Positive Effect of a Pea-Clam Two-Peptide Composite on Hypertension and Organ Protection in Spontaneously Hypertensive Rats.
In the present study, we prepared pea peptides with high angiotensin-converting enzyme (ACE) inhibitory activity in vitro using an enzymatic hydrolysis of pea protein and compounded them with clam peptides to obtain a pea-clam double peptide. The effects of the two-peptide composite and pea peptides on hypertension and the damage-repair of corresponding organs were studied in spontaneously hypertensive rats (SHRs). We found that both pea peptides and the two-peptide composite significantly reduced the blood pressure upon a single or long-term intragastric administration, with the two-peptide composite being more effective. Mechanistically, we found that the two-peptide composite could regulate the renal renin-angiotensin system (RAS), rebalance gut microbial dysbiosis, decrease renal and myocardial fibrosis, and improve renal and cardiac function and vascular remodeling. Additionally, hippocampal lesions caused by hypertension were also eliminated after two-peptide composite administration. Our research provides a scientific basis for the use of this two-peptide composite as a safe antihypertension ingredient in functional foods.


Deep sub-seafloor prokaryotes stimulated at interfaces over geological time.
The sub-seafloor biosphere is the largest prokaryotic habitat on Earth but also a habitat with the lowest metabolic rates. Modelled activity rates are very low, indicating that most prokaryotes may be inactive or have extraordinarily slow metabolism. Here we present results from two Pacific Ocean sites, margin and open ocean, both of which have deep, subsurface stimulation of prokaryotic processes associated with geochemical and/or sedimentary interfaces. At 90 m depth in the margin site, stimulation was such that prokaryote numbers were higher (about 13-fold) and activity rates higher than or similar to near-surface values. Analysis of high-molecular-mass DNA confirmed the presence of viable prokaryotes and showed changes in biodiversity with depth that were coupled to geochemistry, including a marked community change at the 90-m interface. At the open ocean site, increases in numbers of prokaryotes at depth were more restricted but also corresponded to increased activity; however, this time they were associated with repeating layers of diatom-rich sediments (about 9 Myr old). These results show that deep sedimentary prokaryotes can have high activity, have changing diversity associated with interfaces and are active over geological timescales.


Sensitivity and resolution enhanced solid-state NMR for paramagnetic systems and biomolecules under very fast magic angle spinning.
Recent research in fast magic angle spinning (MAS) methods has drastically improved the resolution and sensitivity of NMR spectroscopy of biomolecules and materials in solids. In this Account, we summarize recent and ongoing developments in this area by presenting (13)C and (1)H solid-state NMR (SSNMR) studies on paramagnetic systems and biomolecules under fast MAS from our laboratories. First, we describe how very fast MAS (VFMAS) at the spinning speed of at least 20 kHz allows us to overcome major difficulties in (1)H and (13)C high-resolution SSNMR of paramagnetic systems. As a result, we can enhance both sensitivity and resolution by up to a few orders of magnitude. Using fast recycling (∼ms/scan) with short (1)H T1 values, we can perform (1)H SSNMR microanalysis of paramagnetic systems on the microgram scale with greatly improved sensitivity over that observed for diamagnetic systems. Second, we discuss how VFMAS at a spinning speed greater than ∼40 kHz can enhance the sensitivity and resolution of (13)C biomolecular SSNMR measurements. Low-power (1)H decoupling schemes under VFMAS offer excellent spectral resolution for (13)C SSNMR by nominal (1)H RF irradiation at ∼10 kHz. By combining the VFMAS approach with enhanced (1)H T1 relaxation by paramagnetic doping, we can achieve extremely fast recycling in modern biomolecular SSNMR experiments. Experiments with (13)C-labeled ubiquitin doped with 10 mM Cu-EDTA demonstrate how effectively this new approach, called paramagnetic assisted condensed data collection (PACC), enhances the sensitivity. Lastly, we examine (13)C SSNMR measurements for biomolecules under faster MAS at a higher field. Our preliminary (13)C SSNMR data of Aβ amyloid fibrils and GB1 microcrystals acquired at (1)H NMR frequencies of 750-800 MHz suggest that the combined use of the PACC approach and ultrahigh fields could allow for routine multidimensional SSNMR analyses of proteins at the 50-200 nmol level. Also, we briefly discuss the prospects for studying bimolecules using (13)C SSNMR under ultrafast MAS at the spinning speed of ∼100 kHz.


Monoclonal idiotypic and anti-idiotypic antibodies to human immunodeficiency virus type 1 envelope glycoprotein.
Murine monoclonal antibodies (MAbs) gp41-1 (IgG2a) and gp41-2 (IgG1), directed against the envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1), were produced and characterized. These MAbs recognized both gp160 and gp41 and reacted with divergent HIV-1 isolates. Surface binding assays using viable HIV-infected cells indicated that these MAbs were directed against surface-exposed epitopes. Both MAbs caused a reduction in reverse transcriptase activity. Syngeneic monoclonal antiidiotypic antibodies (anti-ids) against gp41-1 were also generated. Six anti-ids (agp41-11 to agp41-16) were selected by ELISA using F(ab')2 fragments of gp41-1; no reaction was observed when fragments from an irrelevant IgG2a MAb were used. Anti-ids were recognized by both gp41-1 and gp41-2 biotinylated MAbs. Competitive ELISA studies suggested that anti-ids were directed against at least three distinct idiotopes on gp41-1. All anti-ids reacted with idiotopes associated with both heavy and light chains and not with separated chains. The binding of MAbs gp41-1 and gp41-2 to HIV-infected cells was inhibited by each anti-id, except for the binding of gp41-2 which was not affected by the presence of agp41-12. Immunization of rabbits with agp41-11 and agp41-13 resulted in an antibody response against recombinant gp160. These studies indicated that these two anti-ids contain a surrogate image of the antigen recognized by gp41-1.


[Non diabetic hypoglycemia: diagnosis and management].
Organic or non diabetic hypoglycemia (NDH) is a rare disease when it is confirmed, but is often confounded with low blood glucose concentration (between 3 and 4 mmol/I), which is much more frequent. NDH's definition requires the Whipple triad (plasma glucose level <2.8 mmol/l, symptoms of neuroglycopenia and their relief with administration of sugar). The diagnostic approach needs to differentiate the healthy from the sick patient, who's hypoglycemia causes are multiple and frequent, such as: toxic (medicament, OH), organ deficiency, denutrition and sepsis. When hypoglycemia is suspected, without evident causes in healthy persons, it should be investigated by a 72 h fast test, in order to guide the diagnosis. After confirmation of an endogen hyperinsulinism only, sophisticated imaging should be done to localize the tumor and/or to exclude alternatives diagnosis.


Extracting physicochemical features to predict protein secondary structure.
We propose a protein secondary structure prediction method based on position-specific scoring matrix (PSSM) profiles and four physicochemical features including conformation parameters, net charges, hydrophobic, and side chain mass. First, the SVM with the optimal window size and the optimal parameters of the kernel function is found. Then, we train the SVM using the PSSM profiles generated from PSI-BLAST and the physicochemical features extracted from the CB513 data set. Finally, we use the filter to refine the predicted results from the trained SVM. For all the performance measures of our method, Q 3 reaches 79.52, SOV94 reaches 86.10, and SOV99 reaches 74.60; all the measures are higher than those of the SVMpsi method and the SVMfreq method. This validates that considering these physicochemical features in predicting protein secondary structure would exhibit better performances.


Ocean acidification impairs olfactory discrimination and homing ability of a marine fish.
The persistence of most coastal marine species depends on larvae finding suitable adult habitat at the end of an offshore dispersive stage that can last weeks or months. We tested the effects that ocean acidification from elevated levels of atmospheric carbon dioxide (CO(2)) could have on the ability of larvae to detect olfactory cues from adult habitats. Larval clownfish reared in control seawater (pH 8.15) discriminated between a range of cues that could help them locate reef habitat and suitable settlement sites. This discriminatory ability was disrupted when larvae were reared in conditions simulating CO(2)-induced ocean acidification. Larvae became strongly attracted to olfactory stimuli they normally avoided when reared at levels of ocean pH that could occur ca. 2100 (pH 7.8) and they no longer responded to any olfactory cues when reared at pH levels (pH 7.6) that might be attained later next century on a business-as-usual carbon-dioxide emissions trajectory. If acidification continues unabated, the impairment of sensory ability will reduce population sustainability of many marine species, with potentially profound consequences for marine diversity.


Was John Reid right? Smoking, class, and pleasure: a population-based cohort study in England.
To assess whether there is a relationship between smoking and levels of overall quality of life, or with the pleasure domain of quality of life, in lower socio-economic groups (SES). Cohort study involving 9176 individuals aged 50 years and over who participated in the Health Survey for England and were followed up in Wave 1 of the English Longitudinal Study of Ageing in 2002. We classified smokers as never-smokers, ex-smokers and current smokers, and used household wealth as a marker for socio-economic position. Pleasure was assessed using the pleasure subscale of the CASP-19 instrument, a 19-point measure of quality of life that covers four theoretical domains: control, autonomy, self-realization and pleasure. We found that the odds ratio for experiencing lower than median levels of pleasure for smokers with low SES was 1.42 (95% CI 1.16-1.74), and for all smokers was 1.33 (95% CI 1.17-1.51). The same pattern of associations was found when the outcome was total CASP-19 score or positive GHQ-12 score. We found no evidence to support a claim that smoking is associated with heightened levels of pleasure, either in people with low SES or in the general population. In fact, our results suggest the opposite: that smoking is associated with lower levels of pleasure and poorer overall quality of life. Policy decisions on smoking should consider its potentially harmful effect on quality of life and pleasure as well as on other aspects of health.


Immunohistochemistry for PRAME in Dermatopathology.
Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen first identified in a melanoma patient and found to be expressed in most melanomas as well as in variable levels in other malignant neoplasms of epithelial, mesenchymal, or hematolymphoid lineage. Detection of PRAME expression in formalin-fixed paraffin-embedded tissue is possible by immunohistochemistry (IHC) with commercially available monoclonal antibodies. In situ and invasive melanoma frequently show a diffuse pattern of nuclear PRAME immunoreactivity which contrasts with the infrequent and typically nondiffuse staining seen in nevi. In many challenging melanocytic tumors, results of PRAME IHC and other ancillary tests correlate well, but not always: The tests are not interchangeable. Most metastatic melanomas are positive for PRAME, whereas nodal nevi are not. Numerous studies on PRAME IHC have become available in the past few years with results supporting the value of PRAME IHC as an ancillary tool in the evaluation of melanocytic lesions and providing insights into limitations in sensitivity and specificity as well as possible pitfalls that need to be kept in mind by practicing pathologists.


