Hypertension and cardiovascular risk factors in hemodialyzed diabetic patients.
In a retrospective study, the cause of death and the cardiovascular risk conferred by hypertension and other risk factors were analyzed in 200 diabetic and 200 nondiabetic patients who were matched for age, sex, year of admission, and center of treatment. Total and cardiovascular mortality were considerably higher in diabetics, cardiovascular mortality being 4.8 times higher in patients with type I and 3.0 times higher in those with type II diabetes compared to matched controls. Cardiovascular mortality progressively increased with age and had not improved in recent years. In both types I and II diabetes, the rate (58%) and proportion (38%) of deaths from cardiovascular causes were significantly higher in diabetics than in matched controls. Myocardial infarction (13%) and stroke (7%) accounted only for a minority of cardiovascular mortality, the majority (80%) being due to "sudden death of unknown cause." Autopsy was carried out in 33% of patients with sudden death. A documented history of long-standing hypertension increased cardiovascular death in diabetic more than in nondiabetic patients. Diabetic retinopathy (an index of microangiopathy) and absence of peripheral pulses, amputation, or history of myocardial infarction, stroke, or transient ischemic attacks (as evidence of macroangiopathy) caused surprisingly little increase in relative risk for cardiovascular death. In diabetics but not in nondiabetics, cardiomegaly, particularly in association with electrocardiographic abnormalities, was a strong predictor of cardiovascular death.


Distribution of Chromosomal Abnormalities Commonly Observed in Adult Acute Myeloid Leukemia in Pakistan as Predictors of Prognosis
Objectives: The heterogenous response to treatment in acute myeloid leukemia (AML) can be attributed largely to the difference in cytogenetic features identified in between cases. Cytogenetic analysis in acute leukemia is now routinely used to assist patient management, particularly in terms of diagnosis, disease monitoring, prognosis and risk stratification. Knowing about cytogenetic profile at the time of diagnosis is important in order to take critical decisions in management of these patients. The study was conducted to determine the distribution of cytogenetic abnormalities in Pakistani adult patients with AML in order to have insights regarding behavior of the disease. Methods: A retrospective analysis of all the cases of AML (≥15years old) diagnosed at Aga Khan University from January 2011 to December 2016 was performed. Cytogenetic analysis was made for all cases using the trypsin-Giemsa banding technique. Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature (ISCN) criteria. Results: A total of 321 patients were diagnosed with AML during the study period, of which 288 samples successfully yielded metaphase chromosomes. The male to female ratio was 1.7:1. A normal karyotype was present in 61% (n=176) of the cases whereas, 39% (n=112) had an abnormal karyotype. Of the abnormal cases, t (8;21) (q22;q22) and t (15;17) (q22;q12) were identified in 8.3% and 4.9% cases respectively. Adverse prognostic cytogenetic subgroups including complex karyotype, monosomy 7 and t(6;9)(p23;q34) were identified in 9%, 1% and 0.7% patients respectively. Conclusions: This largest cytogenetic data in adult AML from Pakistan showed comparable prevalence of favorable prognostic karyotype to international data. The prevalence of specific adverse prognostic karyotype was low.


High-resolution time-of-flight mass spectrometry fingerprinting of metabolites from cecum and distal colon contents of rats fed resistant starch.
Time-of-flight mass spectrometry along with statistical analysis was utilized to study metabolic profiles among rats fed resistant starch (RS) diets. Fischer 344 rats were fed four starch diets consisting of 55 % (w/w, dbs) starch. A control starch diet consisting of corn starch was compared against three RS diets. The RS diets were high-amylose corn starch (HA7), HA7 chemically modified with octenyl succinic anhydride, and stearic-acid-complexed HA7 starch. A subgroup received antibiotic treatment to determine if perturbations in the gut microbiome were long lasting. A second subgroup was treated with azoxymethane (AOM), a carcinogen. At the end of the 8-week study, cecal and distal colon content samples were collected from the sacrificed rats. Metabolites were extracted from cecal and distal colon samples into acetonitrile. The extracts were then analyzed on an accurate-mass time-of-flight mass spectrometer to obtain their metabolic profile. The data were analyzed using partial least-squares discriminant analysis (PLS-DA). The PLS-DA analysis utilized a training set and verification set to classify samples within diet and treatment groups. PLS-DA could reliably differentiate the diet treatments for both cecal and distal colon samples. The PLS-DA analyses of the antibiotic and no antibiotic-treated subgroups were well classified for cecal samples and modestly separated for distal colon samples. PLS-DA analysis had limited success separating distal colon samples for rats given AOM from those not treated; the cecal samples from AOM had very poor classification. Mass spectrometry profiling coupled with PLS-DA can readily classify metabolite differences among rats given RS diets.


Effects of genotype and environment on free amino acid levels in wheat grain: implications for acrylamide formation during processing.
Acrylamide forms from free asparagine and reducing sugars during cooking, with asparagine concentration being the key parameter determining the formation in foods produced from wheat flour. In this study free amino acid concentrations were measured in the grain of varieties Spark and Rialto and four doubled haploid lines from a Spark x Rialto mapping population. The parental and doubled haploid lines had differing levels of total free amino acids and free asparagine in the grain, with one line consistently being lower than either parent for both of these factors. Sulfur deprivation led to huge increases in the concentrations of free asparagine and glutamine, and canonical variate analysis showed clear separation of the grain samples as a result of treatment (environment, E) and genotype (G) and provided evidence of G x E interactions. Low grain sulfur and high free asparagine concentration were closely associated with increased risk of acrylamide formation. G, E, and G x E effects were also evident in grain from six varieties of wheat grown at field locations around the United Kingdom in 2006 and 2007. The data indicate that progress in reducing the risk of acrylamide formation in processed wheat products could be made immediately through the selection and cultivation of low grain asparagine varieties and that further genetically driven improvements should be achievable. However, genotypes that are selected should also be tested under a range of environmental conditions.


Best Practice Standards in Animal-Assisted Interventions: How the LEAD Risk Assessment Tool Can Help.
Animal-assisted interventions (AAI) in educational and other settings have steadily increased over the last fifty years and a steep rise in AAI has been observed in many countries and settings in recent years. Surprisingly, while different providers and organisations provide a range of guidelines, no unified, standardised guidelines or risk assessment tools for AAI exist. This means that in practice AAI takes place in an unregulated manner and without a gold standard of best practice. In addition, knowledge of which interventions are effective is still scarce and the mechanisms of successful interventions are not yet fully understood. This is partly due to AAI being a relatively new research field and standards of research and practice have often lacked rigour in the past. Furthermore, knowledge and experience of providers undertaking interventions varies greatly as there is no standardised training either. We address the striking lack of standardised guidelines and procedures. In all AAI, high importance should be placed on safety and welfare of all involved. Children and other AAI participants, staff and animals should be given equal consideration when assessing risks and welfare needs. To ensure safe AAI worldwide, we provide urgently needed guidelines on best practice in relation to risk assessment, safeguarding and animal welfare priorities. The guidelines were developed for a large-scale longitudinal, randomised controlled trial AAI project and are relevant to AAIs within educational and other settings. We also provide the first set of comprehensive risk assessment and animal welfare tools to achieve consistent welfare and safety standards for best practice across educational and other settings around the world.


Newly diagnosed pulmonary sarcoidosis in HIV-infected patients.
To determine the radiologic and clinical features of newly diagnosed pulmonary sarcoidosis in human immunodeficiency virus (HIV)-infected patients. Ten HIV-infected patients (seven women, three men; age range, 26-66 years; mean age, 37 years) with newly diagnosed sarcoidosis between 1989 and 1997 were retrospectively identified. Charts were reviewed for the interval between the two diagnoses, CD4 cell count, signs or symptoms, angiotensin-converting enzyme level, and initiation of highly active antiretroviral therapy (HAART). Chest radiographs (n = 10) and computed tomographic (CT) scans (n = 8) were assessed for lymphadenopathy, pulmonary nodules, focal consolidation, reticular or granular opacities (thickened interlobular septa and ground-glass opacities at CT), cysts or cavities, and fibrosis. Mean interval between the two diagnoses was 3 years. Mean CD4 cell count was 213 cells per cubic millimeter. When sarcoidosis was diagnosed, eight patients had pulmonary signs or symptoms. The angiotensin-converting enzyme level was elevated in five of six patients; two developed sarcoidosis after beginning HAART. Chest radiographs revealed lymphadenopathy, pulmonary nodules, focal consolidation, reticular opacities, granular opacities, and cysts or cavities. Chest CT scans revealed lymphadenopathy, nodules, thickened interlobular septa, focal consolidation, reticular opacities, ground-glass opacities, and cysts or cavities. There was no relationship between the radiographic findings of sarcoidosis and the CD4 cell count. The radiologic features of newly diagnosed sarcoidosis in HIV-infected patients resemble the findings of sarcoidosis in non-HIV-infected patients. In HIV-infected patients receiving HAART, sarcoidosis may be a manifestation of disease related to restoration of the immune system.


Serum concentrations of the axonal injury marker neurofilament light protein are not influenced by blood-brain barrier permeability.
A blood biomarker to monitor individual susceptibility to neuronal injury from cranial radiotherapy could potentially help to individualize radiation treatment and thereby reduce the incidence and severity of late effects. An important feature of such a blood biomarker is that its concentration is not confounded by varying degrees of release from the brain into the blood across the blood-brain barrier (BBB). In this study, we investigated serum neurofilament light protein (NFL) concentrations in 21-day old mice following a single dose of cranial irradiation (8Gy). Cranial irradiation resulted in acute cell injury measured as a 12.9-fold increase in caspase activity 6h after irradiation; activation of inflammation measured by levels of CCL2 and increased BBB permeability measured by 14C-sucrose concentration ratios in brain and cerebrospinal fluid (CSF). Serum levels of NFL peaked at 6h after both anesthesia and cranial irradiation, but no timely correlation of serum NFL concentration with BBB permeability was found. Further, three groups of patients with different degrees of BBB impairment (measured as the CSF/serum albumin ratio) were investigated. There was no correlation between serum NFL concentration and CSF/serum albumin ratio (r=0.139, p=0.3513), however a strong correlation was found for NFL concentration in serum and NFL concentration in CSF (r=0.6303, p<0.0001). In conclusion, serum NFL appears to be a reliable blood biomarker for neuronal injury, and its concentration is not confounded by BBB permeability.


