Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death.
In chronic liver injury, hepatic stellate cells (HSCs) proliferate and produce excessive amounts of connective tissue causing liver fibrosis and cirrhosis. Oxidative stress has been implicated as a driving force of HSC activation and proliferation, although contradictory results have been described. To determine the effects of oxidative stress on activated HSC proliferation, survival and signalling pathways. Serum-starved culture-activated rat HSCs were exposed to the superoxide anion donor menadione (5-25 micromol/L) or hydrogen peroxide (0.2-5 mmol/L). Haem oxygenase-1 mRNA expression, glutathione status, cell death, phosphorylation of mitogen-activated protein (MAP) kinases and proliferation were investigated. Menadione induced apoptosis in a dose- and time-dependent, but caspase-independent manner. Hydrogen peroxide induced necrosis only at extremely high concentrations. Both menadione and hydrogen peroxide activated Jun N-terminal kinase (JNK) and p38. Hydrogen peroxide also activated extracellular signal-regulated protein. Menadione, but not hydrogen peroxide, reduced cellular glutathione levels. Inhibition of JNK or supplementation of glutathione reduced menadione-induced apoptosis. Non-toxic concentrations of menadione or hydrogen peroxide inhibited platelet-derived growth factor- or/and serum-induced proliferation. Reactive oxygen species (ROS) inhibit HSC proliferation and promote HSC cell death in vitro. Different ROS induce different modes of cell death. Superoxide anion-induced HSC apoptosis is dependent on JNK activation and glutathione status.


Endophytic colonisation of Bacillus subtilis in the roots of Robinia pseudoacacia L.
The endophytic colonisation of Bacillus subtilis strain GXJM08, isolated from roots of Podocarpus imbricatus B1. Enum. P1. Jav., in roots of the leguminous plant Robinia pseudoacacia L. was investigated. Ultrastructure observations showed that B. subtilis caused morphological changes in the root hair and colonised the plant through infected root hairs. The structure of the infection thread was similar to that of rhizobia, but the structure of infected cells was different. B. subtilis is also different from rhizobia and plant pathogens in terms of the formation of a peribacteroid membrane and the mode of penetration through the host cell wall. Our results provide a basis for studying development of the mutualistic symbiotic relationship between B. subtilis and plants, and a basis for studying the mechanism of the B. subtilis-plant interaction.


Dendriplex-Impregnated Hydrogels With Programmed Release Rate.
Hydrogels are biocompatible matrices for local delivery of nucleic acids; however, functional dopants are required to provide efficient delivery into cells. In particular, dendrimers, known as robust nucleic acid carriers, can be used as dopants. Herein, we report the first example of impregnating neutral hydrogels with siRNA-dendrimer complexes. The surface chemistry of dendrimers allows adjusting the release rate of siRNA-containing complexes. This methodology can bring new materials for biomedical applications.


Creating an LMS ePortfolio Building System That Enhances the Quality of College Life from One That Supports Self-Regulated Learning.
During the recent coronavirus disease 2019 (COVID-19) pandemic, the ability to be a self-regulated learner has become more important with the introduction of online classes. These changes mean that students are now required to review their learning strategies and self-manage their learning time. We have developed a new "ePortfolio system" with the aim of building a system that fosters self-regulated learners and can visualize students' learning outcomes. This paper introduces the concepts of our ePortfolio system as a Learning Management System ePortfolio building system that will provide enhanced functions and become a university-wide initiative.


[Application of ultrasonography in diagnosis and treatment of acute inflammation of soft tissues in maxillofacial region and neck].
We investigated the value of ultrasonography (USG) and ultrasound-guided aspirations in diagnosis and treatment of acute inflammation of soft tissues in maxillofacial region and neck. We performed 174 USG in 136 patients (73 with abscesses and phlegmons, 27 with acute lymphadenitis, 16 with inflamed cysts, 12 with parotitis, 3 with sialolithiasis and 5 with diseases, simulated acute inflammation). Ultrasound-guided aspirations performed in 35 patients. We considered USG to be useful diagnostic tool in acute inflammation of soft tissues in maxillofacial region and neck. USG allowed to determine localization and stage of inflammation, discriminate it from non-inflammatory diseases and improve assessment of its dynamics. Ultrasound-guided aspirations was a valuable tool for diagnostic and treatment purposes in inflamed cysts.


Long-term training on sand changes lower limb muscle activities during running in runners with over-pronated feet.
Running on sand could be a promising exercise intervention for the treatment of over-pronated feet. However, there is a lack of knowledge about the effects of running on sand on muscle activities. Therefore, this study aims to evaluate the long-term effects of running on sand on the activities of selected lower limb muscles in individuals with OPF compared with healthy controls. Sixty recreational adult male runners with over-pronated feet (foot posture index > 10) were divided into two equal groups (intervention and control). Participants ran barefoot at a pre-defined speed (⁓3.3 m/s) over level stable ground both before and after long-term training on the sand. Muscle activities were recorded using a surface bipolar electromyography system. For the intervention group, we found a reduced foot posture index (p < 0.001; d = 2.00) and significant group-by-time interactions for gluteus medius activity during the mid-stance phase (p < 0.028; d = 0.59). Significantly higher gluteus medius activity (p = 0.028, d = 0.569) was found during the post-test. We also observed significant group-by-time interactions for medial gastrocnemius activity during the push-off phase (p < 0.041; d = 0.54). Significantly larger medial gastrocnemius activity (p = 0.041; d = 0.636) was found during the post-test compared to the pre-test. Long-term running on sand resulted in reduced pronation, increased medial gastrocnemius activity, and improved frontal plane pelvic stability due to higher gluteus medius activity. IRCT20191211045704N1. Registered 25 February 2020. Retrospectively registered.


