagnosing the Kaiser: Psychiatry, Wilhelm II and the Question of German War Guilt The William Bynum Prize Essay 2016.
After his abdication in November 1918, the German emperor Wilhelm II continued to haunt the minds of his people. With the abolition of the lese-majesty laws in the new republic, many topics that were only discussed privately or obliquely before could now be broached openly. One of these topics was the mental state of the exiled Kaiser. Numerous psychiatrists, physicians and laypeople published their diagnoses of Wilhelm in high-circulation newspaper articles, pamphlets, and books shortly after the end of the war. Whether these diagnoses were accurate and whether the Kaiser really was mentally ill became the issue of a heated debate.This article situates these diagnoses of Wilhelm II in their political context. The authors of these diagnoses - none of whom had met or examined Wilhelm II in person - came from all political camps and they wrote with very different motives in mind. Diagnosing the exiled Kaiser as mentally ill was a kind of exorcism of the Hohenzollern rule, opening the way for either a socialist republic or the hoped-for rule of a new leader. But more importantly, it was a way to discuss and allocate political responsibility and culpability. Psychiatric diagnoses were used to exonerate both the Emperor (for whom the treaty of Versailles provided a tribunal as war criminal) and the German nation. They were also used to blame the Kaiser's entourage and groups that had allegedly manipulated the weak-willed monarch. Medical concepts became a vehicle for a debate on the key political questions in interwar Germany.


Alcohol research: past, present, and future.
Created forty years ago, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has played a major role in the great strides made in the understanding, treatment, prevention, and public acceptance of alcohol-use disorders. Throughout most of U.S. history "habitual drunkenness" was viewed as a problem of moral degeneracy or character flaw inherent in the individual. However, the wealth of scientific evidence amassed throughout NIAAA's history has established alcoholism as a medical condition, that is, as a disease for which affected individuals should feel no shame or be treated with disdain. We look at the developments in alcohol epidemiology, typology, etiology, prevention, and treatment research over the past 40 years. We also discuss how NIAAA addresses alcohol disorders from a life-course framework, affecting all stages of the lifespan, from fetus through child, adolescent, and young adult, to midlife/senior adult, with each stage involving different risks, consequences, prevention efforts, and treatment strategies.


Chronic health needs immediately after natural disasters in middle-income countries: the case of the 2008 Sichuan, China earthquake.
Few studies have focused on chronic health needs immediately after natural disasters in middle-income countries. This study examines chronic medical needs during the acute phase after the 2008 Sichuan earthquake. A descriptive, cross-sectional study was conducted in an emergency triage clinic in Sichuan, China. Information on physical, social, and public health preparedness was collected in predesigned templates. Descriptive and Pearson's χ association analyses were conducted. One hundred and eighty-two evacuees were received at the triage site. Of these, 54% required trauma treatment and 77% of evacuated patients who required care had underlying chronic medical conditions. Tetanus immunizations and the possession of chronic health medication were low, particularly among older patients. Chronic health needs constituted a significant proportion of emergency care during the acute phase in the study population. Effective post-disaster assistance requires attention to demographic and epidemiological population profiles.


Face perception enhances insula and motor network reactivity in Tourette syndrome.
Tourette syndrome is a neurodevelopmental disorder, characterized by motor and phonic tics. Tics are typically experienced as avolitional, compulsive, and associated with premonitory urges. They are exacerbated by stress and can be triggered by external stimuli, including social cues like the actions and facial expressions of others. Importantly, emotional social stimuli, with angry facial stimuli potentially the most potent social threat cue, also trigger behavioural reactions in healthy individuals, suggesting that such mechanisms may be particularly sensitive in people with Tourette syndrome. Twenty-one participants with Tourette syndrome and 21 healthy controls underwent functional MRI while viewing faces wearing either neutral or angry expressions to quantify group differences in neural activity associated with processing social information. Simultaneous video recordings of participants during neuroimaging enabled us to model confounding effects of tics on task-related responses to the processing of faces. In both Tourette syndrome and control participants, face stimuli evoked enhanced activation within canonical face perception regions, including the occipital face area and fusiform face area. However, the Tourette syndrome group showed additional responses within the anterior insula to both neutral and angry faces. Functional connectivity during face viewing was then examined in a series of psychophysiological interactions. In participants with Tourette syndrome, the insula showed functional connectivity with a set of cortical regions previously implicated in tic generation: the presupplementary motor area, premotor cortex, primary motor cortex, and the putamen. Furthermore, insula functional connectivity with the globus pallidus and thalamus varied in proportion to tic severity, while supplementary motor area connectivity varied in proportion to premonitory sensations, with insula connectivity to these regions increasing to a greater extent in patients with worse symptom severity. In addition, the occipital face area showed increased functional connectivity in Tourette syndrome participants with posterior cortical regions, including primary somatosensory cortex, and occipital face area connectivity with primary somatosensory and primary motor cortices varied in proportion to tic severity. There were no significant psychophysiological interactions in controls. These findings highlight a potential mechanism in Tourette syndrome through which heightened representation within insular cortex of embodied affective social information may impact the reactivity of subcortical motor pathways, supporting programmed motor actions that are causally implicated in tic generation. Medicinal and psychological therapies that focus on reducing insular hyper-reactivity to social stimuli may have potential benefit for tic reduction in people with Tourette syndrome.