Respiration in relation to ion uptake in the crayfish Austropotamobius pallipes (Lereboullet).
1. O2 uptake was determined for periods of 23-46 h in salt-depleted crayfish held in deionized water (DW) or Na-free media at 10 degrees C. These media were replaced by artificial lakewater media (ALW) containing 0-2-0-6 mM Na and O2 uptake was again determined for periods of 24-66 h. 2. During net ion uptake in ALW the metabolic rate was either elevated or depressed. Standard metabolism in ALW altered by amounts equivalent to 0-1 - 15-5% (mean 6-4 (15) +/- 4-4% S. D.) of the metabolic rate measured during salt-depletion. On three occasions the metabolic rate was elevated by 22-0 - 66-7%, but some of this increase may have been due to locomotor activity. 3. The calculated values for thermodynamic work involved in ion transport were 0-056 - 0-268 J/10 g. h at 10 degrees C, or 1-5 - 7-2% of the mean standard metabolic rate. Most of the observed changes in metabolic rate lie within the limits of experimental error (ca. +/- 7%). Hence the energetic cost of ion transport is too small for direct measurement in intact crayfish.


Periarticular injections with continuous perfusion of local anaesthetics provide better pain relief and better function compared to femoral and sciatic blocks after TKA: a randomized clinical trial.
Combined femoral and sciatic nerve blocks for post-operative pain management following total knee arthroplasty (TKA) improve patient satisfaction, decrease narcotic consumption and improve pain. However, accompanying motoric weakness can cause falls and related complications. We wonder whether peri-capsular injections in combination with intra-articular perfusion of local anaesthetics would result in equal or less pain without the related complications of nerve blocks. The objective of the study was to verify these aspects in a prospective randomized trial comparing both treatments. Fifty TKA patients randomly received either a femoral (continuous) and a sciatic (single-shot) nerve block (CFNB group, 25 knees) or periarticular infiltrations and a continuous post-operative intra-articular infusion (PIAC group, 25 knees). VAS for pain, pain medication consumption, functional assessment, straight leg raising as well as KSS were recorded post-operatively for 6 days. VAS (p < 0.001) and KSS (p = 0.05) were significantly better for PIAC. There was increased pain following CFNB compared to PIAC. Catheters stayed for 4 days, a pain 'rebound' occurred after removing in CFNB but not after PIAC. There was no difference in regard to knee function (n.s.), but straight leg raising was significant better following PIAC. There were two falls in patients with CFNB. Peri-capsular injections combined with an intra-articular catheter provide better pain control, no rebound pain with better function and might decrease the risk of complications related to motor weakness. I.


Unmet needs of the patients with obsessive-compulsive disorder.
Obsessive compulsive disorder (OCD) is a disabling mental disorder with the chronic and difficult course. The disorder is accompanied by numerous limitations in personal and interpersonal functioning. OCD decreases the quality of life and the chance to maintain relationships and professional status. The patients with OCD often experience a severe disabling course of the disorder. Even the individuals, who follow treatment advice, are often still highly symptomatic. In the last decade, the concept of the needs has been assessed as an extent of the traditional outcome evaluation in order to focus on the identification of the specific needs of the patients and their relatives, improve the patients´ overall mental condition and quality of life, and also to increase the treatment effectiveness of the mental disorders. The objective of the article was to review the current literature about unmet needs of the OCD patients and their caregivers. A computerized search of the literature published between January 2000 and June 2016 was conducted in MEDLINE, and additional papers were extracted using keywords "obsessive compulsive disorder","needs", "pharmacotherapy", "CBT", and "family" in various combinations. Primary selection selected the total of 449 articles. According to the established criteria, 168 articles were chosen. After a detailed examination of the full texts, 53 articles remained. Secondary articles from the reference lists of primarily selected papers were read and evaluated for the eligibility and added to the final list of the articles (n = 107). The needs of the OCD patients might differ at various stages and severity of the disorder. Four sets of the needs were identified: the needs connected with the symptoms, the treatment, the quality of life, and the family. The patients suffering from OCD often experience many limitations in the fulfillment of their fundamental human needs such as disturbed patients´ functioning in the common life, family, at work, in the ability to realize their goals, skills, potential, capacity to follow prescribed treatment, take medication, cooperate in addressing the root causes of their problems, reduce obsessive thoughts and compulsive behavior, as well as their willingness to realize exposures with the desire to resolve the situation. Monitoring the patients´ needs may be relevant for the treatment of the individuals suffering from OCD. A bigger focus on the patients´ needs could be beneficial and should be targeted in the treatment.


HIV reservoirs as obstacles and opportunities for an HIV cure.
The persistence of HIV reservoirs remains a formidable obstacle to achieving sustained virologic remission in HIV-infected individuals after antiretroviral therapy (ART) is discontinued, even if plasma viremia has been successfully suppressed for prolonged periods of time. Numerous approaches aimed at eradicating the virus, as well as maintaining its prolonged suppression in the absence of ART, have had little success. A better understanding of the pathophysiologic nature of HIV reservoirs and the impact of various interventions on their persistence is essential for the development of successful therapeutic strategies against HIV or the long-term control of infection. Here, we discuss the persistent HIV reservoir as a barrier to cure as well as the current therapeutic strategies aimed at eliminating or controlling the virus in the absence of ART.


Immune Regulation of Intrahepatic Regulatory T Cells in Fibrotic Livers of Mice.
BACKGROUND Liver fibrosis is the result of chronic inflammation and repair, and many immune cells contribute to the process. Regulatory T cells (Tregs) mediate immune tolerance and are highly expressed in liver fibrosis. However, few reports have studied the specific effects of Tregs on regulating immune cells in liver fibrosis. The present study aimed to investigate the regulation of Tregs on intrahepatic immune cells in liver fibrosis by depleting Tregs in mice. MATERIAL AND METHODS Liver fibrosis was induced by carbon tetrachloride, and an anti-CD25 mAb (PC61) was used to deplete Tregs. Liver fibrosis and injury were reflected by immunofluorescence staining and alanine aminotransferase level. The expressions of immune cell Tregs and cytokines were detected by flow cytometry and/or real-time PCR. Interferon-γ (IFN-γ) concentration was measured by ELISA. RESULTS Tregs were rich in fibrotic livers; after Tregs depletion, the intrahepatic CD4+ T cell and Kupffer cells (KC) populations did not change compared with liver fibrosis, but CD8+ T cells were slightly elevated. However, natural killer (NK) cells and IFN-g levels were significantly decreased in fibrosis and increased after Tregs depletion. Interesting, we found Tregs promoted KC M1/M2 balance to M2, because inducible nitric oxide synthase (M1) was increased but arginase-1 (M2) was reduced after depleting Tregs. Furthermore, in isolated KCs from livers, IL-12 (M1) was increased, but TGF-β (M2) was reduced after depleting Tregs, compared with fibrotic livers. CONCLUSIONS Tregs are involved in the immune regulation of liver fibrosis, primarily by suppressing NK cells and M1 KCs, and mildly suppressing CD8+ T cells.


The Belgian health examination survey: objectives, design and methods.
In 2018 the first Belgian Health Examination Survey (BELHES) took place. The target group included all Belgian residents aged 18 years and older. The BELHES was organized as a second stage of the sixth Belgian Health Interview Survey (BHIS). This paper describes the study design, recruitment method and the methodological choices that were made in the BELHES. After a pilot period during the first quarter of the BHIS fieldwork, eligible BHIS participants were invited to participate in the BELHES until a predefined number (n = 1100) was reached. To obtain the required sample size, 4918 eligible BHIS participants had to be contacted. Data were collected at the participant's home by trained nurses. The data collection included: 1) a short set of questions through a face-to-face interview, 2) a clinical examination consisting of the measurement of height, weight, waist circumference, blood pressure and for people aged 50 years and older handgrip strength and 3) a collection of blood and urine samples. The BELHES followed as much as possible the guidelines provided in the framework of the European Health Examination Survey (EHES) initiative. Finally 1184 individuals participated in the BELHES, resulting in a participation rate of 24.1%. Results for all the core BELHES measurements were obtained for more than 90% of the participants. It is feasible to organize a health examination survey as a second stage of the BHIS. The first successfully organized BELHES provides useful information to support Belgian health decision-makers and health professionals. As the BELHES followed EHES recommendations to a large extent, the results can be compared with those from similar surveys in other EU (European Union) member states.


Disparities in Risks of Inadequate and Excessive Intake of Micronutrients during Pregnancy.
Inadequate or excessive intake of micronutrients in pregnancy has potential to negatively impact maternal/offspring health outcomes. The aim was to compare risks of inadequate or excessive micronutrient intake in diverse females with singleton pregnancies by strata of maternal age, race/ethnicity, education, and prepregnancy BMI. Fifteen observational cohorts in the US Environmental influences on Child Health Outcomes (ECHO) Consortium assessed participant dietary intake with 24-h dietary recalls (n = 1910) or food-frequency questionnaires (n = 7891) from 1999-2019. We compared the distributions of usual intake of 19 micronutrients from food alone (15 cohorts; n = 9801) and food plus dietary supplements (10 cohorts with supplement data; n = 7082) to estimate the proportion with usual daily intakes below their age-specific daily Estimated Average Requirement (EAR), above their Adequate Intake (AI), and above their Tolerable Upper Intake Level (UL), overall and within sociodemographic and anthropometric subgroups. Risk of inadequate intake from food alone ranged from 0% to 87%, depending on the micronutrient and assessment methodology. When dietary supplements were included, some women were below the EAR for vitamin D (20-38%), vitamin E (17-22%), and magnesium (39-41%); some women were above the AI for vitamin K (63-75%), choline (7%), and potassium (37-53%); and some were above the UL for folic acid (32-51%), iron (39-40%), and zinc (19-20%). Highest risks for inadequate intakes were observed among participants with age 14-18 y (6 nutrients), non-White race or Hispanic ethnicity (10 nutrients), less than a high school education (9 nutrients), or obesity (9 nutrients). Improved diet quality is needed for most pregnant females. Even with dietary supplement use, >20% of participants were at risk of inadequate intake of ≥1 micronutrients, especially in some population subgroups. Pregnancy may be a window of opportunity to address disparities in micronutrient intake that could contribute to intergenerational health inequalities.