Knowledge of tuberculosis and associated health-seeking behaviour among rural Vietnamese adults with a cough for at least three weeks.
Good general lay knowledge of tuberculosis (TB), its cause and treatment is considered important for both prompt healthcare seeking and adherence to treatment. The main aim of this study was to describe the knowledge of TB among med and women with a cough for more than three weeks and to see how their health seeking related to TB knowledge. A population-based survey was carried out within a demographic surveillance site in Vietnam. The study population included 35,832 adults aged 15 years or over. Cough cases were identified at household level and structures interviews were carried out with all cases of cough in person. A total of 559 people (1.6%) reported coughing with a duration of three weeks or longer (259 men and 300 women). A large proportion of individuals with a cough for more than three weeks had limited knowledge of the causes, transmission modes, symptoms, and curability of TB. Men had a significantly higher knowledge score than women (3.04 vs 2.55). Better knowledge was significantly related to seeking healthcare and seeking hospital care. More men than women did not take any health care action at all. Health education for TB thus seems to be useful, but efforts must be made to ensure that both men and women in different socioeconomic contexts can access the information.


Outcomes from a comprehensive stroke telemedicine program.
Our team has studied the use of telemedicine to overcome obstacles to providing acute stroke care and expanding stroke education. We report a summary of our outcomes to provide evidence supporting greater development of stroke telehealth systems. Stroke telemedicine is audio-video communication (teleconferencing) between a stroke specialist and a remote party requiring stroke services. Using several models, we tested the validity, reliability, and effectiveness of telemedicine versus telephone consultations and face-to-face (traditional) medical care and education. Because of the challenges inherent to technology studies, we found a prospective, case control design most practical for testing hypotheses related to a comparison of telemedicine and traditional service delivery. Telemedicine-assisted neurologic evaluation and stroke diagnosis were as valid and reliable as traditionally delivered services. Clinical effectiveness was demonstrated by shortening times to treatment (17 [telemedicine] vs. 33 [control] minutes; p = 0.003) and increasing tissue plasminogen activator use at a remote hospital (from 5% to 24%). Evaluation of telemedicine as a means to expand stroke education to distant communities revealed that telemedicine and direct education achieve equivalent academic results. Stroke services delivered by telemedicine are safe, efficacious, and comparable to those rendered face-to-face. Telemedicine is a means of providing disability-reducing therapies earlier to a large number of patients. The current, geographically defined scheme for telemedicine service reimbursement fails to recognize that the main barrier to stroke care is lack of available stroke specialists. Contractual and third-party reimbursement structures should be modified to surmount this impediment to extending stroke specialty care and community education.


Olfactory Dysfunction Associated with Cognitive Decline in an Elderly Population.
In many neurological disorders, including Alzheimer disease, early olfactory dysfunction is observed. In order to determine if deficits in olfactory memory are present in the elderly and if olfactory dysfunction correlates with cognitive impairment in the aging population, olfactory testing has been done on seniors from the NuAge cohort accepting to participate in the Olfactory Response Cognition and Aging (ORCA) secondary sub-study. The t-Mini Mental Statement Examination and the Telephone Interview for Cognitive Status tests were done to assess cognition levels. Overall, 94% of the ORCA cohort displayed olfactory dysfunction. Deficits in olfactory memory were also present. A correlation was observed between olfactory function and cognitive test scores. Moreover, in women who smoked, there was an association between olfactory memory and cognitive scores. Our results suggest that olfactory dysfunction may predict impending cognitive decline and highlights the need for olfactory training in seniors to improve olfaction and overall well-being.


Test characteristics of quick brain MRI for shunt evaluation in children: an alternative modality to avoid radiation.
Quick brain magnetic resonance imaging (QB-MRI) is a rapid, radiation-free technique to detect life-threatening CSF shunt malfunction. QB-MRI has not been widely studied or adopted. The primary objective of this study was to evaluate the test characteristics of QB-MRI for detecting shunt malfunction. Test characteristics of brain computed tomography (CT) and QB-MRI were then compared. Secondary objectives included comparison of time to study completion and use of sedatives for both modalities, as well as comparison of time to study completion for QB-MRI before and after implementation of a Pediatric Emergency Department (PED) shunt clinical pathway. A retrospective chart review was performed at 2 tertiary care hospital PEDs. The authors reviewed the charts of children who underwent QB-MRI or CT for suspected shunt malfunction between July 2008 and June 2012. They also reviewed the patients' neuroradiology reports and classified ventricular size as positive (enlarged) or negative (normal, smaller, or unchanged). Shunt malfunction was defined by surgical revision within 30 days. Nine hundred ninety-seven PED visits (involving 724 QB-MRIs and 273 CTs) were included. Surgical revision was performed in 235 cases (23.6%). For QB-MRI, sensitivity was 58.5% (95% CI 51.1%-65.6%) and specificity was 93.3% (90.8%-95.3%). For CT, sensitivity was 53.2% (95% CI 38.1%-67.9%) and specificity was 95.6% (92%-97.9%). The mean time to completion of QB-MRI was 115 minutes versus 83 minutes for CT (difference 32 minutes, 95% CI, 22-42 minutes, p < 0.001). The mean time from presentation to completion of QB-MRI prior to application of the CSF shunt pathway was 132 minutes versus 112 minutes after application of the CSF shunt pathway (difference 20 minutes, 95% CI 5-35 minutes, p = 0.01). Anxiolytic medications were used in 3.7% of CT studies and 4.4% of QB-MRI studies (p = 0.74). QB-MRI and CT have similar test characteristics for detecting CSF shunt malfunction in children and similar requirements for sedation. The longer interval from order placement to imaging completion for QB-MRI is arguably justified by reduction of radiation exposure in this population subject to frequent brain imaging.


Referral Patterns in Neuro-Ophthalmology.
Neuro-ophthalmologists specialize in complex, urgent, vision- and life-threatening problems, diagnostic dilemmas, and management of complex work-ups. Access is currently limited by the relatively small number of neuro-ophthalmologists, and consequently, patients may be affected by incorrect or delayed diagnosis. The objective of this study is to analyze referral patterns to neuro-ophthalmologists, characterize rates of misdiagnoses and delayed diagnoses in patients ultimately referred, and delineate outcomes after neuro-ophthalmologic evaluation. Retrospective chart review of 300 new patients seen over 45 randomly chosen days between June 2011 and June 2015 in one tertiary care neuro-ophthalmology clinic. Demographics, distance traveled, time between onset and neuro-ophthalmology consultation (NOC), time between appointment request and NOC, number and types of providers seen before referral, unnecessary tests before referral, referral diagnoses, final diagnoses, and impact of the NOC on outcome were collected. Patients traveled a median of 36.5 miles (interquartile range [IQR]: 20-85). Median time from symptom onset was 210 days (IQR: 70-1,100). Median time from referral to NOC was 34 days (IQR: 7-86), with peaks at one week (urgent requests) and 13 weeks (routine requests). Median number of previous providers seen was 2 (IQR: 2-4; range:0-10), and 102 patients (34%) had seen multiple providers within the same specialty before referral. Patients were most commonly referred for NOC by ophthalmologists (41% of referrals). Eighty-one percent (242/300) of referrals to neuro-ophthalmology were appropriate referrals. Of the 300 patients referred, 247 (82%) were complex or very complex; 119 (40%) were misdiagnosed; 147 (49%) were at least partially misdiagnosed; and 22 (7%) had unknown diagnoses. Women were more likely to be at least partially misdiagnosed-108 of 188 (57%) vs 39 of 112 (35%) of men (P < 0.001). Mismanagement or delay in care occurred in 85 (28%), unnecessary tests in 56 (19%), unnecessary consultations in 64 (22%), and imaging misinterpretation in 16 (5%). Neuro-ophthalmologists played a major role in directing treatment, such as preserving vision, preventing life-threatening complications, or avoiding harmful treatment in 62 (21%) patients. Most referrals to neuro-ophthalmologists are appropriate, but many are delayed. Misdiagnosis before referral is common. Neuro-ophthalmologists often prevent vision- and life-threatening complications.


Depression, stress and body fat are associated with binge eating in a community sample of African American and Hispanic women.
The purpose of this study was to examine the relationships among depressive symptoms, stress and severity of binge eating symptoms in a community sample of African American and Hispanic or Latina women. Women (African American, n = 127; Hispanic or Latina, n = 44) completed measures of body composition, stress, depression, and binge eating. Scores on a depressive symptom scale indicated that 24.0 % of participants exhibited clinically significant levels of depressive symptoms. Mean binge eating scores were below the threshold for clinically diagnosed binge eating (12.99 ± 7.90). Mean stressful event scores were 25.86 ± 14.26 and the average stress impact score was 78.36 ± 55.43. Linear regression models found that body composition, stress impact score, and being classified as having clinically significant levels of depression were associated with severity of binge eating symptoms. Higher levels of percent body fat, a CES-D score ≥16 and higher WSI-Impact scores were associated with greater severity of binge eating symptoms.


Allowance for random dose estimation errors in atomic bomb survivor studies: a revision.
Allowing for imprecision of radiation dose estimates for A-bomb survivors followed up by the Radiation Effects Research Foundation can be improved through recent statistical methodology. Since the entire RERF dosimetry system has recently been revised, it is timely to reconsider this. We have found that the dosimetry revision itself does not warrant changes in these methods but that the new methodology does. In addition to assumptions regarding the form and magnitude of dose estimation errors, previous and current methods involve the apparent distribution of true doses in the cohort. New formulas give results conveniently and explicitly in terms of these inputs. Further, it is now possible to use assumptions about two components of the dose errors, referred to in the statistical literature as "classical" and "Berkson-type". There are indirect statistical indications, involving non-cancer biological effects, that errors may be somewhat larger than assumed before, in line with recommendations made here. Inevitably, methods must rely on uncertain assumptions about the magnitude of dose errors, and it is comforting to find that, within the range of plausibility, eventual cancer risk estimates are not very sensitive to these.