Therapy-related myelodysplastic syndrome: morphologic subclassification may not be clinically relevant.
In practice, cases of therapy-related myelodysplastic syndrome (t-MDS) are often classified according to morphologic schemes used for de novo MDS. However, there are few data addressing the appropriateness of such classification. We studied 155 patients with therapy-related acute myeloid leukemia (t-AML)/t-MDS to determine whether subclassification by the World Health Organization (WHO) criteria for de novo MDS provides prognostic information in t-MDS. In addition, we assessed whether cytogenetic stratification by the International Prognostic Scoring System (IPSS) guidelines or karyotypic complexity was prognostically important. We found no differences in median survival times among patients classified into the different WHO subgroup of MDS or according to their bone marrow blast percentage; our results indicate a uniformly poor outcome in t-MDS regardless of morphologic classification. However, significant survival differences correlated with cytogenetic stratification according to IPSS guidelines and/or karyotypic complexity. We found only a borderline difference in median survival of patients with an initial t-MDS diagnosis compared with patients with an initial t-AML diagnosis.


Binding of (6R,S)-methyltetrahydrofolate to methyltransferase from Clostridium thermoaceticum: role of protonation of methyltetrahydrofolate in the mechanism of methyl transfer.
The methyltetrahydrofolate:corrinoid/iron-sulfur protein methyltransferase (MeTr) from Clostridium thermoacetium catalyzes transfer of the N5-methyl group of (6S)-methyltetrahydrofolate (CH3-H4folate) to the cob(I)amide center of a corrinoid/iron-sulfur protein (CFeSP), forming H4folate and methylcob(III)amide. We have investigated binding of 13C-enriched (6R,S)-CH3-H4folate and (6R)-CH3-H4folate to MeTr by 13C NMR, equilibrium dialysis, fluorescence quenching, and proton uptake experiments. The results described here and in the accompanying paper [Seravalli, J., Shoemaker, R. K., Sudbeck, M. J., and Ragsdale, S. W. (1999) Biochemistry 38, 5728-5735] constitute the first evidence for protonation of the pterin ring of CH3-H4folate. The pH dependence of the chemical shift in the 13C NMR spectrum for the N5-methyl resonance indicates that MeTr decreases the acidity of the N5 tertiary amine of CH3-H4folate by 1 pK unit in both water and deuterium oxide. Binding of (6R,S)-CH3H4folate is accompanied by the uptake of one proton. These results are consistent with a mechanism of activation of CH3-H4folate by protonation to make the methyl group more electrophilic and the product H4folate a better leaving group toward nucleophilic attack by cob(I)amide. When MeTr is present in excess over (6R,S)-13CH3-H4folate, the 13C NMR signal is split into two broad signals that reflect the bound states of the two diastereomers. This unexpected ability of MeTr to bind both isomers was confirmed by the observation of MeTr-bound (6R)-13CH3-H4folate by NMR and by the measurement of similar dissociation constants for (6R)- and (6S)-CH3-H4folate diastereomers by fluorescence quenching experiments. The transversal relaxation time (T2) of 13CH3-H4folate bound to MeTr is pH independent between pH 5.50 and 7.0, indicating that neither changes in the protonation state of bound CH3-H4folate nor the previously observed pH-dependent MeTr conformational change contribute to broadening of the 13C resonance signal. The dissociation constant for (6R,S)-CH3-H4folate is also pH independent, indicating that the role of the pH-dependent conformational change is to stabilize the transition state for methyl transfer, and not to favor the binding of CH3-H4folate.