Recovery of viscerosensory innervation from the dorsal root ganglia of the adult rat following capsaicin-induced injury.
Capsaicin is a neurotoxin selective for C- and Adelta-type neurons. Systemic treatment with capsaicin is known to reduce this subpopulation in the dorsal root ganglia (DRG) of neonatal rats. To better understand the effects of capsaicin on adult afferent fibers, we examined DRG neurons retrogradely labeled by an i.p. injection of Fast Blue (FB) administered 3, 30, or 60 days after systemic capsaicin treatment (125 mg/kg i.p.). FB labeling in the 12th and 13th thoracic DRG was dramatically reduced 3 and 30 days post capsaicin (50% and 35% of control, respectively). However, the number of retrogradely labeled neurons rose to 65% of control by 60 days post capsaicin. In addition to FB labeling, we quantified the immunoreactivity of NR1, the obligatory N-methyl-D-aspartate receptor subunit, and Na(v)1.8, a DRG-specific sodium channel, in FB-labeled neurons as well as mRNA levels for both proteins in the 5th and 6th lumbar DRG. NR1 immunoreactivity and mRNA expression followed a pattern of early reduction and subsequent partial restoration similar to FB labeling. Na(v)1.8 immunoreactivity and mRNA expression dropped to approximately 50% of control at 3 days post capsaicin but completely recovered by 60 days. These data strongly support the conclusion that restoration of spinal afferent projections and signaling occurs in adult rats following capsaicin-induced damage.


Long-term exposure to outdoor air pollution and incidence of cardiovascular diseases.
Evidence based largely on US cohorts suggests that long-term exposure to fine particulate matter is associated with cardiovascular mortality. There is less evidence for other pollutants and for cardiovascular morbidity. By using a cohort of 836,557 patients age 40 to 89 years registered with 205 English general practices in 2003, we investigated relationships between ambient outdoor air pollution and incident myocardial infarction, stroke, arrhythmia, and heart failure over a 5-year period. Events were identified from primary care records, hospital admissions, and death certificates. Annual average concentrations in 2002 for particulate matter with a median aerodynamic diameter <10 (PM10) and <2.5 microns, nitrogen dioxide (NO2), ozone, and sulfur dioxide at a 1 × 1 km resolution were derived from emission-based models and linked to residential postcode. Analyses were performed using Cox proportional hazards models adjusting for relevant confounders, including social and economic deprivation and smoking. While evidence was weak for relationships with myocardial infarction, stroke, or arrhythmia, we found consistent associations between pollutant concentrations and incident cases of heart failure. An interquartile range change in PM10 and in NO2 (3.0 and 10.7 µg/m, respectively) both produced a hazard ratio of 1.06 (95% confidence interval = 1.01-1.11) after adjustment for confounders. There was some evidence that these effects were greater in more affluent areas. This study of an English national cohort found evidence linking long-term exposure to particulate matter and NO2 with the development of heart failure. We did not, however, replicate associations for other cardiovascular outcomes that have been reported elsewhere.


Neurochemical and behavioural evidence for mediation of the hyperphagic action of 8-OH-DPAT by 5-HT cell body autoreceptors.
Administration of 60 micrograms/kg s.c. of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a dose previously shown to cause hyperphagia in satiated rats (but not to cause the 5-HT behavioural syndrome) decreased 5-HIAA and 5-HIAA/5-HT ratio in several brain regions, the most marked effects being in pons + medulla oblongata, a region containing 5-HT cell bodies and ascending 5-HT axons. Micro-infusion of 8-OH-DPAT (250 and 500 ng) into the dorsal or medial raphe nuclei significantly increased food intake and feeding duration but did not produce the 5-HT behavioural syndrome. Results suggest that 8-OH-DPAT induced hyperphagia is mediated via a agonist action on somatodendritic 5-HT autoreceptors.


Inside Speech: Multisensory and Modality-specific Processing of Tongue and Lip Speech Actions.
Action recognition has been found to rely not only on sensory brain areas but also partly on the observer's motor system. However, whether distinct auditory and visual experiences of an action modulate sensorimotor activity remains largely unknown. In the present sparse sampling fMRI study, we determined to which extent sensory and motor representations interact during the perception of tongue and lip speech actions. Tongue and lip speech actions were selected because tongue movements of our interlocutor are accessible via their impact on speech acoustics but not visible because of its position inside the vocal tract, whereas lip movements are both "audible" and visible. Participants were presented with auditory, visual, and audiovisual speech actions, with the visual inputs related to either a sagittal view of the tongue movements or a facial view of the lip movements of a speaker, previously recorded by an ultrasound imaging system and a video camera. Although the neural networks involved in visual visuolingual and visuofacial perception largely overlapped, stronger motor and somatosensory activations were observed during visuolingual perception. In contrast, stronger activity was found in auditory and visual cortices during visuofacial perception. Complementing these findings, activity in the left premotor cortex and in visual brain areas was found to correlate with visual recognition scores observed for visuolingual and visuofacial speech stimuli, respectively, whereas visual activity correlated with RTs for both stimuli. These results suggest that unimodal and multimodal processing of lip and tongue speech actions rely on common sensorimotor brain areas. They also suggest that visual processing of audible but not visible movements induces motor and visual mental simulation of the perceived actions to facilitate recognition and/or to learn the association between auditory and visual signals.


Continuity of care for children in foster care.
To compare the continuity of care experienced by children who are in foster care with that of children who are not in foster care and are covered under Medicaid managed care and Medicaid fee-for-service (FFS). This retrospective cohort study used Medicaid claims/encounter data from Washington state. A total of 903 children who were in foster care and continuously enrolled in Medicaid for 24 months (1998-1999) were matched by age, gender, and rural/urban residence to 903 Medicaid managed care enrollees and 903 FFS beneficiaries who were not in foster care. Indices of the continuity of primary care experienced were calculated for each patient, and differences in continuity among the cohorts were assessed by running 3 multiple linear regression models for all possible pairings of cohorts, controlling for age, gender, rural/urban residence, and total number of primary care visits. Foster care status was associated with decreased continuity of care relative to nonfoster managed care status (beta = -0.12; 95% confidence interval [CI]: -0.15 to -0.09). Nonfoster FFS status was associated with lower continuity than managed care (beta = -0.09; 95% CI: -0.12 to -0.06) and slightly higher continuity than foster care status (beta = 0.03; 95% CI: 0.01-0.06). Although not dramatically different, continuity seems somewhat lacking for children in foster care. It is unclear to what degree the observed difference is confounded by the managed care/FFS distinction. As the enrollment of children in foster care into managed care plans has been controversial, efforts to promote the consistency of contact with providers while maintaining the flexibility afforded by FFS coverage seem warranted.


Experience replay is associated with efficient nonlocal learning.
To make effective decisions, people need to consider the relationship between actions and outcomes. These are often separated by time and space. The neural mechanisms by which disjoint actions and outcomes are linked remain unknown. One promising hypothesis involves neural replay of nonlocal experience. Using a task that segregates direct from indirect value learning, combined with magnetoencephalography, we examined the role of neural replay in human nonlocal learning. After receipt of a reward, we found significant backward replay of nonlocal experience, with a 160-millisecond state-to-state time lag, which was linked to efficient learning of action values. Backward replay and behavioral evidence of nonlocal learning were more pronounced for experiences of greater benefit for future behavior. These findings support nonlocal replay as a neural mechanism for solving complex credit assignment problems during learning.


Digital speckle correlation method based on wavelet-packet noise-reduction processing.
Despite the advantages of being highly sensitive and nondestructive, the digital speckle correlation method (DSCM) may have difficulties in detecting tiny defects such as delaminations in multilayer ceramic capacitors. This is because the presence of background noise always complicates the data processing. We present a new algorithm, which employs the wavelet-packet noise-reduction process together with the improved DSCM, to improve data processing. Both the computational error and the noise are shown to be reduced successfully by this new algorithm. The accuracy (or precision) of the improved DSCM is increased after operation of the wavelet-packet noise-reduction process. The most important feature of this new algorithm is that it can extract a small hillock signal from a large noisy background in a DSCM deformation result. This helps to save time in the detection of tiny defects, such as delamination, in a miniaturized electronic component.


QMOD: physically meaningful QSAR.
Computational methods for predicting ligand affinity where no protein structure is known generally take the form of regression analysis based on molecular features that have only a tangential relationship to a protein/ligand binding event. Such methods have utility in retrospective rationalization of activity patterns of substituents on a common scaffold, but are limited when either multiple scaffolds are present or when ligand alignment varies significantly based on structural changes. In addition, such methods generally assume independence and additivity of effect from scaffold substituents. Collectively, these non-physical modeling assumptions sharply limit the utility of widely used QSAR approaches for prospective prediction of ligand activity. The recently introduced Surflex-QMOD approach, by virtue of constructing physical models of binding sites, comes closer to a modeling approach that is congruent with protein ligand binding events. A set of congeneric CDK2 inhibitors showed that induced binding pockets can be quite congruent with the enzyme's active site but that model predictivity within a chemical series does not necessarily depend on congruence. Muscarinic antagonists were used to show that the QMOD approach is capable of making accurate predictions in cases where highly non-additive structure activity effects exist. The QMOD method offers a means to go beyond non-causative correlations in QSAR analysis.