Patient perspectives on the treatment burden of injectable medication for hereditary angioedema.
Hereditary angioedema (HAE) is a rare, chronic disease characterized by debilitating swelling episodes in various parts of the body. Patients experience significant burdens related to the symptoms and management of HAE, which can affect their daily lives and reduce their overall quality of life. Prophylactic treatment options have expanded in the past decade to the benefit of patients; however, these therapies require scheduled injections, which can be painful, burdensome, and time consuming. We conducted an online survey of patients with HAE in the USA to better understand their experiences with available prophylactic medications and the associated treatment burdens. Our survey results suggest that most patients are satisfied with their current therapies but desire novel medications with a simpler route of administration and that, although most patients experience significant treatment-related burdens, they learn to cope with these challenges over time.


Dielectric fluctuations in force microscopy: noncontact friction and frequency jitter.
Electric force microscopy, in which a charged probe oscillates tens to hundreds of nanometers above a sample surface, provides direct mechanical detection of relaxation in molecular materials. Noncontact friction, the damping of the probe's motions, reflects the dielectric function at the resonant frequency of the probe, while fluctuations in the probe frequency are induced by slower molecular motions. We present a unified theoretical picture of both measurements, which relates the noncontact friction and the power spectrum of the frequency jitter to dielectric properties of the sample and to experimental geometry. Each observable is related to an equilibrium correlation function associated with electric field fluctuations, which is determined by two alternative, complementary strategies for a dielectric continuum model of the sample. The first method is based on the calculation of a response function associated with the polarization of the dielectric by a time-varying external charge distribution. The second approach employs a stochastic form of Maxwell's equations, which incorporate a fluctuating electric polarization, to compute directly the equilibrium correlation function in the absence of an external charge distribution. This approach includes effects associated with the propagation of radiation. In the experimentally relevant limit that the tip-sample distance is small compared to pertinent wavelengths of radiation, the two methods yield identical results. Measurements of the power spectrum of frequency fluctuations of an ultrasensitive cantilever together with measurements of the noncontact friction over a poly(methylmethacrylate) film are used to estimate the minimum experimentally detectable frequency jitter. The predicted jitter for this polymer is shown to exceed this threshold, demonstrating the feasibility of the measurement.


Monarchs in decline: a collateral landscape-level effect of modern agriculture.
We review the postulated threatening processes that may have affected the decline in the eastern population of the monarch butterfly, Danaus plexippus L. (Lepidoptera: Nymphalidae), in North America. Although there are likely multiple contributing factors, such as climate and resource-related effects on breeding, migrating, and overwintering populations, the key landscape-level change appears to be associated with the widespread use of genetically modified herbicide resistant crops that have rapidly come to dominate the extensive core summer breeding range. We dismiss misinterpretations of the apparent lack of population change in summer adult count data as logically flawed. Glyphosate-tolerant soybean and maize have enabled the extensive use of this herbicide, generating widespread losses of milkweed (Asclepias spp.), the only host plants for monarch larvae. Modeling studies that simulate lifetime realized fecundity at a landscape scale, direct counts of milkweeds, and extensive citizen science data across the breeding range suggest that a herbicide-induced, landscape-level reduction in milkweed has precipitated the decline in monarchs. A recovery will likely require a monumental effort for the re-establishment of milkweed resources at a commensurate landscape scale.


Asia-Pacific ICEMR: Understanding Malaria Transmission to Accelerate Malaria Elimination in the Asia Pacific Region.
Gaining an in-depth understanding of malaria transmission requires integrated, multifaceted research approaches. The Asia-Pacific International Center of Excellence in Malaria Research (ICEMR) is applying specifically developed molecular and immunological assays, in-depth entomological assessments, and advanced statistical and mathematical modeling approaches to a rich series of longitudinal cohort and cross-sectional studies in Papua New Guinea and Cambodia. This is revealing both the essential contribution of forest-based transmission and the particular challenges posed by Plasmodium vivax to malaria elimination in Cambodia. In Papua New Guinea, these studies document the complex host-vector-parasite interactions that are underlying both the stunning reductions in malaria burden from 2006 to 2014 and the significant resurgence in transmission in 2016 to 2018. Here we describe the novel analytical, surveillance, molecular, and immunological tools that are being applied in our ongoing Asia-Pacific ICEMR research program.


The moral domain of the medical record: the routine ethics evaluation.
The structure, content, and orientation of the contemporary medical record inadequately reflect the appropriate influence of patients' rights and bioethics on health care. Most tellingly, the medical chart reveals a remarkable absence of attention to medical ethics, except in the case of crisis management. But medical ethics informs both crisis decision-making and virtually all clinical interventions. Indeed, clinical care embodies a complex array of choices influenced by individual and cultural values, themselves reflecting religious beliefs, personal histories, psychologies, and social mores. But the typical medical chart, which records clinical descriptions, analyses, and rationales for treatment, rarely identifies or accounts for this value-laden dimension of care and thus both over-simplifies and distorts the depiction of a patient's illness and its treatment. To better reflect the complex moral domain of clinical care, and assist in organizing its complex structure, a systematic procedure is proposed here to evaluate the ethical status of every patient: As a routine part of the clinical evaluation, in a designated Ethical Concerns section of the medical record, an "ethics work-up' is designed to serve as a moral 'diagnostic' analogous to its scientific counterpart. Adapted to the needs of individual patients, such evaluations should identify ethical problems, coordinate related data, resources, and opinion, and define the rationale for choices made and actions pursued. In establishing improved integration of the 'epistemologies' of care and the 'ethics' of care, the goals of a more humane, patient-centered medicine may be better met.


Predictive gender and education bias in Kessler's psychological distress Scale (k10).
Kessler's Psychological Distress Scale (K10) is a ten-item measure of psychological distress that has been used in recent epidemiological research and as a screen for mental disorders. Moderate relationships have been reported between the K10 and measures of related constructs, such as diagnoses of mental disorders and associated disability. However, it is unclear whether the validity of the K10 is consistent across important demographic, cultural, and socio-economic groups such as gender and educational history or whether there is evidence of predictive bias or inconsistency across these groups. Differential validity or predictive bias in the relationship between K10 scores and disability days, SF12 Mental Component Summary (MCS) scores, and 1-month Composite International Diagnostic Interview (CIDI) diagnoses of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Anxiety and Depressive disorders due to gender and completing secondary school were examined using hierarchical linear and logistic regression analyses in the Australian National Survey of Mental Health and Wellbeing data set. Very small slope and/or intercept biases in the relationship between the K10 and disability days, the SF12 MCS, and 1-month CIDI diagnoses of anxiety and depression were found [effect sizes, the ratio of variance explained to unexplained variance (Cohen's f2), varied from 0.0001 to 0.004]. Gender and educational predictive biases in the relationship between the K10 and disability days, SF12 MCS, and 1-month diagnoses were found to be very small and are unlikely to have any practical impact. This analysis adds to evidence supporting the use of the K10 in epidemiological research.


Radiography of the wrist. A new device for standardized radiographs.
A number of methods exist for determination of carpal bone angles on lateral wrist radiographs. However, there is no general or precise definition of the angles measured. In this study the positioning of the wrist is emphasized and a device used to obtain standardized radiographs is presented. An analysis of variance of two series of patients revealed no radiological difference between the contralateral wrists in the same person. We conclude that the asymptomatic wrist can be used as normal reference in the assessment of carpal bone angles in the pathological wrist and a difference between the carpal bone angles in the two wrists in the same person exceeding 5 degrees can be considered significant.


Did Health Care Reform Help Kentucky Address Disparities in Coverage and Access to Care among the Poor?
To evaluate the impact of Kentucky's full rollout of the Affordable Care Act on disparities in access to care due to poverty. Restricted version of the Behavioral Risk Factor Surveillance System (BRFSS) for Kentucky and years 2011-2015. We use a difference-in-differences framework to compare trends before and after implementation of the Affordable Care Act (ACA) in health insurance coverage, several access measures, and health care utilization for residents in higher versus lower poverty ZIP codes. Much of the reduction in Kentucky's uninsured rate appears driven by large uptakes in coverage from areas with higher concentrations of poverty. Residents in high-poverty communities experienced larger reductions, 8 percentage points (pp) in uninsured status and 7.5 pp in reporting unmet needs due to costs, than residents of lower poverty areas. These effects helped remove pre-ACA disparities in uninsured rates across these areas. Because we observe positive effects on coverage and reductions in financial barriers to care among those from poorer communities, our findings suggest that expanding Medicaid helps address the health care needs of the impoverished.


Characterization of a major histocompatibility complex class I antigen-binding glycoprotein from adenovirus type 35, a type associated with immunocompromised hosts.
Adenovirus type 35 (Ad35) is a group B adenovirus that has been isolated primarily from patients with acquired immunodeficiency syndrome and other immunodeficiency disorders. We have studied the interaction of this unique adenovirus with the immune system by analyzing Ad35 early viral proteins in infected HeLa cells. We have identified a 29,000-Mr Ad35 early glycoprotein, E29, which associates with class I antigens of the major histocompatibility complex (MHC) in the endoplasmic reticulum. Ad35 E29 is analogous to the group C Ad2 early glycoprotein E3-19K (E19), which has been shown to interfere with the expression of class I antigens on the cell surface (H. Burgert and S. Kvist, Cell 41:987-997, 1985). In contrast to the Ad2 glycoprotein, Ad35 E29 was synthesized in much smaller amounts, was more extensively glycosylated, and did not cross-react with polyclonal antibody against the Ad2 protein. As a control, a class I antigen-binding glycoprotein from another group B adenovirus, Ad7, was also characterized and was found to have properties similar to those of Ad35 E29. Therefore, the differences in the glycosylation and quantity of class I antigen-binding glycoproteins between Ad35 and Ad2 are group related. Inhibition of the expression of MHC class I antigens, which are needed for cytotoxic-T-lymphocyte recognition of virus-infected cells, appears to play a vital role in the adenovirus life cycle in vivo. Our data indicate that this function has been conserved despite significant differences in the MHC class I antigen-binding glycoprotein and in the pathogenicity between serotypes.