An evidence-based update on hepatic encephalopathy.
Hepatic encephalopathy (HE) is a disturbance of the central nervous system (CNS) function secondary to porto-systemic shunting. It usually occurs in the setting of advanced liver cirrhosis or acute fulminant hepatic failure. An extensive Medline search was undertaken and all relevant papers found were critically examined. Special emphasis was paid to clinical trials and meta-analyses. All guidelines and conference proceedings related to hepatic encephalopathy were also examined. HE presents with a spectrum of neuropsychiatric manifestations that may be quite subtle (minimal HE) or overt, ranging from disturbance of the sleep pattern to deep hepatic coma. Most patients with HE may be diagnosed on clinical grounds only after excluding other causes of neurological disease, but a wide variety of neuropsychological, neurophysiological, and neuroradiological tests may be utilized. The first step in the management of patients with HE should be supportive care. Following that, a significant effort must be exerted to find and correct possible exacerbating factors which may include: renal impairment, infection, constipation, drugs, gastrointestinal bleeding and other factors. Medications used to treat patients with encephalopathy aim to reduce toxin production, increase toxin elimination, and protect the brain from the harmful effects of these toxins. A critical analysis of the evidence concerning most of the available management modalities is presented. Ultimately, all patients with HE must be considered for liver transplantation. It is concluded that early recognition, positive diagnosis, and a multi-target management plan constitutes appropriate management of patients with HE.


Detecting the Dependence of Diversification on Multiple Traits from Phylogenetic Trees and Trait Data.
Species diversification may be determined by many different variables, including the traits of the diversifying lineages. The state-dependent speciation and extinction (SSE) framework contains methods to detect the dependence of diversification on these traits. For the analysis of traits with multiple states, MuSSE (multiple-states dependent speciation and extinction) was developed. However, MuSSE and other SSE models have been shown to yield false positives, because they cannot separate differential diversification rates from dependence of diversification on the observed traits. The recently introduced method HiSSE (hidden-state-dependent speciation and extinction) resolves this problem by allowing a hidden state to affect diversification rates. Unfortunately, HiSSE does not allow traits with more than two states, and, perhaps more interestingly, the simultaneous action of multiple traits on diversification. Herein, we introduce an R package (SecSSE: several examined and concealed states-dependent speciation and extinction) that combines the features of HiSSE and MuSSE to simultaneously infer state-dependent diversification across two or more examined (observed) traits or states while accounting for the role of a possible concealed (hidden) trait. Moreover, SecSSE also has improved functionality when compared with its two "parents." First, it allows for an observed trait being in two or more states simultaneously, which is useful for example when a taxon is a generalist or when the exact state is not precisely known. Second, it provides the correct likelihood when conditioned on nonextinction, which has been incorrectly implemented in HiSSE and other SSE models. To illustrate our method, we apply SecSSE to seven previous studies that used MuSSE, and find that in five out of seven cases, the conclusions drawn based on MuSSE were premature. We test with simulations whether SecSSE sacrifices statistical power to avoid the high Type I error problem of MuSSE, but we find that this is not the case: for the majority of simulations where the observed traits affect diversification, SecSSE detects this.


Prediction of Safety Risk Levels of Veterinary Drug Residues in Freshwater Products in China Based on Transformer.
Early warning and focused regulation of veterinary drug residues in freshwater products can protect human health and stabilize social development. To improve the prediction accuracy, this paper constructs a Transformer-based model for predicting the safety risk level of veterinary drug residues in freshwater products in China to conduct a comprehensive assessment and prediction of the three veterinary drug residues with the maximum detection rate in freshwater products, including florfenicol, enrofloxacin and sulfonamides. Using the national sampling data and consumption data of freshwater products from 2019 to 2021, this paper constructs a self-built dataset, combined with the k-means algorithm, to establish the risk-level space. Finally, based on a Transformer neural network model, the safety risk assessment index is predicted on a self-built dataset, with the corresponding risk level for prediction. In this paper, comparison experiments are conducted on the self-built dataset. The experimental results show that the prediction model proposed in this paper achieves a recall rate of 94.14%, which is significantly better than other neural network models. The model proposed in this paper provides a scientific basis for the government to implement focused regulation, and it also provides technical support for the government's intervention regulation.