The impact of PEGylation on biological therapies.
The term PEGylation describes the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer, and is used as a strategy to overcome disadvantages associated with some biopharmaceuticals. PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug. In general, PEGylation improves drug solubility and decreases immunogenicity. PEGylation also increases drug stability and the retention time of the conjugates in blood, and reduces proteolysis and renal excretion, thereby allowing a reduced dosing frequency. In order to benefit from these favorable pharmacokinetic consequences, a variety of therapeutic proteins, peptides, and antibody fragments, as well as small molecule drugs, have been PEGylated. This paper reviews the chemical procedures and the conditions that have been used thus far to achieve PEGylation of biomedical molecules. It also discusses the importance of structure and size of PEGs, as well as the behavior of linear and branched PEGs. A number of properties of the PEG polymer--e.g. mass, number of linking chains, the molecular site of PEG attachment--have been shown to affect the biological activity and bioavailability of the PEGylated product. Releasable PEGs have been designed to slowly release the native protein from the conjugates into the blood, aiming at avoiding any loss of efficacy that may occur with stable covalent PEGylation. Since the first PEGylated drug was developed in the 1970s, PEGylation of therapeutic proteins has significantly improved the treatment of several chronic diseases, including hepatitis C, leukemia, severe combined immunodeficiency disease, rheumatoid arthritis, and Crohn disease. The most important PEGylated drugs, including pegademase bovine, pegaspargase, pegfilgrastim, interferons, pegvisomant, pegaptanib, certolizumab pegol, and some of the PEGylated products presently in an advanced stage of development, such as PEG-uricase and PEGylated hemoglobin, are reviewed. The adaptations and applications of PEGylation will undoubtedly prove useful for the treatment of many previously difficult-to-treat conditions.


Jumping mechanography: a potential tool for sarcopenia evaluation in older individuals.
Muscular function declines with advancing age and is associated with increased risk for falls and fragility fractures. No single methodology ideally quantitatively evaluates this decline. Jumping mechanography (JM) may prove useful to quantitatively measure muscular function in older adults. This study begins to evaluate the safety of JM and the relationship of jump power and lean mass in older adults. Eighty adults, 40 aged 20-30 yr and 40 aged 60 yr or older, distributed equally by gender, participated. They performed countermovement jumps to assess jump power and height. Self-reported pain before and after jumping and need for assistance was recorded. In the older group, dual-energy X-ray absorptiometry was used to measure bone mineral density, to estimate lean body mass, and to determine vertebral fracture status. Jumping was well tolerated without injury or increased pain. No new vertebral fractures occurred with jumping in the older group. Young individuals had greater jump power and height compared with the older group. Older age was negatively correlated, whereas lean mass positively correlated with jump power and height. JM appears to be a safe and potentially useful method to assess muscular function in older adults.


Uncomplicated resistance training and health-related outcomes: evidence for a public health mandate.
Compared to aerobic training (AT), resistance training (RT) has received far less attention as a prescription for general health. However, RT is as effective as AT in lowering risk for cardiovascular disease, diabetes, and other diseases. There is a clear ability of RT, in contrast to AT, to promote gains, maintenance, or slow loss of skeletal muscle mass/strength. Thus, as an antisarcopenic exercise treatment, RT is of greater benefit than AT; given the aging of our population, this is of primary importance. In our view, a substantial barrier to greater adoption of RT is the incorrectly perceived importance of variables such as external load, intensity, and volume, leading to complex, difficult-to-follow regimes. We propose a more feasible and easier-to-adhere-to paradigm for RT that could affect how RT is viewed and adopted as a prescription for public health.


Thyroid hormone induction of an autocrine growth factor secreted by pituitary tumor cells.
Thyroid hormones stimulate the rate of cell division by poorly understood mechanisms. The possibility that thyroid hormones increase cell growth by stimulating secretion of a growth factor was investigated. Thyroid hormones are nearly an absolute requirement for the division of GH4C1 rat pituitary tumor cells plated at low density. Conditioned media from cells grown with or without L-triiodothyronine (T3) were treated with an ion exchange resin to remove T3 and were tested for ability to stimulate the division of GH4C1 cells. Conditioned medium from T3-treated cells was as active as thyroid hormone at promoting GH4C1 cell growth but did not elicit other thyroid hormone responses, induction of growth hormone, and down-regulation of thyrotropin-releasing hormone receptors, as effectively as T3 did. A substance or substances associated with T3-induced growth stimulatory activity migrated at high molecular weight at neutral pH and was different from known growth-promoting hormones induced by T3. The results demonstrate that thyroid hormones stimulate the division of GH4C1 pituitary cells by stimulating the secretion of an autocrine growth factor.


Construction and analysis of protein-protein interaction networks.
Protein-protein interactions form the basis for a vast majority of cellular events, including signal transduction and transcriptional regulation. It is now understood that the study of interactions between cellular macromolecules is fundamental to the understanding of biological systems. Interactions between proteins have been studied through a number of high-throughput experiments and have also been predicted through an array of computational methods that leverage the vast amount of sequence data generated in the last decade. In this review, I discuss some of the important computational methods for the prediction of functional linkages between proteins. I then give a brief overview of some of the databases and tools that are useful for a study of protein-protein interactions. I also present an introduction to network theory, followed by a discussion of the parameters commonly used in analysing networks, important network topologies, as well as methods to identify important network components, based on perturbations.


Factors associated with depressive symptoms in young long-term breast cancer survivors.
Long-term breast cancer survivors frequently report distress (i.e., depressive symptoms) that impacts their quality of life. Previous studies have found that negative social interactions ("social constraints") from partners contribute to long-term, unresolved cycling of intrusive thoughts and cognitive avoidance, resulting in psychological distress. However, these relationships have not been tested in long-term breast cancer survivors. Furthermore, the effect of partners' depressive symptoms on the survivors' depressive symptoms has not been tested within the context of these relationships. Therefore, the purpose of this study was to test relationships between breast cancer survivors' depressive symptoms and (1) social constraints, cognitive avoidance, and intrusive thoughts, and (2) partners' depressive symptoms. Data were from a cross-sectional descriptive study of breast cancer survivors (N = 222) 3-8 years post-diagnosis and their partners, who completed surveys assessing demographic characteristics, social constraints, intrusive thoughts, cognitive avoidance, and depressive symptoms. Structural equation modeling confirmatory path analyses were conducted to determine significant relationships between survivors' depressive symptoms and all other variables. Our model fits the data well. Breast cancer survivors' depressive symptoms were predicted by social constraints and intrusive thoughts. The relationship between survivors' depressive symptoms and partners' depressive symptoms was close but not significant. As hypothesized, depressive symptoms were predicted by social constraints and intrusive thoughts. Further research is needed to understand the possible relationship between survivors' long-term depressive symptoms and cognitive avoidance and partners' depressive symptoms. Our findings highlight the negative impact of social constraints from partners on psychological outcomes in long-term breast cancer survivors.


Experimental staphylococcal endocarditis and aortitis. Morphology of the initial colonization.
The initial colonization, by Staphylococcus aureus, of the catheter damaged aortic valve and aorta of the rabbit, was examined by light and electron microscopy at 15 min, 3 h and 24 h post inoculation (PI). At 15 min PI, the majority of bacteria (80%) were located on the lateral surfaces of the thrombic vegetations while 20% were attached directly to the connective tissue of the aortic valve and aorta in areas where the endothelial lining was disrupted. By 3 h the bacteria on the thrombic vegetations were covered by fibrin. At this time, the bacteria both within the vegetations and on the surface of the vasculature were undergoing multiplication to form small groups. The precipitation of thrombus around the bacteria attached to the surface of the aorta to form microscopic infected vegetations had occurred by 24 h PI. The colonizing bacteria did not elicit any phagocytic response. The colonization of the cardiovasculature by Staph. aureus did not necessarily require pre-existing vegetations.


Association and release of the major intrinsic membrane glycoprotein from peripheral nerve myelin.
Hypo-osmotic homogenization of the endoneurium from the adult-rat sciatic nerve and subsequent evaluation of the 197 000 g aqueous supernatant by sodium dodecyl sulphate pore-gradient electrophoresis (SDS-p.g.e.) revealed a release of the major glycoprotein (P0) (29 000 Mr) from peripheral nerve myelin. Immunological verification of the presence of this asparagine-linked glycoprotein in the aqueous supernatant was obtained by immune overlay after SDS-p.g.e. and electrophoretic transfer to nitrocellulose using anti-P0 gamma-globulin followed by autoradiographic detection with 125I-protein A. A comparison of successive hypo- and iso-osmotic extractions of the endoneurium revealed that the hypo-osmotic extraction released increasing amounts of P0 into the supernatant fraction, whereas the iso-osmotic treatment revealed lower levels of P0 extracted from the myelin and lesser amounts with each successive extraction. Three successive hypo-osmotic extractions resulted in a 2.0-, 2.9-, and 9.5-fold increase in the amount of P0 released compared with the successive iso-osmotic extractions. Although these results suggest that this major myelin glycoprotein has properties similar to those of extrinsic membrane proteins, temperature-dependent phase-partitioning experiments with Triton X-114 revealed that this glycoprotein is recovered in the detergent-enriched lower phase. These results indicate that this major myelin glycoprotein is an amphipathic integral membrane protein with a distinct hydrophobic domain and yet has solubility characteristics typical of an extrinsic membrane protein. P0 labelled in vitro with [3H]mannose could be immunoprecipitated from the aqueous supernatant with anti-P0 gamma-globulin by centrifugation at 197000g without the addition of second antibody or protein A. Analysis of such an immune precipitate after incorporation in vitro with [14C]acetate to label endoneurial lipids revealed that all major endoneurial lipid classes contained radioactive label, as determined by fluorography after high-performance t.l.c. The mechanism of release of this intrinsic glycoprotein from the myelin membrane, therefore, involves the osmotic-dependent formation of mixed micelles or membrane vesicles with endogenous membrane lipids.


High-level SLP-2 expression and HER-2/neu protein expression are associated with decreased breast cancer patient survival.
There is sufficient evidence that human stomatin-like protein 2 (SLP-2) is a novel cancer-related gene. Its protein is overexpressed in many human cancers. SLP-2 can contribute to the promotion of cell growth, cell adhesion, and tumorigenesis in esophageal squamous cell carcinoma and lymph node metastasis in laryngeal squamous cell carcinoma. Immunohistochemical detection of SLP-2, estrogen and progesterone receptors, and HER-2/neu were performed on 263 cases of primary invasive breast cancer with a tissue microarray. Of 263 cases, 138 (52.5%) showed high expression of SLP-2 protein, and 125 (47.5%) showed low or absent expression. In addition, there were significant positive associations between tumor stage and size (P = .020), lymph node metastasis (P < .001), clinical stage (P < .001), distant metastasis (P = .002), and HER-2/neu protein expression (P = .037) and high-level SLP-2 expression. High-level SLP-2 expression was associated with decreased overall survival (P = .011) and was more often found in patients with tumors larger than 20 mm, lymph node metastasis, advanced clinical stage, distant metastasis, and HER-2/neu protein-positive expression. More important, lymph node metastasis, HER-2/neu-positive expression, and high-level SLP-2 expression were associated with significantly decreased survival.