Estimating Components of Univariate Gaussian Mixtures Using Prony's Method.
A new technique for estimating the component parameters of a mixture of univariate Gaussian distributions using the method of moments is presented. The method of moments basically involves equating the sample moments to the corresponding mixture moments expressed in terms of component parameters and solving these equations for the unknown parameters. These moment equations, however, are nonlinear in the unknown parameters, and heretofore, an analytic solution of these equations has been obtained only for two-component mixtures [2]. Numerical solutions also tend to be unreliable for more than two components, due to the large number of nonlinear equations and parameters to be solved for. In this correspondence, under the condition that the component distributions have equal variances or equal means, the nonlinear moment equations are transformed into a set of linear equations using Prony's method. The solution of these equations for the unknown parameters is analytically feasible and numerically reliable for mixtures with several components. Numerous examples using the proposed technique for two-, three-, and four-component mixtures are presented.


Pediatric Minoxidil Exposures Reported to Texas Poison Centers.
It has been suggested that ingestion of even small amounts of minoxidil by young children may result in serious adverse effects. The intent of this study was to describe pediatric minoxidil exposures reported to a statewide poison center system. Cases were minoxidil exposures among patients 5 years or younger reported to Texas poison centers during 2000 to 2014. The distribution by various demographic and clinical factors was determined. Of 125 total cases, 58% were male and 78% aged 1 to 2 years. Ingestion alone was reported in 92% of the exposures. Ninety-eight percent of the exposures were unintentional, and 94% occurred at the patient's own residence. Sixty-two percent of the patients were managed on site. The outcome was not serious (no effect, minor effect, not followed [nontoxic], not followed [minimal effects]) in 88% of the exposures. The most common adverse effect was vomiting, reported in 8% of the exposures. The most common treatments were dilution/irrigation/wash (53%), activated charcoal (18%), food/snack (17%), and intravenous fluids (8%). Few pediatric minoxidil exposures were reported to Texas poison centers. Of these exposures, most involved ingestion, were unintentional, and involved patients who were male and aged 1 to 2 years. Although it has been suggested that pediatric minoxidil ingestions might result in serious adverse effects, this study suggests that most pediatric minoxidil exposures reported to poison centers are not likely to have serious outcomes and may be managed at home.


Evaluation of intraoperative scrape cytology for sentinel lymph node biopsy in patients with breast cancer.
The techniques for intraoperative evaluation of sentinel lymph nodes (SLNs) vary. The most common methods include frozen section, imprint cytology/touch preparation cytology, and scrape cytology (SC). The purpose of this study was to evaluate whether there is concordance between the intraoperative SC and the final pathology of SLNs in patients with breast cancer. From October 2001 to June 2005, sentinel lymph node biopsies were attempted in 181 patients with breast cancer using a combination of blue dye and radioisotope. A lymph node was considered an SLN when it was stained with blue dye, had a blue lymphatic afferent, had increased radioactivity, or was abnormal by palpation. SLNs were successfully identified in 180 patients, for an identification rate of 99.4%. Forty-five patients had positive SLNs. In 16 (35%) of those patients, the SLNs were negative intraoperatively by SC. All of the false negatives occurred in SLNs with micrometastases. Thus, SC is an excellent method for identifying macrometastases intraoperatively, but less successful for micrometastases.


Reliability and Validity of the Kannada Version of the Consensus Auditory-Perceptual Evaluation of Voice.
Purpose The purpose of this study was to evaluate the reliability and validity of the Kannada version of the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V). Method The Kannada version of CAPE-V comprises six phrases that are phonetically designed as per the CAPE-V requirements. Sixty-five (21 individuals with dysphonia and 44 asymptomatic) participants were enrolled for the instrument psychometric validation. The interrater and intrarater reliability as well as validity were assessed. Results High level of agreement was noted between the three raters across all the CAPE-V parameters, highest for pitch (intraclass correlation coefficient value = .98) and lowest for loudness (intraclass correlation coefficient value = .96). High intrarater reliability agreement (intraclass correlation coefficient value > .97) was also noted for all the parameters. Among the correlation for parameters that are comparable between CAPE-V and the Grade, Roughness, Breathiness, Asthenia, and Strain scale, the highest correlation was noted for overall severity. There was a significant difference noted between the study and control groups for all parameters except loudness. The discriminant function analysis and classification revealed that 98% were correctly identified. Conclusion The Kannada version of CAPE-V has been proven to be a psychometrically reliable and valid tool to use for auditory-perceptual evaluation of voice.


Staging and therapy of chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease. Some patients require no therapy and have prolonged survival. Others have brief survival despite intensive treatment. Several staging systems have been developed. These are useful in predicting outcome and need of therapy, but controversies exist. Additional prognostic factors have been identified such as cytogenetics, lymphocyte levels or doubling time, bone marrow morphology, and others. Patients with low-stage CLL have not been shown to benefit from treatment. In patients with intermediate disease, combination chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) has not been shown to be superior to chlorambucil with or without prednisone. The therapy of high stage CLL is controversial; therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) may be superior to CVP. Future directions of therapeutic research include the treatment of patients with low stage disease, more precise identification of patients requiring therapy, and more precise definition of therapeutic response.


Evaluation of MucorGenius® mucorales PCR assay for the diagnosis of pulmonary mucormycosis.
We aimed to assess the clinical relevance of the marketed pan-mucorales real-time PCR assay MucorGenius® (Pathonostics) on pulmonary specimens relative to that of in-house PCR assays and conventional mycology for the diagnosis of mucormycosis. In total, 319 pulmonary samples from severely immunosuppressed patients at risk for invasive mold disease (IMD) were retrospectively included. Direct examination, mycological culture, and PCR testing were performed using three genus-specific in-house mucorales real-time PCR assays and MucorGenius®PCR. Results from Aspergillus testing, including galactomannan and PCR, were also collected. The 319 patients were graded according to modified EORTC-MSG criteria as proven/probable mucormycosis (n=6), proven/probable invasive aspergillosis (IA) (n=63), Aspergillus-mucorales co-infections (n=4), possible IMD (n=152), and excluded IMD (n=94). The in-house and MucorGenius®PCR assays were positive for 33 (10.3%) and 27 (8.5%) samples, respectively, whereas culture was positive for only 10 (3.1%). The in-house and MucorGenius®PCR assays showed a sensitivity of 100% (10/10) and 90% (9/10) and a specificity of 95.7% and 97.9%, respectively. Both PCR assays allowed the detection of mucorales DNA in samples from 10 possible cases and six IA, all missed by culture. MucorGenius® showed good performance, despite missing some low fungal burden. Combining mucorales PCR with EORTC-MSG criteria greatly improved the diagnosis of mucormycosis.


Genetic deficiency of human mast cell alpha-tryptase.
Human alpha- and beta-tryptases are proteases secreted by mast cells. Beta (but not alpha) tryptases are implicated in asthma. Genes encoding both types of tryptases cluster on chromosome 16p13.3. This study examines the hypothesis, generated from mapping data, that alpha-alleles compete with some beta-alleles at one locus and that an adjacent locus contains beta-alleles exclusively. This hypothesis predicts that beta-alleles outnumber alpha and that some genomes lack alpha genes altogether. To test this hypothesis, we developed PCR-based techniques to distinguish alpha from beta genes. We then genotyped genomic DNA from individuals and tryptase-expressing cell lines. In support of our hypothesis, we find that alpha-tryptase deficiency affects 80/274 (29%) of individuals surveyed. The genotype of the alpha-deficient individuals is betabetabetabeta, due to inheritance of four beta genes. The percentage of the population with the mixed genotypes alphaalphabetabeta and alphabetabetabeta is 21% and 50%, respectively. Accounting for all alpha- and beta-alleles at the tandem loci on 16p13.3, overall alpha-allele frequency is only 0.23, with beta-alleles considerably outnumbering alpha as hypothesized. In samples of defined ethnicity, alpha deficiency affects 45% of Caucasians, but a much lower percentage of other backgrounds, including African-Americans and Asians. Examination of cell lines reveals that HMC-1 and U-937 lack alpha-genes; thus, lack of alpha transcripts in these cells is due to absence of alpha-genes rather than beta-selective transcription. By contrast, alpha-transcribing Mono Mac 6 and KU812 cells contain alpha- and beta-genes. Genetic alpha-tryptase deficiency is common and varies strikingly between ethnic groups. Because beta-tryptases are implicated in allergic disorders, inherited differences in alpha/beta-genotype may affect disease susceptibility, severity and response to tryptase inhibitor therapy.


Identification and prediction of group-based glycemic control trajectories during the transition to adolescence.
To identify trajectories of glycemic control over a period of 3 years in a pediatric sample of youth diagnosed with Type 1 diabetes transitioning to adolescence. A second aim was to examine a set of modifiable individual and family level baseline predictors of glycemic control group membership. This multisite, prospective study included 239 children and adolescents (ages 9-11 years at baseline) diagnosed with Type 1 diabetes and their caregivers. Glycemic control was based on hemoglobin A1c (HbA1c) collected at 6-month intervals over a period of 3 years. Predictors of glycemic control membership included baseline global executive functioning, diabetes self-management, diabetes-specific family conflict, blood glucose monitoring frequency, and relevant individual and family level covariates. Group-based trajectory analyses were used to describe patterns of glycemic control from baseline to 36 months and 3 trajectories were identified: low risk (42.9%), elevated risk (44.6%), and high risk (12.1%) subgroups. Baseline maternal-reported family conflict, blood glucose monitoring frequency, and gender were significant predictors of glycemic control group membership. Higher levels of baseline family conflict, lower frequency of blood glucose monitoring, and female gender were associated with elevated and high-risk group membership. These findings underscore the importance of examining trajectories of HbA1c across time. These results suggest that problematic trajectories of glycemic control are evident during the transition to adolescence. Furthermore, there are modifiable individual and family level characteristics that predict group membership and hence could be targeted in interventions to ensure adequate glycemic control is maintained over time and that risks for diabetes-related complications are reduced.