A 19F-qNMR-Guided Mathematical Model for G Protein-Coupled Receptor Signaling.
GPCRs exhibit a wide range of pharmacological efficacies, yet the molecular mechanisms responsible for the differential efficacies in response to various ligands remain poorly understood. This lack of understanding has hindered the development of a solid foundation for establishing a mathematical model for signaling efficacy. However, recent progress has been made in delineating and quantifying receptor conformational states and associating function with these conformations. This progress has allowed us to construct a mathematical model for GPCR signaling efficacy that goes beyond the traditional ON/OFF binary switch model. In this study, we present a quantitative conformation-based mathematical model for GPCR signaling efficacy using the adenosine A2A receptor (A2AR) as a model system, under the guide of 19F quantitative NMR (19F-qNMR) experiments. This model encompasses two signaling states, a fully activated state, and a partially activated state, defined as being able to regulate the cognate Gas nucleotide exchange with respective G protein recognition capacity. By quantifying the population distribution of each state, we can now in turn examine GPCR signaling efficacy. This advance provides a foundation for assessing GPCR signaling efficacy using a conformation-based mathematical model in response to ligand binding. Significance Statement Mathematical models to describe signaling efficacy of G protein-coupled receptors (GPCRs) mostly suffer from considering only two states (ON/OFF). However, research indicates that a GPCR possesses multiple active-(like) states that can interact with Gabg independently, regulating varied nucleotide exchanges. With the guide of 19F-qNMR, the transitions among these states are quantified as a function of ligand and Gabg, serving as a foundation for a novel conformation-based mathematical signaling model.


Endoplasmic reticulum stress-associated cone photoreceptor degeneration in cyclic nucleotide-gated channel deficiency.
Cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 account for >70% of all known cases of achromatopsia. Cones degenerate in achromatopsia patients and in CNGA3(-/-) and CNGB3(-/-) mice. This work investigates the molecular basis of cone degeneration in CNG channel deficiency. As cones comprise only 2-3% of the total photoreceptor population in the wild-type mouse retina, we generated mouse lines with CNG channel deficiency on a cone-dominant background, i.e. CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) mice. The retinal phenotype and potential cell death pathways were examined by functional, biochemical, and immunohistochemical approaches. CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) mice showed impaired cone function, opsin mislocalization, and cone degeneration similar to that in the single knock-out mice. The endoplasmic reticulum stress marker proteins, including Grp78/Bip, phospho-eIF2α, phospho-IP(3)R, and CCAAT/enhancer-binding protein homologous protein, were elevated significantly in CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, compared with the age-matched (postnatal 30 days) Nrl(-/-) controls. Along with these, up-regulation of the cysteine protease calpains and cleavage of caspase-12 and caspase-7 were found in the channel-deficient retinas, suggesting an endoplasmic reticulum stress-associated apoptosis. In addition, we observed a nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G in CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, implying a mitochondrial insult in the endoplasmic reticulum stress-activated cell death process. Taken together, our findings suggest a crucial role of endoplasmic reticulum stress in cone degeneration associated with CNG channel deficiency.


The ability of a novel blue laser imaging system for the diagnosis of invasion depth of colorectal neoplasms.
Fujifilm has developed a novel endoscope system with two kinds of lasers that enables us to allow narrow-band light observation with blue laser imaging (BLI). The aim of this study was to evaluate BLI magnification in comparison with narrow-band imaging (NBI) magnification for the diagnosis of colorectal neoplasms. This was a multicenter open study. A total of 104 colorectal neoplasms were examined with BLI and NBI magnifications in Kyoto Prefectural University of Medicine and Fukuoka University Chikushi Hospital. Vascular and surface patterns of tumors under BLI magnification were compared with those under NBI magnification, using a published NBI classification. The main outcome was the correlation between the NBI classification diagnosed by BLI or NBI magnification and the histopathological analyses. Sixty-two cases of adenoma, 34 cases of intramucosal cancer and shallowly invaded submucosal cancer, and eight cases of deeply invaded submucosal cancer were diagnosed. The diagnostic accuracy of BLI magnification in the NBI classification was 74.0 % (77/104), similar to that of NBI magnification (77.8 %). The consistency rate between BLI and NBI magnification in the NBI classification was 74.0 %. Concerning image evaluation, the interobserver variability of two expert endoscopists (N.Y. and T.H.) in BLI magnification was κ = 0.863. On the other hand, the intraobserver variability of the two endoscopists was κ = 0.893 (N.Y.) and 0.851 (T.H.). BLI magnification by laser source could predict histopathological diagnosis and invasion depth of colorectal neoplasms. The diagnostic effectiveness of this method was similar to that of NBI magnification.