Collective cell migration drives morphogenesis of the kidney nephron.
Tissue organization in epithelial organs is achieved during development by the combined processes of cell differentiation and morphogenetic cell movements. In the kidney, the nephron is the functional organ unit. Each nephron is an epithelial tubule that is subdivided into discrete segments with specific transport functions. Little is known about how nephron segments are defined or how segments acquire their distinctive morphology and cell shape. Using live, in vivo cell imaging of the forming zebrafish pronephric nephron, we found that the migration of fully differentiated epithelial cells accounts for both the final position of nephron segment boundaries and the characteristic convolution of the proximal tubule. Pronephric cells maintain adherens junctions and polarized apical brush border membranes while they migrate collectively. Individual tubule cells exhibit basal membrane protrusions in the direction of movement and appear to establish transient, phosphorylated Focal Adhesion Kinase-positive adhesions to the basement membrane. Cell migration continued in the presence of camptothecin, indicating that cell division does not drive migration. Lengthening of the nephron was, however, accompanied by an increase in tubule cell number, specifically in the most distal, ret1-positive nephron segment. The initiation of cell migration coincided with the onset of fluid flow in the pronephros. Complete blockade of pronephric fluid flow prevented cell migration and proximal nephron convolution. Selective blockade of proximal, filtration-driven fluid flow shifted the position of tubule convolution distally and revealed a role for cilia-driven fluid flow in persistent migration of distal nephron cells. We conclude that nephron morphogenesis is driven by fluid flow-dependent, collective epithelial cell migration within the confines of the tubule basement membrane. Our results establish intimate links between nephron function, fluid flow, and morphogenesis.


Persistent left superior vena cava: Two case reports and a review from nephrologists' perspective.
Thoracic venous anomalies without congenital heart anomalies are present in minority of the population, but they are frequent enough to be encountered while placing hemodialysis catheters through the jugular or subclavian veins. Persistent left superior vena cava is the most commonly seen anomaly and it is rarely noticed before the observation of an unusual course of hemodialysis catheter or guidewire on chest X-ray. We present two patients with previously unspotted persistent left superior vena cava and uncomplicated hemodialysis catheter insertions through the internal jugular veins with good catheter functions. Review of the relevant literature from a nephrologists' perspective with technical aspects is provided.


Presumptive Late-Onset Ankylosing Spondylitis Simulating Osteoblastic Skeletal Metastasis in a Patient With a History of Prostate Carcinoma: A Diagnostic Challenge.
The purpose of this report is to present a presumptive case of ankylosing spondylitis with late stage progression that simulated osteoblastic metastasis in a patient with a history of prostate carcinoma. A 67-year-old white man presented to a chiropractic clinic complaining of severe and worsening acute low back pain and right foot "numbness." Further questioning also revealed a history of prostate carcinoma. Imaging examination revealed a sclerotic pedicle and increased uptake of radiopharmaceutical on a nuclear medicine bone scan highly suggestive of osteoblastic skeletal metastasis. Further evaluation, however, revealed that the bone sclerosis was not the result of skeletal metastasis, but more consistent with a seronegative spondyloarthritis such as ankylosing spondylitis. This report describes a presumptive case of ankylosing spondylitis simulating skeletal metastasis in a patient with a past medical history of prostate cancer. This atypical presentation illustrates the inherent uncertainty of diagnosis and how that uncertainty can be challenging in clinical practice. It also reinforces that it is critical for healthcare providers to consider a wide spectrum of differential diagnoses to avoid misdiagnoses and inappropriate interventions.


The effect of lateral opening wedge distal femoral osteotomy on medial knee opening: clinical and biomechanical factors.
The case of a patient with knee valgus and instability due to combined ACL-MCL laxity who underwent lateral opening wedge distal femoral osteotomy (DFO) is presented. The symptoms of instability resolved following the surgery. It was unclear whether the increase in valgus stability was related only to a decrease in valgus moments during stance or also to a medial tensioning effect. We therefore performed a laboratory cadaveric study. The purpose of this study was to examine whether after MCL and ACL sectioning, lateral opening wedge DFO would result in decrease in medial opening under static conditions of valgus stress. Medial knee opening under valgus load of 9.8 Nm was tested in 8 cadaveric specimens in scenarios of MCL and ACL sectioning and compared before and after performing lateral opening wedge DFO. When the superficial MCL was sectioned, medial knee opening in 30° flexion decreased after lateral opening wedge DFO compared to medial opening before the osteotomy (i.e. from 6.5 ± 0.5° to 5.6 ± 0.5°, p = 0.01). When the superficial MCL, deep MCL, and ACL were all sectioned, medial knee opening in extension decreased after lateral opening wedge DFO compared to medial opening before the osteotomy but this was not significant (i.e. from 6.8 ± 0.5° to 6.1 ± 0.5°, p = n.s.). In superficial MCL-transected knees, medial laxity at 30° of knee flexion decreased after lateral opening wedge DFO. However, the clinical relevance of the laxity decrease observed remains uncertain since the reduction was small in magnitude.


Trigger values for investigation of hormonal activity in drinking water and its sources using CALUX bioassays.
To screen for hormonal activity in water samples, highly sensitive in vitro CALUX bioassays are available which allow detection of estrogenic (ERα), androgenic (AR), progestagenic (PR), and glucocorticoid (GR) activities. This paper presents trigger values for the ERα, AR, PR, and GR CALUX bioassays for agonistic hormonal activities in (drinking) water, which define a level above which human health risk cannot be waived a priori and additional examination of specific endocrine activity may be warranted. The trigger values are based on 1) acceptable or tolerable daily intake (ADI/TDI) values of specific compounds, 2) pharmacokinetic factors defining their bioavailability, 3) estimations of the bioavailability of unknown compounds with equivalent hormonal activity, 4) relative endocrine potencies, and 5) physiological, and drinking water allocation factors. As a result, trigger values of 3.8ng 17β-estradiol (E2)-equivalents (eq)/L, 11ng dihydrotestosterone (DHT)-eq/L, 21ng dexamethasone (DEX)-eq/L, and 333ng Org2058-eq/L were derived. Benchmark Quotient (BQ) values were derived by dividing hormonal activity in water samples by the derived trigger using the highest concentrations detected in a recent, limited screening of Dutch water samples, and were in the order of (value) AR (0.41)>ERα (0.13)>GR (0.06)>PR (0.04). The application of trigger values derived in the present study can help to judge measured agonistic hormonal activities in water samples using the CALUX bioassays and help to decide whether further examination of specific endocrine activity followed by a subsequent safety evaluation may be warranted, or whether concentrations of such activity are of low priority with respect to health concerns in the human population. For instance, at one specific drinking water production site ERα and AR (but no GR and PR) activities were detected in drinking water, however, these levels are at least a factor 83 smaller than the respective trigger values, and therefore no human health risks are to be expected from hormonal activity in Dutch drinking water from this site.


Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults.
Community-acquired pneumonia is a leading infectious cause of hospitalization and death among U.S. adults. Incidence estimates of pneumonia confirmed radiographically and with the use of current laboratory diagnostic tests are needed. We conducted active population-based surveillance for community-acquired pneumonia requiring hospitalization among adults 18 years of age or older in five hospitals in Chicago and Nashville. Patients with recent hospitalization or severe immunosuppression were excluded. Blood, urine, and respiratory specimens were systematically collected for culture, serologic testing, antigen detection, and molecular diagnostic testing. Study radiologists independently reviewed chest radiographs. We calculated population-based incidence rates of community-acquired pneumonia requiring hospitalization according to age and pathogen. From January 2010 through June 2012, we enrolled 2488 of 3634 eligible adults (68%). Among 2320 adults with radiographic evidence of pneumonia (93%), the median age of the patients was 57 years (interquartile range, 46 to 71); 498 patients (21%) required intensive care, and 52 (2%) died. Among 2259 patients who had radiographic evidence of pneumonia and specimens available for both bacterial and viral testing, a pathogen was detected in 853 (38%): one or more viruses in 530 (23%), bacteria in 247 (11%), bacterial and viral pathogens in 59 (3%), and a fungal or mycobacterial pathogen in 17 (1%). The most common pathogens were human rhinovirus (in 9% of patients), influenza virus (in 6%), and Streptococcus pneumoniae (in 5%). The annual incidence of pneumonia was 24.8 cases (95% confidence interval, 23.5 to 26.1) per 10,000 adults, with the highest rates among adults 65 to 79 years of age (63.0 cases per 10,000 adults) and those 80 years of age or older (164.3 cases per 10,000 adults). For each pathogen, the incidence increased with age. The incidence of community-acquired pneumonia requiring hospitalization was highest among the oldest adults. Despite current diagnostic tests, no pathogen was detected in the majority of patients. Respiratory viruses were detected more frequently than bacteria. (Funded by the Influenza Division of the National Center for Immunizations and Respiratory Diseases.).


Impact of medical subsidy disqualification on children's healthcare utilization: A difference-in-differences analysis from Japan.
Financial support for children's medical expenses has been introduced in many countries. Limited work has been done on price elasticity in children's healthcare demand, especially in countries other than the United States. Moreover, it remains unclear how the effects of a change in the cost sharing rate on healthcare demand would differ by medical condition. We investigated the impact of an increase in the cost sharing rate on medical service utilization among school children as a whole and for each of nine common conditions, applying a difference-in-differences approach. The study period ranged from April 1, 2012, to March 30, 2014. Participants were elementary school children in an urban area who were eligible for National Health Insurance (a community-based public insurance) during the study period and who were enrolled in the 2nd, 3rd, or 4th grade in April 2013. We collected observations from 2896 persons and 69,504 (2896 × 24 months) person-months. When elementary school children were promoted to the 4th grade, they became disqualified for a municipal medical subsidy. The control group was the children promoted to the 2nd or the 3rd grade, who remained eligible for the subsidy. All data were obtained from health insurance claims. We identified the nine most common medical conditions among the subject children, and stratified the analyses by the condition diagnosed. We found that an increase in the cost sharing rate reduced outpatient service utilization as a whole. Also, we observed an increase in inpatient service utilization, not because of worsened health conditions, but rather due to substitution of inpatient service for outpatient service. The reductions in outpatient service were heterogeneous across medical conditions; declines were sharper for mild or chronic conditions. These findings may help to characterize how a change in cost sharing rate affects health outcomes in children.