Mechanisms and potential molecular markers of early response to combination epigenetic therapy in patients with myeloid malignancies.
Combination epigenetic treatment (EGT) utilizing DNA methyl transferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) may be more efficacious than single agent treatment in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The molecular mechanisms behind the potential clinical efficacy of combination EGT treatment are incompletely understood and the frequently lengthy EGT regimes required to determine clinical response have generated a significant demand for early molecular markers of treatment response. Our study aimed to identify the effect of combination azacitidine (AZA) and panobinostat (LBH589) on expression levels of a panel of genes implicated in the pathogenesis of high-risk MDS or AML in HL-60 cells. We also characterized gene expression profiles in peripheral blood mononuclear (PBMCs) from patients in a recently reported phase Ib/II clinical trial using the combination of AZA and LBH589 and correlated these findings with clinical response to treatment. In vitro analysis demonstrated increased expression of caspase-3, Nor-1, NUR77, p15INK4B and p21WAF1/CIP1 and decreased expression of Bcl‑xL in HL-60 cells treated with combination EGT. Analysis of patient samples prior to treatment demonstrated a significant reduction in NUR77 and p21WAF1/CIP1 expression compared to healthy controls. NUR77 and p21WAF1/CIP1 levels were similar between treatment non‑responders and responders at screening. Early post first cycle treatment (day 25) analysis demonstrated a significant increase in expression of both NUR77, and p21WAF1/CIP1. A significant increase in NUR77, and p21WAF1/CIP1 together with a trend to increase in p15INK4B first cycle expression was observed in treatment responders compared to non-responders. In summary, combination AZA and LBH589 epigenetic treatment is associated with in vitro and in vivo modulation of genes implicated in the pathogenesis of MDS/AML. Early expression of NUR77 and p21WAF1/CIP1 correlated with clinical response to combination EGT suggesting investigation for potential use as molecular markers of early treatment response may be warranted.


Determination of heterocyclic aromatic amines in human urine by using hollow-fibre supported liquid membrane extraction and liquid chromatography-ultraviolet detection system.
A hollow-fibre supported liquid membrane (HF-SLM) extraction method has been developed for determination of 11 heterocyclic aromatic amines (HCAs) in human urine samples by using high performance liquid chromatography (HPLC) equipped with an ultraviolet (UV) absorbance detector. These compounds were extracted from an alkaline urine sample (donor phase) into the organic solvent residing in the pores of a polypropylene hollow fibre and then back extracted into an acidic solution (acceptor phase) inside the lumen of the hollow fibre. After extraction, HCAs were analyzed by injecting the analyte enriched acceptor phase into the HPLC. The analyte enrichment factors ranged between 241 and 339 obtained in a 90 min extraction time, and method detection limits (MDL) ranged between 0.1 and 0.5 microg L(-1) with relative standard deviation (RSD) values between 3.4% and 11%. The extraction technique employed in this work is easy to use and rapid as it involves only a few minutes manipulation of each sample. It is the most economical sample preparation/preconcentration technique to our knowledge as compared to other microextraction techniques.


Isofagomine lactams, synthesis and enzyme inhibition.
The synthesis of isofagomine lactams (2-oxoisofagomines) corresponding to the biologically important hexoses is presented. The D-glucose/D-mannose analogue (3S,4R,5R)-3,4-dihydroxy-5-hydroxymethylpiperidin-2-one (9) was synthesised in 9 steps from D-arabinose, the D-galactose analogue (3S,4S,5R)-3,4-dihydroxy-5-hydroxymethylpiperidin-2-one (10) was synthesised in 11 steps from D-arabinose and the L-fucose analogue (3R,4R,5R)-3,4-dihydroxy-5-methylpiperidin-2-one (11) was synthesised in 12 steps from L-arabinose. The three lactams 9-11 were found to be glycosidase inhibitors with micro- to nanomolar inhibition constants. The lactam 10 showed slow onset inhibition of beta-galactosidase from A. Oryzae. The rate constants for this process were determined to be k(on) = 2.55 x 10(4) M-1 s-1 and k(off) = 1.7 x 10(-3) s-1. The activation energies and standard thermodynamic functions were also determined.


Synaptic connections of relay and local circuit neurons in the monkey's dorsal lateral geniculate nucleus.
The synaptic inputs to a single neuron's dendritic tree can be analyzed using electronmicroscopic reconstructions after intracellular injections of horseradish peroxidase. In the monkey's dorsal lateral geniculate nucleus, the proximal dendrites of magnocellular and parvocellular relay cells received retinal synapses and inhibitory synapses, while the intermediate and distal dendrites received cortical synapses. A local circuit neuron had both similar synaptic inputs and similar physiology to parvocellular relay neurons, but additionally had presynaptic dendrites and no axon. These results provide a wiring diagram for the neuronal types in this nucleus.


Cdc6 protein causes premature entry into S phase in a mammalian cell-free system.
We exploit an improved mammalian cell-free DNA replication system to analyse quiescence and Cdc6 function. Quiescent 3T3 nuclei cannot initiate replication in S phase cytosol from HeLa or 3T3 cells. Following release from quiescence, nuclei become competent to initiate semiconservative DNA replication in S phase cytosol, but not in G0 phase cytosol. Immunoblots show that quiescent cells lack Cdc6 and that minichromosome maintenance (MCM) proteins are not associated with chromatin. Competence of G1 phase nuclei to replicate in vitro coincides with maximum Cdc6 accumulation and MCM protein binding to chromatin in vivo. Addition of recombinant Cdc6 to permeabilized, but not intact, G1 nuclei causes up to 82% of the nuclei to initiate and accelerates G1 progression, making nuclei competent to replicate prematurely.


Comparison of dendritic calcium transients in juvenile wild type and SOD1(G93A) mouse lumbar motoneurons.
Previous studies of spinal motoneurons in the SOD1 mouse model of amyotrophic lateral sclerosis have shown alterations long before disease onset, including increased dendritic branching, increased persistent Na(+) and Ca(2+) currents, and impaired axonal transport. In this study dendritic Ca(2+) entry was investigated using two photon excitation fluorescence microscopy and whole-cell patch-clamp of juvenile (P4-11) motoneurons. Neurons were filled with both Ca(2+) Green-1 and Texas Red dextrans, and line scans performed throughout. Steps were taken to account for different sources of variability, including (1) dye filling and laser penetration, (2) dendritic anatomy, and (3) the time elapsed from the start of recording. First, Ca(2+) Green-1 fluorescence was normalized by Texas Red; next, neurons were reconstructed so anatomy could be evaluated; finally, time was recorded. Customized software detected the largest Ca(2+) transients (area under the curve) from each line scan and matched it with parameters above. Overall, larger dendritic diameter and shorter path distance from the soma were significant predictors of larger transients, while time was not significant up to 2 h (data thereafter was dropped). However, Ca(2+) transients showed additional variability. Controlling for previous factors, significant variation was found between Ca(2+) signals from different processes of the same neuron in 3/7 neurons. This could reflect differential expression of Ca(2+) channels, local neuromodulation or other variations. Finally, Ca(2+) transients in SOD1(G93A) motoneurons were significantly smaller than in non-transgenic motoneurons. In conclusion, motoneuron processes show highly variable Ca(2+) transients, but these transients are smaller overall in SOD1(G93A) motoneurons.


Ginger Extract Decreases Susceptibility to Dextran Sulfate Sodium-Induced Colitis in Mice Following Early Antibiotic Exposure.
Background: Intestinal microbial colonization in early life plays a crucial role in immune development and mucosal homeostasis in later years. Antibiotic exposure in early life increases the risk of inflammatory bowel disease (IBD). Ginger acts like a prebiotic and has been used in traditional Chinese medicine for colitis. We investigated the protective effect of ginger against dextran sulfate sodium (DSS)-induced colitis in mice exposed to antibiotic in their early years. Methods: A weaned mouse model exposed to azithromycin (AZT) for 2 weeks was used to mimic antibiotic exposure in childhood among humans. A diet containing ginger extract was administered to mice for 4 weeks after antibiotic exposure. The susceptibility to DSS-induced colitis was evaluated in terms of weight loss, disease activity index (DAI) score, colon length, colitis biomarkers, and intestinal barrier function. The gut microbiota was analyzed in terms of 16S rRNA levels. Results: Ginger extract prevented weight loss, colon shortening, inflammation, and intestinal barrier dysfunction in mice exposed to antibiotics in early life. Ginger increased the bacterial diversity and changed the abundance of bacterial belonging to family Peptococcaceae and Helicobacter species to modulate microbiota structure and composition adversely affected by early antibiotic exposure. Conclusion: Ginger has a protective effect in potentially decreasing the susceptibility to colitis in mice exposed to antibiotics early in life.


Use of a nonnegative constrained principal component regression chemical mass balance model to study the contributions of nearly collinear sources.
In this study, a nonnegative constrained principal component regression chemical mass balance (NCPCRCMB) model was used to solve the near collinearity problem among source profiles for source apportionment. The NCPCRCMB model added the principle component regression route into the CMB model iteration. The model was tested with the synthetic data sets, which involved contributions from eleven actual sources, with a serious near collinearity problem among them. The actual source profiles were randomly perturbed and then applied to create the synthetic receptor. The resulting synthetic receptor concentrations were also randomly perturbed to simulate measurement errors. The synthetic receptors were separately apportioned by CMB and NCPCRCMB model. The result showed that source contributions estimated by the NCPCRCMB model were much closer to the true values than those estimated by the CMB model. Next, five real ambient data sets from five cities in China were analyzed using the NCPCRCMB model to test the model practicability. Reasonable results were obtained in all cases. It is shown that the NCPCRCMB model has an advantage over the traditional CMB model when dealing with near collinearity problems in source apportionment studies.


Vitamin B12Co-60 readily passes the placenta into fetal organs and nursing provides B12 from mother to pup. A record of its distribution.
The placenta is permeable to B(12)Co(60). Together with salts, sugar, amino acids, vitamins, and proteins, the B(12) is contributed to the growing embryos from the mother's body stores. At birth, the placenta contains a liberal amount of B(12), which the mother regains by ingestion of the placentas. Nursing draws a liberal amount of B(12)Co(60) from the mother's stores and contributes it to the body of the pups where it is absorbed and distributed in the various organs, much as noted when adult dogs are injected with B(12)Co(60). A redistribution is noted as the months pass; but the high values in the heart, liver, and gastric mucosa persist, and the brain usually shows a slow increase. Enterohepatic circulation of B(12) may involve bile and enteric content plus hepatic, gastric, and pancreatic epithelial secretion. This type of body recycling of radioactive B(12) is discussed but not proven. High values of B(12) in the heart, brain, gastric mucosa, and liver indicate that the vitamin is functionally active, not an inert fraction.