Indirectly-seeded optical parametric generation in periodically poled lithium niobate.
We report a technique for injection-seeding optical parametric generation (OPG) in periodically poled lithium niobate in which the wavelength of the seed is neither that of the signal nor of the idler waves; instead, it is the wavelength resulting from the sum-frequency mixing of the pump and signal waves. We show that pulsed OPG can be appropriately seeded in this way even if the sum-frequency process is not quasi-phasematched if a pulsed laser is used as a seed, and if it is quasi-phase-matched even a low power (15 mW) HeNe beam can substantially reduce the bandwidth of the generated signal wave.


Physical activity before and after primary total hip arthroplasty: a registry-based study.
Detailed assessment of activity before and after total hip arthroplasty (THA) including a long-term followup period is lacking. Our objectives were to evaluate patient activity levels prior to disease onset, prior to THA, and at 5 and 10 years after surgery, and to determine the predictors of high activity 5 years after surgery. We included elective primary THAs performed between 1996 and 2012. A cross-sectional analysis compared mean University of California, Los Angeles (UCLA) activity scores over 4 periods: prior to symptom onset of osteoarthritis, prior to surgery, 5 years after surgery, and 10 years after surgery. Analyses of activity levels were performed and stratified by sex, age, body mass index (BMI), American Society of Anesthesiology (ASA) classes, and preoperative activity level. A prospective study was conducted to identify baseline characteristics associated with a high activity level (UCLA score ≥7) 5 years after surgery using logistic regression. The mean UCLA activity scores prior to symptom onset (n = 189), prior to THA (n = 203), 5 years after surgery (n = 1,085), and 10 years after surgery (n = 757) were 6.9, 3.5, 5.7, and 5.5, respectively. Postoperative scores were close to values prior to symptom onset in patients ages ≥55 years, but were lower in those who were younger. High activity was reported by 49% of patients prior to symptom onset, 5% of patients prior to surgery, and 28% of patients at both 5 and 10 years after surgery. The predictors of high activity at 5 years were younger age, male sex, a lower BMI, a lower ASA score, and an active lifestyle prior to surgery. Five and 10 years after primary THA, physical activity levels were substantially higher in men and women and in all age categories as compared to before surgery.


Identification of peak bone mass QTL in a spontaneously osteoporotic mouse strain.
The whole genome scan for quantitative trait loci (QTLs) specifying peak bone mass was performed with the F2 intercrosses of SAMP6, an established murine model of senile osteoporosis, exhibiting a significantly lower peak bone mass, and SAMP2, exhibiting a higher peak bone mass. Cortical thickness index (CTI), a parameter of bone mass of femurs, was measured in 488 F2 progeny at 4 months of age, when the animals attained peak bone mass by microphotodensitometry. Genetic markers were typed at 90 loci spanning all chromosomes except the Y. By interval mapping of 246 male F2 mice, two loci were identified with significant linkage to peak bone mass, one on Chromosome (Chr) 11 and another on Chr 13, with a maximum lod score of 10.8 (22.2% of the total variance) and 5.8 (10.0%), respectively. Another locus on the X Chr was suggestive of a QTL associated oppositely with a low peak bone mass to the SAMP2 allele. This association was consistent with the distribution of peak bone mass in the F1 and F2. These findings should be useful to elucidate the genetics of osteoporosis.


Sparse multi-output Gaussian processes for online medical time series prediction.
For real-time monitoring of hospital patients, high-quality inference of patients' health status using all information available from clinical covariates and lab test results is essential to enable successful medical interventions and improve patient outcomes. Developing a computational framework that can learn from observational large-scale electronic health records (EHRs) and make accurate real-time predictions is a critical step. In this work, we develop and explore a Bayesian nonparametric model based on multi-output Gaussian process (GP) regression for hospital patient monitoring. We propose MedGP, a statistical framework that incorporates 24 clinical covariates and supports a rich reference data set from which relationships between observed covariates may be inferred and exploited for high-quality inference of patient state over time. To do this, we develop a highly structured sparse GP kernel to enable tractable computation over tens of thousands of time points while estimating correlations among clinical covariates, patients, and periodicity in patient observations. MedGP has a number of benefits over current methods, including (i) not requiring an alignment of the time series data, (ii) quantifying confidence regions in the predictions, (iii) exploiting a vast and rich database of patients, and (iv) inferring interpretable relationships among clinical covariates. We evaluate and compare results from MedGP on the task of online prediction for three patient subgroups from two medical data sets across 8,043 patients. We find MedGP improves online prediction over baseline and state-of-the-art methods for nearly all covariates across different disease subgroups and hospitals. The MedGP framework is robust and efficient in estimating the temporal dependencies from sparse and irregularly sampled medical time series data for online prediction. The publicly available code is at https://github.com/bee-hive/MedGP .