Prader-Willi syndrome due to uniparental disomy in a patient with a balanced chromosomal translocation.
In contrast to most human autosomal genes which are expressed biallelically, the expression of imprinted genes depends on the parental origin of the allele. Prader-Willi syndrome is a neurobehavioral disorder in which the expression of active paternal alleles of imprinted genes from chromosomal region 15q11-q13 is abolished by deletions, maternal uniparental disomy or imprinting defects. We report an unusual case of maternal uniparental disomy of chromosome 15 due to a balanced translocation t(8;15)(q24.1;q21.2) leading to Prader-Willi syndrome in a 3-year-old girl. Cytogenetic investigation revealed a balanced translocation t(8;15)(q24.1;q21.2) in the patient and subsequently also in her unaffected mother. Fluorescence in situ hybridization analysis did not reveal any deletion of the PWS critical region, but methylation analysis of the SNRPN gene showed an abnormal methylation pattern indicating the absence of paternal chromosome 15. Microsatellite analysis of multiple loci and methylation-specific MLPA analysis confirmed maternal uniparental heterodisomy of chromosome 15 as the cause of PWS in the patient. This example emphasizes the importance of uniparental disomy testing in pregnancies of carriers of chromosomal aberrations with participation of chromosomes carrying imprinted genes involved in human diseases.


The use of 18F-FDG PET/CT in colorectal liver metastases--comparison with CT and liver MRI.
We compared 18-fluoro-2-deoxyglucose ((18)F-FDG) positron emission tomography-CT (PETCT) with contrast-enhanced whole-body CT (ceCT) in identifying extrahepatic disease and with manganese dipyridoxyl diphosphate (Mn-DPDP) liver MRI for liver metastases in patients with colorectal liver metastases being considered for surgery. Sixty-five patients (median age 65 years; 42 men) with colorectal cancer and known or suspicious liver metastases and who underwent a PETCT, ceCT and Mn-DPDP MRI were identified. Results were retrospectively reviewed for extrahepatic disease on PETCT and ceCT, and for the presence and number of liver metastases on PETCT and Mn-DPDP MRI. Proof of metastases was based on histopathology or clinical/imaging follow-up, demonstrating disease progression or response. PETCT identified unexpected extrahepatic disease not detected on ceCT, leading to change in surgical management in 17%. There were three other false-positive cases on PETCT. For liver metastases on a per-patient basis, the sensitivity and specificity of both PETCT and Mn-DPDP MRI were 98% and 100%, respectively. On a per-lesion basis, PETCT and MRI were discordant in 15% (10/66 scans). MRI correctly identified more sub-centimeter metastases in eight scans. PETCT correctly identified more metastases in one case and confirmed disease in one equivocal MRI. PETCT has incremental benefit over conventional ceCT in identifying extrahepatic disease in metastatic colorectal cancer. PETCT has high sensitivity and specificity for the presence of liver metastases and should be included early in initial pre-surgical evaluation and could potentially guide the use of Mn-DPDP MRI. However, Mn-DPDP MRI is superior for small liver metastases and remains a prerequisite for surgical planning in patients with confined liver metastases.


Pharmacokinetics of orally administered ABT-751 in children with neuroblastoma and other solid tumors.
To describe the pharmacokinetics of orally administered ABT-751 and its conjugated metabolites in children with neuroblastoma and other solid tumors and to relate pharmacokinetic parameters to toxicity and therapeutic outcomes. Patients (median age, 11 years) with neuroblastoma (n = 37) or other solid tumors (n = 25) had pharmacokinetic sampling after the first dose of ABT-751 (75-250 mg/m(2)/day) on a 7-day or 21-day schedule. ABT-751 and its glucuronide and sulfate metabolites were quantified with an HPLC/MS/MS assay. Pharmacokinetic parameters were derived with non-compartmental methods. The relative bioavailability of more water soluble capsule and suspension formulations was assessed. ABT-751 peaked in plasma at 2 h and declined monoexponentially with a t (1/2) of 5.1 h. The apparent clearance was 33 ml/min/m(2) and was age-independent. The AUC(0-infinity) increased in proportion to the dose, and at 200 mg/m(2) the median AUC(0-infinity) was 91 mcg h/ml and the C (ave) was 3.9 mcg/ml. Inter-and intra-patient variability was low. The metabolites were detected in plasma 30 min post-dose and peaked 3-5 h after the dose. The glucuronide:sulfate molar AUC(0-infinity) ratio was 0.57. Less than 1% of the dose was excreted in urine as parent drug; 13% of the dose was excreted as sulfate metabolite and 10% as glucuronide metabolite. The relative bioavailability of the water soluble capsule and suspension formulations was 105 and 93%, respectively. AUC(0-infinity) was higher in patients experiencing dose-limiting toxicity. Oral ABT-751 pharmacokinetics was dose-proportional and age-independent with minimal intra- and inter-patient variability in children.


The Role of Diet and Nutrition in Migraine Triggers and Treatment: A Systematic Literature Review.
Migraine is a disabling primary headache disorder often associated with triggers. Diet-related triggers are a common cause of migraine and certain diets have been reported to decrease the frequency of migraine attacks if dietary triggers or patterns are adjusted. The systematic literature review was conducted to qualitatively summarize evidence from the published literature regarding the role of diet patterns, diet-related triggers, and diet interventions in people with migraine. A literature search was carried out on diet patterns, diet-related triggers, and diet interventions used to treat and/or prevent migraine attacks, using an a priori protocol. MEDLINE and EMBASE databases were searched to identify studies assessing the effect of diet, food, and nutrition in people with migraine aged ≥18 years. Only primary literature sources (randomized controlled trials or observational studies) were included and searches were conducted from January 2000 to March 2019. The NICE checklist was used to assess the quality of the included studies of randomized controlled trials and the Downs and Black checklist was used for the assessment of observational studies. A total of 43 studies were included in this review, of which 11 assessed diet patterns, 12 assessed diet interventions, and 20 assessed diet-related triggers. The overall quality of evidence was low, as most of the (68%) studies assessing diet patterns and diet-related triggers were cross-sectional studies or patient surveys. The studies regarding diet interventions assessed a variety of diets, such as ketogenic diet, elimination diets, and low-fat diets. Alcohol and caffeine uses were the most common diet patterns and diet-related triggers associated with increased frequency of migraine attacks. Most of the diet interventions, such as low-fat and elimination diets, were related to a decrease in the frequency of migraine attacks. There is limited high-quality randomized controlled trial data on diet patterns or diet-related triggers. A few small randomized controlled trials have assessed diet interventions in preventing migraine attacks without strong results. Although many patients already reported avoiding personal diet-related triggers in their migraine management, high-quality research is needed to confirm the effect of diet in people with migraine.


Generalization of occupational therapy effects in psychiatric rehabilitation.
Psychoeducation procedures dominate the treatment used by occupational therapists in psychiatric rehabilitation. The underlying assumption of skills training is that the skills taught generalize, that is, they persist beyond the treatment session and are used by the client in the community. This paper surveys occupational therapy literature to evaluate the generalization of skills taught to adult psychiatric clients by occupational therapists. Of the 77 studies reviewed, only 13 (17%) mentioned anything related to generalization. Seven of these articles statistically evaluated the outcome of skills training, but only four specifically assessed generalization of therapy. It is concluded that occupational therapists in psychiatry predominantly do not assess generalization of therapy. Discussion focuses on how four classes of generalization strategies (modifying the community environment, modifying the therapy environment, altering the style of therapy, and promoting client involvement) can enhance the effectiveness of occupational therapists in psychiatry.


Lung transplant airway hypoxia: a diathesis to fibrosis?
Chronic rejection, manifested pathologically as airway fibrosis, is the major problem limiting long-term survival in lung transplant recipients. Airway hypoxia and ischemia, resulting from a failure to restore the bronchial artery (BA) circulation at the time of transplantation, may predispose patients to chronic rejection. To address this possibility, clinical information is needed describing the status of lung perfusion and airway oxygenation after transplantation. To determine the relative pulmonary arterial blood flow, airway tissue oxygenation and BA anatomy in the transplanted lung was compared with the contralateral native lung in lung allograft recipients. Routine perfusion scans were evaluated at 3 and 12 months after transplantation in 15 single transplant recipients. Next, airway tissue oximetry was performed in 12 patients during surveillance bronchoscopies in the first year after transplant and in 4 control subjects. Finally, computed tomography (CT)-angiography studies on 11 recipients were reconstructed to evaluate the post-transplant anatomy of the BAs. By 3 months after transplantation, deoxygenated pulmonary arterial blood is shunted away from the native lung to the transplanted lung. In the first year, healthy lung transplant recipients exhibit significant airway hypoxia distal to the graft anastomosis. CT-angiography studies demonstrate that BAs are abbreviated, generally stopping at or before the anastomosis, in transplant airways. Despite pulmonary artery blood being shunted to transplanted lungs after transplantation, grafts are hypoxic compared with both native (diseased) and control airways. Airway hypoxia may be due to the lack of radiologically demonstrable BAs after lung transplantation.