Molecular regulation of gonadotropin secretion by gonadotropin-releasing hormone in salmonid fishes.
Gonadotropin-releasing hormone (GnRH) plays a central role in the control of reproductive function in vertebrates. In salmonids, salmon GnRH (sGnRH) secreted by preoptic GnRH neurons regulates gonadal maturation through stimulation of synthesis and release of pituitary gonadotropins (GTHs). In addition, several lines of our evidence indicate that sGnRH is involved in spawning behavior, and serves to integrate the gonadal maturation with the reproductive behavior. A growing number of studies show that the effects of GnRH are mediated by multiple subtypes of GnRH receptors, successive multiple signaling pathways, and finally multiple transcription factors which act cooperatively to stimulate transcription of GTH subunit genes. This complex regulatory system of the action of GnRH may serve as a molecular basis of divergent physiological strategies of reproductive success in various vertebrate species. In this article, recent data on the molecular mechanisms of action of GnRH are reviewed with special reference to the regulation of synthesis and release of GTHs in the pituitary of salmonids to elucidate the multifunctional action of GnRH.


Alcohol use in Hawaii.
This article provides a review of the existing literature on alcohol use in Hawaii (i.e., epidemiology, reasons for use, associated problems, and intervention) and offers clinical implications of the findings and suggestions for further areas of research. In general, Caucasians, Hawaiians, younger Filipinos, males, adolescents, young adults, and those with lower educational attainment were found to be at higher risk. Overall, Hawaii's rates were either comparable or lower than those for the entire United States. Factors associated with different rates of alcohol use included accessibility, ability to resist offers, parent use and sanctions, peer influence and use, attitudes and beliefs (e.g., perceived normal drinking, dangerousness), religious affiliation, social occasions, and school intervention. Variable rates and trends in help-seeking behaviors, treatment admissions, and treatment utilization reflected the socio-cultural diversity in Hawaii. Perceived effectiveness of different treatments were generally consistent across ethnic groups, but did not necessarily represent actual efficacy. There is a clear need for additional prevention, screening, and intervention programs in Hawaii, including socio-culturally appropriate ones, as well as a need for further research.


Correlation between magnetic resonance imaging and histopathological tumor response after neoadjuvant chemotherapy in breast cancer.
To evaluate the accuracy of magnetic resonance imaging in assessing tumor response following neoadjuvant chemotherapy in patients with locally advanced breast cancer. Twenty-six patients entered a phase II study of neoadjuvant chemotherapy, undergoing bilateral breast magnetic resonance imaging before therapy and before surgery. Tumor response was classified using RECIST criteria, using tumor size at magnetic resonance imaging. The latter was then compared to residue found at histopathological examination. Magnetic resonance imaging showed 6 (23%) complete responses, 17 (65%) partial responses, 3 (11.5%) disease stabilizations and no disease progressions. Twenty-three tumors (88.5%) were considered responsive and 3 (11.5%) unresponsive. Pathological tumor response was: 6 complete responses (23%), 17 partial responses (65%), 2 stable disease (8%), 1 progression (4%). When results of the preoperative magnetic resonance imaging were compared to pathological tumor response, magnetic resonance imaging overestimated tumor size in 12 cases (46%) and underestimated it in 9 (35%). However, preoperative magnetic resonance imaging failed to detect invasive tumor in 2 false-negative cases (8%), 1 of which was multifocal. Mastectomy was performed in 12 cases: 1 case of disease progression even though the neoplasm appeared smaller at magnetic resonance imaging, 3 cases with stable disease, and 4 cases with T3 or T4 disease. The 9th patient was T2N2 with initial retroareolar disease and negative magnetic resonance imaging after chemotherapy. The 10th patient, affected by lobular cancer, was in partial remission but was T3N1. The 11th patient was 57 years old but was not interested in conservative surgery. The 12th patient requested bilateral prophylactic mastectomy due to her positive family history of breast cancer. Magnetic resonance imaging of the breast allowed conservative surgery in 54% of the patients. This low value is primarily due to overestimation of tumor size, with a negative predictive value of 67% in our population. However, surgeons were able to choose conservative surgery with relative safety in cases of small residual disease.


An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge.
Molecular dynamics (MD) has become increasingly popular due to the development of hardware and software solutions and the improvement in algorithms, which allowed researchers to scale up calculations in order to speed them up. MD simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile analysis over time. In recent years, the development of new tools able to deeply explore a potential energy surface (PES) has allowed researchers to focus on the dynamic nature of the binding recognition process and binding-induced protein conformational changes. Moreover, modern approaches have been demonstrated to be effective and reliable in calculating some kinetic and thermodynamic parameters behind the host-guest recognition process. Starting from all of these considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug discovery. Knowledge retrieved from MD can, in fact, be exploited as a starting point to build pharmacophores or docking constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden binding modes and help the optimisation of the molecular structure of a lead compound. Based on these outcomes, researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable binding sites, including protein-protein interactions and allosteric sites on a protein surface. As a matter of fact, the use of MD has been recognised as vital to the discovery of selective protein-protein interaction modulators. The use of a dynamic overview on how the host-guest recognition occurs and of the relative conformational modifications induced allows researchers to optimise small molecules and small peptides capable of tightly interacting within the cleft between two proteins. In this review, we aim to present the most recent applications of MD as an integrated tool to be used in the rational design of small molecules or small peptides able to modulate undruggable targets, such as allosteric sites and protein-protein interactions.


Long-term outcomes after deep vein thrombosis: postphlebitic syndrome and quality of life.
In this review, we critically assess the literature on the incidence of postphlebitic syndrome, risk factors for its occurrence, available therapeutic options, and its effects on quality of life. As well, we describe available tools to measure postphlebitic syndrome. Recent prospective studies indicate that postphlebitic syndrome, a chronic, potentially disabling condition characterized by leg swelling, pain, venous ectasia, and skin induration, is established by 1 year after deep vein thrombosis (DVT) in 17% to 50% of patients. The only prospectively identified risk factor for its occurrence is recurrent ipsilateral DVT. In the sole randomized study available, daily use of elastic compression stockings after proximal DVT reduced the incidence of postphlebitic syndrome by 50%. Treatment options for established postphlebitic syndrome are limited, but include compression stockings and intermittent compressive therapy with an extremity pump for severe cases. To date, quality of life after DVT has received little attention in the literature. The recent development of the VEINES-QOL questionnaire, a validated venous-disease-specific measure of quality of life, should encourage researchers to include quality of life as a routine outcome measure after DVT. There is no criterion standard for the diagnosis of postphlebitic syndrome, but a validated clinical scoring system does exist. More research on postphlebitic syndrome is needed to enable us to provide DVT patients with comprehensive, evidence-based information regarding their long-term prognosis, to help quantify the prevalence and health care burden of postphlebitic syndrome, and by identifying predictors of poor outcome, to develop new preventive strategies in patients at risk of developing this condition.


SIA: a scalable interoperable annotation server for biomedical named entities.
Recent years showed a strong increase in biomedical sciences and an inherent increase in publication volume. Extraction of specific information from these sources requires highly sophisticated text mining and information extraction tools. However, the integration of freely available tools into customized workflows is often cumbersome and difficult. We describe SIA (Scalable Interoperable Annotation Server), our contribution to the BeCalm-Technical interoperability and performance of annotation servers (BeCalm-TIPS) task, a scalable, extensible, and robust annotation service. The system currently covers six named entity types (i.e., chemicals, diseases, genes, miRNA, mutations, and organisms) and is freely available under Apache 2.0 license at https://github.com/Erechtheus/sia .


Time-dependent probability distribution for number of infection in a stochastic SIS model: case study COVID-19.
We derive the time-dependent probability distribution for the number of infected individuals at a given time in a stochastic Susceptible-Infected-Susceptible (SIS) epidemic model. The mean, variance, skewness, and kurtosis of the distribution are obtained as a function of time. We study the effect of noise intensity on the distribution and later derive and analyze the effect of changes in the transmission and recovery rates of the disease. Our analysis reveals that the time-dependent probability density function exists if the basic reproduction number is greater than one. It converges to the Dirac delta function on the long run (entirely concentrated on zero) as the basic reproduction number tends to one from above. The result is applied using published COVID-19 parameters and also applied to analyze the probability distribution of the aggregate number of COVID-19 cases in the United States for the period: January 22, 2020-March 23, 2021. Findings show that the distribution shifts concentration to the right until it concentrates entirely on the carrying infection capacity as the infection growth rate increases or the recovery rate reduces. The disease eradication and disease persistence thresholds are calculated.


The Paradox of Bone Formation and Bone Loss in Ankylosing Spondylitis: Evolving New Concepts of Bone Formation and Future Trends in Management.
The purpose of the study is to briefly review the molecular mechanisms that leads to structural damage in ankylosing spondylitis (AS), defined as new bone formation resulting in complete or incomplete ankylosis of the spine, and the impact of treatment with biologics to retard this process. The understanding of molecular mechanisms leading to new bone formation in AS has significantly improved but is still incomplete. Availability of biologics has greatly enhanced the treatment of patients with AS, but its impact on slowing the structural damage is still a matter of debate, although a few observational studies have shown that long term use of TNF-α blockers may slow radiographic progression. The availability of newer biologics targeting IL-17/1L23 has shown some promising results in slowing radiographic progression in AS. Although the availability of TNF-inhibitors has greatly enhanced the treatment options for patients with AS, their impact on slowing the structural damage is still not clearly established. However, preliminary results using newer biologics targeting IL-17/1L23 axis are more encouraging but longer follow-up is needed.