[Randomized controlled study on the effectiveness of community pharmacists' advice for smoking cessation by Nicorette--evaluation at three months after initiation].
We conducted a randomized, controlled study to evaluate whether pharmacists' advice on smoking cessation would result in a higher smoking cessation rate using Nicorette (nicotine gum preparation). Fourteen pharmacies in Tokyo, Kanagawa, and Nagano participated. Smokers who visited pharmacies to buy Nicorette from March 1, 2002, through August 31, 2002, were recruited and randomly assigned to two groups. For the intervention group (A), pharmacists provided both regular instructions on Nicorette use and smoking cessation advice at the first sale and then gave follow-up advice just before starting a cessation and 1, 3, and 8 weeks and 3 months thereafter. For the control group (B), pharmacists provided regular instructions alone. The primary outcome measure was the self-reported smoking cessation rate and the secondary outcome measure was the relationship between the smoker's egogram and effectiveness of intervention. Twenty-eight smokers were enrolled and randomized into group A (n=11) or group B (n=17). The absolute abstinence rate in groups A and B at 3 months was 45.5% and 31.2%, respectively. The odds ratio was 1.83, which was not statistically significant. There was no difference in egogram score between absolute abstinence subjects and nonabstinence subjects in group A. The egogram scores in Adapted Child of absolute abstinence subjects in group B were significantly higher than in nonabstinence subjects. In conclusion, instructions and advice given by pharmacists may improve the smoking cessation rate in smokers receiving nicotine replacement therapy.


Trophic niche width increases with bill-size variation in a generalist passerine: a test of niche variation hypothesis.
The niche variation hypothesis (NVH) predicts that populations with wider niches are phenotypically more variable than populations with narrower niches, which is frequently used to explain diversifying processes such as ecological release. However, not all empirical evidence supports the NVH. Furthermore, a relationship between population phenotypic variation and niche width can be caused by sexual selection or environmental gradients, which should be carefully considered along with competition in explaining niche variation. In this study, we used eight populations of a generalist passerine species, Paradoxornis webbianus (vinous-throated parrotbill), to test the NVH. We assessed evidence of ecological sexual dimorphism and environmental gradients in bill morphology of P. webbianus. A total of 170 P. webbianus from eight sites ranging 24-2668 m in altitude were included in this study. We used two principal components to quantify bill morphology: one describes bill size and the other describes bill slenderness. We used stable carbon and nitrogen isotope values of bird feathers to quantify trophic positions, and we estimated population trophic niche width using Bayesian standardized ellipse area. Paradoxornis webbianus with larger and more slender bills fed at higher trophic levels and population trophic niche width tended to increase with bill-size variation, supporting the NVH. The males had larger bills and marginally higher nitrogen isotope values than the females, suggesting ecological sexual dimorphism. Despite a positive correlation between bill size and wing length indicating sexual selection for larger male size, only three of the eight populations showed both male-biased bill size and male-biased wing length. Sexual dimorphism explained 13%-64% of bill-size variation across sites, suggesting its role in niche variation could vary greatly among populations. The variation in bill slenderness in P. webbianus increased with elevation. However, neither bill-size variation nor trophic niche width changed with elevation. Therefore, environmental gradients that could be reflected in the elevation are not likely to drive the observed morphological and niche variation. This study provides an empirical case for the NVH and highlights the importance of investigating sexual dimorphism and environmental gradients in studies of niche dynamics.


Electron microscopic studies of lipopolysaccharides from phase I and phase II Coxiella burnetii.
Lipopolysaccharides from phase I (LPSI) Coxiella burnetii Ohio and Nine Mile strains and from phase II (LPSII) Nine Mile stain were negatively and positively and examined with the electron microscope. The ultrastructure of LPSI and LPSII positively stained with uranyl formate or uranyl acetate was ribbon-like. When negatively stained with uranyl acetate, LPSI was ribbon-like but LPSII exhibited hexagonal lattice structures. However, LPSII stained negatively with sodium phosphotungstate and ammonium molybdate exhibited hexagonal lattice ultrastructures which were not identical to those observed when negatively stained with uranyl acetate. The hexagonal lattice structures formed in vitro were due to the interactions of LPSII and the staining reagents rather than to protein-LPS interactions. The differences in the ultrastructures of LPSI and LPSII are undoubtedly based on variations in their chemical composition.