A novel quenched fluorescent activity-based probe reveals caspase-3 activity in the endoplasmic reticulum during apoptosis.
The caspases are a family of cysteine proteases that are key regulators of apoptosis and their activity may thus serve as a good marker to monitor cell death. We have developed a quenched fluorescent activity-based probe (qABP) that is selective for caspase-3 activity and emits a fluorescent signal after covalently modifying its target. The probe has a wide range of potential applications, e.g. in real-time imaging, FACS analysis or biochemical quantification of caspase activity in intact cells. Application of the probe allowed us to monitor caspase-3 activation after chemotherapy-treatment and to distinguish between apoptosis sensitive and resistant cells. Moreover, it enabled real-time high-resolution visualization of active caspase-3 during apoptosis. This led to the surprising finding that in cancerous cells active caspase-3 is not only found at the familiar cellular locations but also in mitochondria and the endoplasmic reticulum. Thus, our novel covalent probe allows high spatial and temporal resolution imaging of caspase-3 activation and may thus be used as an effective tool to study molecular mechanisms of programmed cell death in healthy and disease states.


Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.
Myeloproliferative neoplasms (MPNs) originate from genetically transformed hematopoietic stem cells that retain the capacity for multilineage differentiation and effective myelopoiesis. Beginning in early 2005, a number of novel mutations involving Janus kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), TET oncogene family member 2 (TET2), Additional Sex Combs-Like 1 (ASXL1), Casitas B-lineage lymphoma proto-oncogene (CBL), Isocitrate dehydrogenase (IDH) and IKAROS family zinc finger 1 (IKZF1) have been described in BCR-ABL1-negative MPNs. However, none of these mutations were MPN specific, displayed mutual exclusivity or could be traced back to a common ancestral clone. JAK2 and MPL mutations appear to exert a phenotype-modifying effect and are distinctly associated with polycythemia vera, essential thrombocythemia and primary myelofibrosis; the corresponding mutational frequencies are approximately 99, 55 and 65% for JAK2 and 0, 3 and 10% for MPL mutations. The incidence of TET2, ASXL1, CBL, IDH or IKZF1 mutations in these disorders ranges from 0 to 17%; these latter mutations are more common in chronic (TET2, ASXL1, CBL) or juvenile (CBL) myelomonocytic leukemias, mastocytosis (TET2), myelodysplastic syndromes (TET2, ASXL1) and secondary acute myeloid leukemia, including blast-phase MPN (IDH, ASXL1, IKZF1). The functional consequences of MPN-associated mutations include unregulated JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling, epigenetic modulation of transcription and abnormal accumulation of oncoproteins. However, it is not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation.


Errors and electronic prescribing: a controlled laboratory study to examine task complexity and interruption effects.
To examine the effect of interruptions and task complexity on error rates when prescribing with computerized provider order entry (CPOE) systems, and to categorize the types of prescribing errors. Two within-subject factors: task complexity (complex vs simple) and interruption (interruption vs no interruption). Thirty-two hospital doctors used a CPOE system in a computer laboratory to complete four prescribing tasks, half of which were interrupted using a counterbalanced design. Types of prescribing errors, error rate, resumption lag, and task completion time. Errors in creating and updating electronic medication charts that were measured included failure to enter allergy information; selection of incorrect medication, dose, route, formulation, or frequency of administration from lists and drop-down menus presented by the CPOE system; incorrect entry or omission in entering administration times, start date, and free-text qualifiers; and omissions in prescribing and ceasing medications. When errors occurred, the error rates across the four prescribing tasks ranged from 0.5% (1 incorrect medication selected out of 192 chances for selecting a medication or error opportunities) to 16% (5 failures to enter allergy information out of 32 error opportunities). Any impact of interruptions on prescribing error rates and task completion times was not detected in our experiment. However, complex tasks took significantly longer to complete (F(1, 27)=137.9; p<0.001) and when execution was interrupted they required almost three times longer to resume compared to simple tasks (resumption lag complex=9.6 seconds, SD=5.6; resumption lag simple=3.4 seconds, SD=1.7; t(28)=6.186; p<0.001). Most electronic prescribing errors found in this study could be described as slips in using the CPOE system to create and update electronic medication charts. Cues available within the user interface may have aided resumption of interrupted tasks making CPOE systems robust to some interruption effects. Further experiments are required to rule out any effect interruption might have on CPOE error rates.


Quantification of reduced health-related quality of life in patients with rheumatoid arthritis compared to the general population.
To compare levels of health-related quality of life (HRQOL) among patients with rheumatoid arthritis (RA) to those of the general population. Disease burden was assessed using a generic health status instrument (Medical Outcome Study Short Form-36) for measurements of HRQOL and SF-6D to calculate utility scores in representative patients aged 20 to 79 years from the Oslo RA Register (n = 1052), and in individuals in the general population (n = 2323). Comparisons were performed with respect to sex and age, and standardized difference scores (s-scores) were calculated for comparisons with the norm. HRQOL in patients with RA was reduced compared to the general population on all scales of the SF-36 for both males and females and for all age groups. s-scores adjusted for age and education ranged from -1.39 for physical functioning to -0.27 for mental health. The overall difference in utility was 0.16 and ranged from 0.13 (in female patients below 50 yrs) to 0.20 (patients 50-60 years). This implies that RA of 1 year duration entails a disease burden of 14-20 quality-adjusted life-years in 100 RA patients. RA inflicts a substantial disease burden, and the disease affects all HRQOL dimensions as measured by the SF-36 in both sexes and in all age groups. Physical functioning is predominantly affected, but RA has social and mental consequences.


A survey on the intended purposes and perceived utility of preoperative cardiology consultations.
Cardiology consultations are often requested by surgeons and anesthesiologists for patients with cardiovascular disease. There can be confusion, however, regarding both the reasons for a consultation and their effect on patient management. This study was designed to determine the attitudes of physicians toward preoperative cardiology consultations and to assess the effect of such consultations on perioperative management. A multiple-choice survey regarding the purposes and utility of cardiology consultations was sent to randomly selected New York metropolitan area anesthesiologists, surgeons, and cardiologists. In addition, the charts of 55 consecutive patients aged >50 yr who received preoperative cardiology consultations were examined to determine the stated purpose of the consult, recommendations made, and concordance by surgeons and anesthesiologists with cardiologists' recommendations. Of the 400 surveys sent to each specialty, 192 were returned from anesthesiologists, 113 were returned from surgeons, and 129 were returned from cardiologists. There was substantial disagreement on the importance and purposes of a cardiology consult: intraoperative monitoring, "clearing the patient for surgery," and advising as to the safest type of anesthesia were regarded as important by most cardiologists and surgeons but as unimportant by anesthesiologists (all P < 0.05). Most surgeons (80.2%) felt obligated to follow a cardiologist's recommendations, whereas few anesthesiologists (16.6%) felt so obligated (P < 0.05). The most commonly stated purpose of the 55 cardiology consultations examined was "preoperative evaluation." Only 5 of these (9%) were obtained for patients in whom there was a new finding. Of the cardiology consultations, 40% contained no recommendations other than "proceed with case," "cleared for surgery," or "continue current medications." Recommendations regarding intraoperative monitoring or cardiac medications were largely ignored. We conclude that there seems to be considerable disagreement among anesthesiologists, cardiologists, and surgeons as to the purposes and utility of cardiology consultations. A review of 55 consecutive cardiology consultations suggests that most of them give little advice that truly affects management.


Portrayal of tobacco use in prime-time TV dramas: trends and associations with adult cigarette consumption--USA, 1955-2010.
Although portrayal of television (TV) and movie tobacco use has been linked with initiation of cigarette smoking in adolescents, its association with smoking in adults has not been assessed. Therefore, we examined long-term and annual changes in tobacco portrayal in popular US TV dramas and their associations with comparable trends in national adult cigarette consumption. Tobacco use in 1838 h of popular US TV dramas was coded from 1955-2010. The long-term trend and annual deviations from trend were studied in relation to comparable trends in adult per capita cigarette consumption using correlational and time-series methods that controlled for other potential predictors. TV tobacco portrayal has trended downward since 1955 in line with the historical trend in cigarette consumption. Controlling for changes in cigarette prices and other factors, annual changes of one tobacco instance per episode hour across 2 years of programming were associated with annual change of 38.5 cigarettes per US adult. The decline in TV tobacco portrayal was associated with nearly half the effect of increases in cigarette prices over the study period. The correlation between tobacco portrayal in TV dramas and adult cigarette consumption is consistent with well-established effects of exposure to tobacco cues that create craving for cigarettes in adult smokers. Although tobacco use in TV dramas along with movies has declined over time, portrayal of smoking on screen media should be a focus for future adult tobacco control research and policy.


Implicit influence of affective postures on the perception of others: you can't show me how I feel.
This study examined how one's own posture influences the perception of another's posture in a task with implicit affective information. In 2 experiments, participants assumed or viewed a body posture and then compared that posture with a viewed posture. They were not told that postures varied in affective valence: positive, negative, neutral-abstract, or neutral-meaningful. Posture affect influenced both accuracy and response time measures of posture discrimination. Participants were slower and less accurate for targets that matched an assumed posture, but only for affective postures. This pattern did not hold for matching affectively neutral postures (meaningful or not), nonmatching postures, or for purely visual comparisons. These results are consistent with both cognitive embodiment theories postulating that personal body posture influences the perception of other's postures and emotional embodiment theories postulating sensorimotor and emotional simulation processes that create correspondences between one's own and another's emotional postures. Nonetheless, these findings differ from studies finding facilitation for explicit emotional judgments of affective congruence. People use different information depending on task requirements. The assumption of an affective posture may activate simulations of personal emotional experiences that may, in turn, serve to differentiate personal posture perception from ostensibly the same posture in another person.


EARS to cyber incidents in health care.
Connected medical devices and electronic health records have added important functionality to patient care, but have also introduced a range of cybersecurity concerns. When a healthcare organization suffers from a cybersecurity incident, its incident response strategies are critical to the success of its recovery. In this article, we identify gaps in research concerning cybersecurity response plans in healthcare. Through a systematic literature review, we develop aggregated strategies that professionals can use to construct better response strategies in their organizations. We reviewed journal articles on cyber incident response plans in healthcare published in PubMed and Web of Science. We sought to collect articles on the intersection of cybersecurity and healthcare that focused on incident response strategies. We identified and reviewed 13 articles for cybersecurity response recommendations. We then extracted information such as research methods, findings, and implications. Finally, we synthesized the recommendations into a framework of eight aggregated response strategies (EARS) that fall under managerial and technological categories. We conducted a systematic review of the literature on cybersecurity response plans in healthcare and developed a novel framework for response strategies that could be deployed by healthcare organizations. More work is needed to evaluate incident response strategies in healthcare.