Varenicline effects on cocaine self administration and reinstatement behavior.
This study tested the effects of the nicotine addiction treatment varenicline on cocaine self administration (SA) and reinstatement. In one SA experiment, rats were trained to self-administer cocaine (0.75 mg/kg/infusion). Thereafter, daily SA sessions continued as before except that every fourth session was preceded by a presession injection of varenicline (0.0, 0.3, 1.0 and 2.0 mg/kg, SC, 50-min presession). In three reinstatement experiments, animals were exposed sequentially to SA training, extinction training, and several reinstatement test sessions. In two of the reinstatement experiments, cocaine-seeking was reinstated by presentation of cocaine-predictive cues at the onset of the test session (cue reinstatement). In a third reinstatement experiment, cocaine-seeking was reinstated by a presession injection of cocaine (drug reinstatement). Each reinstatement session was preceded by an injection of either vehicle or varenicline (dose range of 0.1-2.0 mg/kg). The SA and reinstatement experiments showed that low-dose varenicline decreases reinstatement behavior, without significantly affecting cocaine SA. In contrast, high-dose varenicline increases reinstatement of cocaine-directed behavior and decreases cocaine SA. A control study showed that sucrose-directed behavior is unaltered by varenicline. On the basis of these findings, low-varenicline doses might decrease relapse in cocaine-addicted individuals, but high doses of varenicline might have the opposite effect.


Using two preferred retinal loci for different lighting conditions in patients with central scotomas.
Using a scanning laser ophthalmoscope, it was found that some patients with relative central scotomas reliably used two different preferred retinal loci (PRLs) at different stimulus illuminances. This article describes adaptations in a patient's PRL for fixation when dimming the stimulus increased the relative scotoma size. Twenty-eight patients with macular diseases had their dense and relative macular scotoma borders mapped with the scanning laser ophthalmoscope. The high-illuminance PRL (PRLhi) and low-illuminance PRL (PRLlo) were operationally defined as the PRLs that patients used to fixate a high or low illuminance stimulus, respectively. The PRLs' abilities to do visual tasks and their characteristics at the corresponding illuminances were assessed. The PRL consistently shifted between the PRLhi and the PRLlo as the stimulus illuminance was changed. Brightness permitting, the visual system prefers to use the PRLhi with generally better performance in visual function such as fixation stability. There were no significant differences between the PRLhi and the PRLlo in pursuit and saccadic abilities, when assessed by subjective ratings. The illuminances that induced shifting ranged from 106 to 3437 trolands. The PRLhi was always located within an area of relative scotoma, usually at the fovea or just outside a dense scotoma. The PRLlo was located in relatively healthy retinal area, and usually below or to the left of the PRLhi in the visual field. In the visual system, two well-defined PRLs can develop when visual function is adapting to maculopathy, with the use of each depending on the brightness of objects used in visual tasks. Rehabilitation and treatment strategies should consider the existence of multiple PRLs.


Factors Associated With HIV Testing Among Men in Haiti: Results From the 2012 Demographic and Health Survey.
HIV testing serves as the gateway to HIV prevention and treatment. However, research examining men's HIV testing behaviors in the Caribbean remains limited. The Andersen Behavioral Model of Health Services Utilization was used to examine factors associated with HIV testing among 7,354 men who participated in the 2012 Demographic and Health Survey conducted in Haiti. Few men (35%) reported having ever been tested for HIV. Logistic regression analyses revealed that HIV testing increased with education and wealth. Marital status was associated with HIV testing, with married men more likely to have been tested (adjusted odds ratio: 2.57, 95% CI [2.07, 3.19]) than unmarried men. Positive attitudes toward people living with HIV, indicated by willing to care for a relative who has HIV/AIDS, was also correlated with higher odds of having been tested (adjusted odds ratio: 1.28, 95% CI [1.08, 1.51]). Men who reported condom use during last sex were more likely to have been tested (odds ratio: 1.58, 95% CI [1.33, 1.88). The findings indicate that HIV testing rates remain low among men in Haiti and more efforts are needed to increase HIV testing among men who are not married, have low level of education, and engage in unprotected sex.


Halothane requirement during pregnancy and lactation in rats.
Near-term pregnancy is associated with a decrease in the minimum alveolar concentration (MAC) for halothane in ewes. Although increased progesterone levels might account for this change, a correlation between MAC and the known variations of progesterone levels which occur throughout gestation and the postpartum period has not been performed. Therefore, MAC for halothane was determined in nonpregnant, 10 days pregnant, term, and postpartum lactating rats. MAC values were significantly decreased by 19 per cent on the tenth day of pregnancy, and by 16 per cent at term, but they returned to control values 5 days postpartum. These changes did not correlate with the known changes in progesterone levels during pregnancy and lactation, and the authors conclude that progesterone is not responsible for the reduction in halothane MAC.


Evaluating consumer preferences for healthy eating from Community Kitchens in low-income urban areas: A discrete choice experiment of Comedores Populares in Peru.
Many low-income individuals from around the world rely on local food vendors for daily sustenance. These small vendors quickly provide convenient, low-priced, tasty foods, however, they may be low in nutritional value. These vendors serve as an opportunity to use established delivery channels to explore the introduction of healthier products, e.g. fresh salad and fruits, to low-income populations. We sought to understand preferences for items prepared in Comedores Populares (CP), government-supported food vendors serving low-income Peruvians, to determine whether it would be feasible to introduce healthier items, specifically fruits and vegetables. We used a best-worst discrete choice experiment (DCE) that allowed participants to select their favorite and least favorite option from a series of three hypothetical menus. The characteristics were derived from a series of formative qualitative interviews conducted previously in the CPs. We examined preferences for six characteristics: price, salad, soup, sides, meat and fruit. A total of 432 individuals, from two districts in Lima, Peru responded to a discrete choice experiment and demographic survey in 2012. For the DCE, price contributed the most to individual's utility relative to the other attributes, with salad and soup following closely. Sides (e.g. rice and beans) were the least important. The willingness to pay for a meal with a large main course and salad was 2.6 Nuevos Soles, roughly a 1 Nuevo Sol increase from the average menu price, or USD $0.32 dollars. The willingness to pay for a meal with fruit was 1.6 Nuevo Soles. Overall, the perceived quality of service and food served in the CPs is high. The willingness to pay indicates that healthier additions to meals are feasible. Understanding consumer preferences can help policy makers design healthier meals in an organization with the potential to scale up to reach a considerable number of low-income families.


Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF.
A comparison was made of the permeabilities of different neurotrophic factors at the blood-brain barrier (BBB) and blood-nerve barrier (BNB) in normal adult rats by quantifying the permeability coefficient-surface area (PS) product after correction for the residual plasma volume (Vp) occupied by the protein in the capillary bed of the nerve endoneurium or different brain regions. The i.v. bolus injection technique was used in the cannulated brachial vein and artery using the same protein radioiodinated with a second isotope of iodine (125I vs. 131I) to separately determine the PS and Vp values. The plasma washout showed a decreasing plasma half-life in the order of brain-derived neurotrophic factor (BDNF) < neurotrophin-3 (NT-3) < ciliary neurotrophic factor (CNTF) < nerve growth factor (NGF). The PS at the BNB for NGF was 1.40 +/- 0.15 x 10(-6) ml/g/s (mean +/- SEM). The other neurotrophic proteins were all significantly higher than NGF (CNTF: 9.5 x ; NT-3: 20.8 x ; BDNF: 18.9 x ). The Vp for NGF at the BNB was 1.92 +/- 0.12 microliters/g and was not significantly different from the other proteins except for NGF vs. BDNF (P < 0.05). The PS for NGF at the BBB ranged from 1.5 to 2.7 x 10(-6) ml/g/s for six different brain regions. The PS for CNTF ranged from 6.0 to 8.0-fold higher than NGF; NT-3: 10.6 to 15.2-fold higher; and BDNF: 11.3 to 16.4-fold higher. The Vp values were not significantly different except for CNTF in the hippocampus and cortex (P < 0.05). SDS-PAGE analyses of all the radioiodinated neurotrophic proteins after 60 min of uptake revealed intact protein in the endoneurium and in the six different brain regions with exposure times of 2-42 days. The quantification of the permeability of these neurotrophic proteins provides baseline values for comparison of different protein modifications that enhance the PS while still preserving the neurotrophic activity (e.g., protein glycation; Poduslo and Curran, Mol. Brain Res., 23 (1994) 157). Enhanced permeability following modification might allow the use of systematic delivery of these proteins for practical therapeutic treatment of various neurodegenerative disorders.


Routine screening for HIV in rheumatology practice.
The rheumatologic manifestations of human immunodeficiency virus (HIV) infection have been recognized since the early days of the epidemic and are characteristic of this disorder. It has been noted that the clinical spectrum of rheumatic disorders in patients with HIV infection has changed since the advent of highly active antiretroviral therapy (HAART) in the mid-1990s. Furthermore, HIV infection may become clinically apparent in rheumatic disease patients during or after they are treated with immunosuppressive therapy. The emergence of manifestations of HIV infection may develop during or after such therapy and may be confused with clinical manifestations known to be associated with the underlying rheumatic disease. In patients with established rheumatologic disease, it is difficult to consider the diagnosis of HIV especially in individuals with few or no known risk factors. In this review, we report 2 cases with established systemic rheumatic disease who developed complications originally thought to be secondary to the underlying inflammatory disorder or antirheumatic therapy. Ultimately, both patients were found to be HIV positive. Recognition of the overlapping signs or symptoms of systemic rheumatic diseases, antirheumatic therapy, and HIV infection can be lifesaving. We propose that all patients with systemic rheumatic diseases, especially those receiving or being considered for disease-modifying antirheumatic therapy, be evaluated systematically for the presence of HIV, taking into consideration the recent Centers for Disease Control and Prevention recommendations for routine opt-out HIV screening in all healthcare settings for those aged 13 to 64 years.


Surgical threshold for bicuspid aortic valve aneurysm: a case for individual decision-making.
The bicuspid aortic valve (BAV) affects 1-2% of the population and may be associated with important valvular disease and an increased risk of aortic root and/or ascending aortic aneurysm and dissection. BAV aortic aneurysm and dissection occur earlier in life than when these disorders are associated with a tricuspid aortic valve (TAV). Alterations in the aortic media and differences in aortic elastic properties and wall stress also accompany BAV aortopathy. With appropriate follow-up and timely surgery, population studies have documented a survival rate for patients with BAV no different from age-matched controls. Guidelines have previously recommended prophylactic aortic surgery at a smaller aortic aneurysm size for patients with BAV compared with aneurysms in patients with a TAV. Recent guidelines have presented differing indications regarding the appropriate timing of prophylactic surgery for BAV aneurysms, giving the recommendation for surgery when the aortic root and/or ascending aortic exceeds 5.5 cm (unless certain factors are present), the same size for which TAV-associated aortic aneurysm surgery is recommended. We review the pathophysiology of BAV aortopathy, the clinical history of BAV ascending aortic disease, areas of uncertainty and make a case for a patient-centered, individualised decision regarding the optimal timing of aortic aneurysm surgery in BAV disease.


Long-term Reliability of Diurnal Intraocular Pressure Patterns in Healthy Asians.
To determine the long-term repeatability of diurnal intraocular pressure (IOP) patterns in healthy Asian subjects without glaucoma. Twenty-three eyes in 23 healthy Asian subjects without glaucoma underwent diurnal IOP measurements using Goldmann applanation tonometry every 2 hours from 9 AM to 11 PM during two visits that were 8 weeks apart. To validate repeatability between visits, we calculated intra-class correlation coefficients (ICCs) mean IOP, peak IOP, minimum IOP, and IOP fluctuation at each time point and expressed the results as the difference between peak IOP and minimum IOP or as the standard deviation of all diurnal IOP values in the diurnal IOP curve. IOP repeatability was excellent at all time points, with ICCs ranging from 0.812 to 0.946 (p < 0.001). The 9 AM IOP showed the best repeatability between visits (ICCs, 0.946). Repeatability of mean IOP, peak IOP, and minimum IOP was also excellent (ICCs ranging from 0.899 to 0.929). However, IOP fluctuations showed poor repeatability, with an ICC lower than 0.15. Long-term repeatability of diurnal IOP patterns in healthy Asian subjects was excellent. These findings suggest that IOP measurements at standardized times of the day will be useful for assessing the effectiveness of glaucoma therapy.


Nonpharmacological therapies for atrial fibrillation.
In recent years, nonpharmacological therapies for atrial fibrillation (AF) have emerged given the limitations of medical therapy. Advancements in particular have been made in the areas of radiofrequency catheter ablation and AF surgery, and have been accompanied by substantial technological improvements. This article will discuss several different modalities of nonpharmacological AF management including catheter ablation, AF surgery and device-based therapy.


How to assess pain in children and young people.
Emergency nurse practitioners often experienced difficulties when attempting to assess pain in children accurately. This article refers to a case study to discuss the complexities of measuring paediatric pain, reviews two of the most well-known pain assessment scales and emphasises the importance of family involvement in situations where children are asked to self-report their experiences.


Association of y balance test reach asymmetry and injury in division I athletes.
The Y balance test (YBT) is a screen of dynamic balance requiring stance leg balance while the contralateral leg reaches in anterior (ANT), posteromedial (PM), and posterolateral (PL) directions. YBT has been proposed as a screen for injury risk; however, limited research has examined the association between YBT and injury. The purpose of this study was to examine the association between YBT (asymmetry and composite score (CS)) and noncontact injury in a sample of Division I (DI) college athletes from multiple sports. DI college athletes were screened with the YBT during the preparticipation examination to determine asymmetry (absolute difference between legs in ANT, PL, and PM) and CS (summed average of right/left ANT, PL, and PM normalized to leg length). Participants were followed throughout the sport season, and noncontact injuries requiring athletic training staff intervention were recorded for analysis. Demographic variables between injured and uninjured athletes were assessed with independent t-tests. Receiver operating characteristic (ROC) curves determined optimal cut points for predicting injury on the basis of CS and asymmetry. CS was analyzed as a continuous variable, as ROC curves were unable to maximize sensitivity and specificity. Logistic regression models adjusted for sport and previous injury determined the odds of injury on the basis of asymmetry and CS. One hundred and eighty-four participants were included in analysis; 81 were injured. ROC curves determined asymmetry >4 cm (sensitivity, 59%; specificity, 72%) as the optimal cut point for predicting injury. Only ANT asymmetry was significantly associated with noncontact injury (odds ratio, 2.33; 95% confidence interval, 1.15-4.76). ANT asymmetry >4 cm was associated with increased risk of noncontact injury. CS in this sample of DI athletes was not associated with increased risk of injury.


World's first telepathology experiments employing WINDS ultra-high-speed internet satellite, nicknamed "KIZUNA".
Recent advances in information technology have allowed the development of a telepathology system involving high-speed transfer of high-volume histological figures via fiber optic landlines. However, at present there are geographical limits to landlines. The Japan Aerospace Exploration Agency (JAXA) has developed the "Kizuna" ultra-high speed internet satellite and has pursued its various applications. In this study we experimented with telepathology in collaboration with JAXA using Kizuna. To measure the functionality of the Wideband InterNet working engineering test and Demonstration Satellite (WINDS) ultra-high speed internet satellite in remote pathological diagnosis and consultation, we examined the adequate data transfer speed and stability to conduct telepathology (both diagnosis and conferencing) with functionality, and ease similar or equal to telepathology using fiber-optic landlines. We performed experiments for 2 years. In year 1, we tested the usability of the WINDS for telepathology with real-time video and virtual slide systems. These are state-of-the-art technologies requiring massive volumes of data transfer. In year 2, we tested the usability of the WINDS for three-way teleconferencing with virtual slides. Facilities in Iwate (northern Japan), Tokyo, and Okinawa were connected via the WINDS and voice conferenced while remotely examining and manipulating virtual slides. Network function parameters measured using ping and Iperf were within acceptable limits. However; stage movement, zoom, and conversation suffered a lag of approximately 0.8 s when using real-time video, and a delay of 60-90 s was experienced when accessing the first virtual slide in a session. No significant lag or inconvenience was experienced during diagnosis and conferencing, and the results were satisfactory. Our hypothesis was confirmed for both remote diagnosis using real-time video and virtual slide systems, and also for teleconferencing using virtual slide systems with voice functionality. Our results demonstrate the feasibility of ultra-high-speed internet satellite networks for use in telepathology. Because communications satellites have less geographical and infrastructural requirements than landlines, ultra-high-speed internet satellite telepathology represents a major step toward alleviating regional disparity in the quality of medical care.


The relation between serum leptin levels and max VO2 in male patients with type I diabetes and healthy sedentary males.
This study aimed at investigating leptin levels in male diabetes type I patients who were on insulin treatment and also healthy sedentary males. The study included 10 male type I diabetes patients and 17 healthy sedentary males. Leptin levels of type I diabetes patients and healthy sedentary males with body mass index (BMI) over 25 kg/m2 were evaluated separately. The relation between serum leptin, max VO2, blood lactic acid levels before and after exercise, and effort durations of participants were investigated. At the end of the tests, no difference was found between leptin levels, max VO2 values, lactic acid values before exercise, and test durations of male type I diabetes patients and healthy sedentary males (p > .05), whereas lactic acid levels after exercise were found to be lower in healthy sedentary males (p < .05). Leptin levels in the group with BMI above 25 kg/m2 were higher than those in the group with BMI below 25 kg/m2 (p < .001). It was also seen that max VO2 values and test durations were higher in the group with BMI below 25 kg/m2 (p < .05). In conclusion, leptin levels of male type I diabetes patients are close to those of healthy sedentary males. The increase in leptin levels in both groups is in proportion to the BMI of individuals.


DEMMI Scores, Length of Stay, and 30-Day Readmission of Acute Geriatric Patients in Denmark: A Cross-Sectional Observational Study with Longitudinal Follow-Up.
The aims of this study are to describe the mobility of acute geriatric patients, the length of stay, and to characterise patients who were readmitted within 30 days based on the De Morton Mobility Index (DEMMI). A cross-sectional observational study with longitudinal follow-up was conducted in the period from 1 March 2016 to 31 August 2016. Inclusion criteria were acute geriatric patients hospitalised for a minimum of 24 h. Of the 418 patients hospitalised during the study period, 246 (59%) participated in this study (44% male, median age 83 years [70; 94]). For patients in an acute geriatric department, the median DEMMI score was 41 and the mean score was 39.95. Patients with a DEMMI score ≤40 show a significantly lower Barthel 100 index, lower 30 s. sit-to-stand scores and were significantly more likely to be bedridden or, amongst those not bedridden, to use a mobility aid. Lower DEMMI scores were associated with longer admissions. DEMMI seems to have the ability to predict discharge within one week. There was no significant association between a lower DEMMI score and higher risk for 30-day readmission. Further research is needed to determine whether the DEMMI is suitable for identifying the patient's need for further rehabilitation following the discharge.


Clinical evaluation of ricin A-chain immunotoxins in patients with Hodgkin's lymphoma.
Immunotoxins (ITs) consist of cell binding ligands coupled to toxins or their subunits. Hodgkin's lymphoma (HL) is an excellent target for ITs since lymphocyte activation markers such as CD25 and CD30 are expressed in large numbers. The ITs RFT5.dgA (anti CD25) and Ki-4.dgA (anti CD30) were constructed by linking the monoclonal antibodies RFT5 and Ki-4 to deglycosylated ricin A-chain (dgA). Both ITs showed potent specific activity against HL cells in vitro and in vivo in animal models, and were subsequently evaluated in phase I/II clinical trials in humans. In two separate trials, the ITs were administered i.v. four times every other day over 4 h. The objectives of the phase I trials included the determination of the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, antitumor activity and immune response against the IT. Twenty-seven patients with refractory HL were included in the phase I/II study of RFT5.dgA and 17 patients were included in the phase I study of Ki-4.dgA. The MTD of RFT5.dgA was 15 mg/m(2), whereas that of Ki-4.dgA was 5 mg/m(2). DLTs were related to vascular leak syndrome, consisting of edema, tachycardia, dyspnea, weakness and myalgia. Measurement of serum levels of RFT5.dgA demonstrated a C(max) of 0.2-9.7 micro g/ml with a half-life (t()) varying from 4 to 10.5 h. Peak serum concentration of Ki-4.dgA ranged from 0.23 to 1.7 micro g/ml. In both trials approximately 60% of patients developed human anti-mouse and/or anti-dgA antibodies. Seventeen of 18 patients treated at the MTD of RFT5.dgA were evaluable for clinical response. Responses included two partial remissions (PR), one minor response (MR) and five stable diseases (SD). Fifteen of 17 patients treated with Ki-4.dgA were evaluable for clinical response. Responses included one PR, one MR and two SD. RFT5.dgA and Ki-4.dgA showed moderate efficacy in heavily pretreated refractory patients with HL. Ki-4.dgA was less well tolerated than RFT5.dgA. This might be due, at least in part, to the formation of Ki-4.dgA/sCD30 complexes.