Diabetes treatment and hypoglycaemic episodes in elderly patients at nursing homes in Uppsala County.
The aim of this study was to examine the situation for elderly patients with diabetes living in nursing homes with regard to diabetes treatment, clinical variables, and vascular complications associated with diabetes. A second aim was to evaluate if the patients were at risk of hypoglycaemia. This was a cross-sectional study including diabetes patients from all 30 nursing homes in Uppsala County, Sweden. Current antidiabetic medications, HbA1c, hypoglycaemic events, and diabetes complications were registered from the medical records. The patients were stratified into a general group and divided into three groups according to HbA1c (<52, 52-73, and >73 mmol/mol). Of 1,350 individuals, 218 patients were identified with diabetes mellitus. The diabetes duration was 11.2 ± 9.4 years and their serum HbA1c concentration 56.0 ± 1.2 mmol/mol. Hypoglycaemic events were reported in 24% of the diabetic individuals, and 43.1% of them had HbA1c <52 mmol/mol (mean value 44.0 ± 1.1 mmol/mol). Of these, 36% were taking antidiabetic drugs. Another 35.8% of the patients had HbA1c values between 52-73 mmol/mol (mean value 60.0 ± 1.1 mmol/mol), and 82% of these patients were taking antidiabetic drugs. Almost 80% of the diabetic patients had either micro- or macrovascular complications, with diabetes duration as an association for both micro- or macrovascular complications and hypoglycaemic events. A reduction of the use of antidiabetic drugs with follow-up of HbA1c level should be considered, especially for multimorbid elderly patients with low HbA1c and hypoglycaemia.


Pervasive horizontal transfer of rolling-circle transposons among animals.
Horizontal transfer (HT) of genes is known to be an important mechanism of genetic innovation, especially in prokaryotes. The impact of HT of transposable elements (TEs), however, has only recently begun to receive widespread attention and may be significant due to their mutagenic potential, inherent mobility, and abundance. Helitrons, also known as rolling-circle transposons, are a distinctive subclass of TE with a unique transposition mechanism. Here, we describe the first evidence for the repeated HT of four different families of Helitrons in an unprecedented array of organisms, including mammals, reptiles, fish, invertebrates, and insect viruses. The Helitrons present in these species have a patchy distribution and are closely related (80-98% sequence identity), despite the deep divergence times among hosts. Multiple lines of evidence indicate the extreme conservation of sequence identity is not due to selection, including the highly fragmented nature of the Helitrons identified and the lack of any signatures of selection at the nucleotide level. The presence of horizontally transferred Helitrons in insect viruses, in particular, suggests that this may represent a potential mechanism of transfer in some taxa. Unlike genes, Helitrons that have horizontally transferred into new host genomes can amplify, in some cases reaching up to several hundred copies and representing a substantial fraction of the genome. Because Helitrons are known to frequently capture and amplify gene fragments, HT of this unique group of DNA transposons could lead to horizontal gene transfer and incur dramatic shifts in the trajectory of genome evolution.


Effects of cell-mediated osteoprotegerin gene transfer and mesenchymal stem cell applications on orthodontically induced root resorption of rat teeth.
The aim of this study is to evaluate and compare therapeutic effects of mesenchymal stem cell (MSCs) and osteoprotegerin (OPG) gene transfer applications on inhibition and/or repair of orthodontically induced inflammatory root resorption (OIIRR). Thirty Wistar rats were divided into four groups as untreated group (negative control), treated with orthodontic appliance group (positive control), MSCs injection group, and OPG transfected MSCs [gene therapy (GT) group]. About 100g of orthodontic force was applied to upper first molar teeth of rats for 14 days. MSCs and transfected MSC injections were performed at 1st, 6th, and 11th days to the MSC and GT group rats. At the end of experiment, upper first molar teeth were prepared for genetical, scanning electron microscopy (SEM), fluorescent microscopy, and haematoxylin eosin-tartrate resistant acid phosphatase staining histological analyses. Number of total cells, number of osteoclastic cells, number of resorption lacunae, resorption area ratio, SEM resorption ratio, OPG, RANKL, Cox-2 gene expression levels at the periodontal ligament (PDL) were calculated. Paired t-test, Kruskal-Wallis, and chi-square tests were performed. Transferred MSCs showed marked fluorescence in PDL. The results revealed that number of osteoclastic cells, resorption lacunae, resorption area ratio, RANKL, and Cox-2 were reduced after single MSC injections significantly (P < 0.05). GT group showed the lowest number of osteoclastic cells (P < 0.01), number of resorption lacunae, resorption area ratio, and highest OPG expression (P < 0.001). Taken together all these results, MSCs and GT showed marked inhibition and/or repair effects on OIIRR during orthodontic treatment on rats.


Repetitive immunization enhances the susceptibility of mice to peripherally administered prions.
The susceptibility of humans and animals to prion infections is determined by the virulence of the infectious agent, by genetic modifiers, and by hitherto unknown host and environmental risk factors. While little is known about the latter two, the activation state of the immune system was surmised to influence prion susceptibility. Here we administered prions to mice that were repeatedly immunized by two initial injections of CpG oligodeoxynucleotides followed by repeated injections of bovine serum albumin/alum. Immunization greatly reduced the required dosage of peripherally administered prion inoculum necessary to induce scrapie in 50% of mice. No difference in susceptibility was observed following intracerebral prion challenge. Due to its profound impact onto scrapie susceptibility, the host immune status may determine disease penetrance after low-dose prion exposure, including those that may give rise to iatrogenic and variant Creutzfeldt-Jakob disease.


Endothelial cells on the move: dynamics in vascular morphogenesis and disease.
The vascular system is a hierarchically organized network of blood vessels that play crucial roles in embryogenesis, homeostasis and disease. Blood vessels are built by endothelial cells - the cells lining the interior of blood vessels - through a process named vascular morphogenesis. Endothelial cells react to different biomechanical signals in their environment by adjusting their behavior to: (1) invade, proliferate and fuse to form new vessels (angiogenesis); (2) remodel, regress and establish a hierarchy in the network (patterning); and (3) maintain network stability (quiescence). Each step involves the coordination of endothelial cell differentiation, proliferation, polarity, migration, rearrangements and shape changes to ensure network integrity and an efficient barrier between blood and tissues. In this review, we highlighted the relevance and the mechanisms involving endothelial cell migration during different steps of vascular morphogenesis. We further present evidence on how impaired endothelial cell dynamics can contribute to pathology.


Exact analysis of the evanescent coupling between two indiffused optical waveguides.
An exact scalar wave analysis of a directional coupler obtained by coupling two identical graded-index wave-guides having exponential profiles is given. This analysis has been used to study the validity of the widely used coupled-mode theory for studying such problems. The study shows that coupled-mode theory indeed leads to very good results for weak coupling but may lead to quite inaccurate results for sufficiently strong coupling.


Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells.
Myeloid dendritic cells (DCs) are pivotal in the recognition of alloantigens and, therefore, in the induction of allograft rejection. Induction of alloreactive T cell proliferation by myeloid DCs depends on the maturation of DCs, the expression of costimulatory molecules, and the cytokine environment. This study investigated the effects of tacrolimus and cyclosporine A (CsA) on DC maturation and allostimulatory capacity. Myeloid DCs were propagated from normal blood monocytes with interleukin (IL) 4 and GM-CSF for 7 days in the presence or absence of tacrolimus (FK506; 10 nM) or CsA (1 microg/mL). Exposure of DCs during maturation to tacrolimus or CsA resulted in no significant change in the expression of DC phenotypic markers, including CD80, CD86, and HLA Class I and II antigens determined by flow cytometry. T cell proliferation in one-way, mixed-leukocyte reaction experiments revealed a decreased allostimulatory capacity of DCs that matured in the presence of tacrolimus or CsA compared with untreated controls (P<0.02). Production of inflammatory cytokines, tumor necrosis factor alpha (P<0.04) and IL-12 (P<0.04) in response to lipopolysaccharide (1 microg/mL) or staphylococcal enterotoxin B (1 microg/mL) induction was significantly reduced in DCs exposed to tacrolimus or CsA during maturation. In contrast, production of the immuninhibitory cytokine IL-10 was not decreased in tacrolimus- or CsA-treated DCs. These results suggest that tacrolimus and CsA inhibit the allostimulatory capacity of in vitro-generated myeloid DCs without significant effects on DC phenotypic maturation. Decreased production of IL-12 and tumor necrosis factor alpha, but not of IL-10, is likely to contribute to the impaired accessory-cell function of tacrolimus- and CsA-treated DCs. Thus, tacrolimus and CsA can inhibit recognition of alloantigens by decreasing the accessory-cell capacity of monocyte-derived myeloid DCs.


Characterization of Novel Rhabdoviruses in Chinese Bats.
Bats, the second largest order of mammals worldwide, harbor specific characteristics such as sustaining flight, a special immune system, unique habits, and ecological niches. In addition, they are the natural reservoirs of a variety of emerging or re-emerging zoonotic pathogens. Rhabdoviridae is one of the most diverse families of RNA viruses, which consists of 20 ecologically diverse genera, infecting plants, mammals, birds, reptiles, and fish. To date, three bat-related genera are described, named Lyssavirus, Vesiculovirus, and Ledantevirus. However, the prevalence and the distribution of these bat-related rhabdoviruses remain largely unknown, especially in China. To fill this gap, we performed a large molecular retrospective study based on the real-time reverse transcription polymerase chain reaction (RT-qPCR) detection of lyssavirus in bat samples (1044 brain and 3532 saliva samples, from 63 different bat species) originating from 21 provinces of China during 2006-2018. None of them were positive for lyssavirus, but six bat brains (0.6%) of Rhinolophus bat species, originating from Hubei and Hainan provinces, were positive for vesiculoviruses or ledanteviruses. Based on complete genomes, these viruses were phylogenetically classified into three putative new species, tentatively named Yinshui bat virus (YSBV), Taiyi bat virus (TYBV), and Qiongzhong bat virus (QZBV). These results indicate the novel rhabdoviruses circulated in different Chinese bat populations.