Half-Quantum Vortices in an Antiferromagnetic Spinor Bose-Einstein Condensate.
We report on the observation of half-quantum vortices (HQVs) in the easy-plane polar phase of an antiferromagnetic spinor Bose-Einstein condensate. Using in situ magnetization-sensitive imaging, we observe that pairs of HQVs with opposite core magnetization are generated when singly charged quantum vortices are injected into the condensate. The dynamics of HQV pair formation is characterized by measuring the temporal evolutions of the pair separation distance and the core magnetization, which reveals the short-range nature of the repulsive interactions between the HQVs. We find that spin fluctuations arising from thermal population of transverse magnon excitations do not significantly affect the HQV pair formation dynamics. Our results demonstrate the instability of a singly charged vortex in the antiferromagnetic spinor condensate.


Estimates of Total Burned Surface Area by Emergency Department Clinicians and Burn Specialists.
Introduction Correctly assessing burn size is extremely important since it is directly associated with a patient's subsequent management. Further, an accurate assessment of the total body surface area (TBSA) involved is crucial to decide if specialty care in a burn unit is necessary, whereby overestimation has the potential to lead to unnecessary patient transfers and undesirable burdens on the healthcare system and inconvenience to patients. The goal of this study was to identify whether burn injury estimates of TBSA percentage correlate between emergency department (ED) clinician and burn specialists. Methods This was a retrospective study conducted between February 1, 2018 and July 31, 2019 of patients with a burn injury who were evaluated by both an ED clinician and a burn specialist during the same ED visit. Charts were reviewed to identify the documentation of TBSA by pre-hospital personnel, ED nursing staff, ED mid-level providers (MLP), ED attending physicians, burn consultant MLPs, and burn consultant attending physicians. Results During the study period, 189 subjects with both an ED and burn consultant. The median age was 11 years [interquartile range (IQR) 1-49], and 103 (54%) were males. More than half of the subjects (n=106, 56%) were under the age of 18. There was a statistically significant correlation between estimates of TBSA between ED and burn consultants overall (p<0.0001). Furthermore, there was a statistically significant correlation between ED and burn MLPs (p<0.0001) as well as ED and burn attending physicians (p<0.0001). When adjusted for MLP and attending sex, there was still a correlation among all groups (p<0.0001). Conclusions In this study, there was a statistically significant correlation between estimates of TBSA between ED and burn consultants.


The importance of tachyphylaxis and release of cyclooxygenase products in the modulation of endothelin-1-induced responses in rat and guinea pig tracheal chains.
Responses to endothelin-1 (ET-1) were studied in both rat and guinea pig tracheal chains in vitro. Indomethacin potentiated contractile responses to ET-1 in the guinea pig but had no effect in the rat. Furthermore, relaxation responses to ET-1 observed in some guinea pig preparations only were abolished by indomethacin. Studies using repeated full cumulative dose-response curves and repeated single-dosing techniques demonstrated tachyphylaxis to ET-1 in both rat and guinea pig. However, the degree of tachyphylaxis in the guinea pig was dependent on the initial response to the peptide, and in single-dose studies in this species, tachyphylaxis to ET-1 was more prominent in the presence of indomethacin. It is suggested that both tachyphylaxis and inconsistent release of cyclooxygenase products may be responsible for the wide differences in potency estimates for ET-1 that have been observed in airways smooth muscle.


Fusarial toxins: secondary metabolites of Fusarium fungi.
Exposure to mycotoxins occurs worldwide, even though there are geographic and climatic differences in the amounts produced and occurrence of these substances.Mycotoxins are secondary chemical metabolites of different fungi. They are natural contaminants of cereals, so their presence is often inevitable. Among many genera that produce mycotoxins, Fusarium fungi are the most widespread in cereal-growing areas of the planet. Fusarium fungi produce a diversity of mycotoxin types, whose distributions are also diverse. What is produced and where it is produced is influenced primarily by environmental conditions, and crop production and storage methods. The amount of toxin produced depends on physical (viz., moisture, relative humidity, temperature, and mechanical damage), chemical (viz., carbon dioxide,oxygen, composition of substrate, insecticides and fungicides), and biological factors (viz., plant variety, stress, insects, spore load, etc.). Moisture and temperature have a major influence on mold growth rate and mycotoxin production.Among the most toxic and prevalent fusaria) toxins are the following: zearalenone,fumonisins, moniliformin and trichothecenes (T-2/HT-2 toxin, deoxynivalenol,diacetoxyscirpenol, nivalenol). Zearalenone (ZEA; ZON, F-2 toxin) isaphy to estrogenic compound, primarily a field contaminant, which exhibits estrogenic activity and has been implicated in numerous mycotoxicoses of farm animals,especially pigs. Recently, evidence suggests that ZEA has potential to stimulate the growth of human breast cancer cells. Fumonisins are also cancer-promoting metabolites,of which Fumonisin 8 I (FBI) is the most important. Moniliformin (MON) isalso highly toxic to both animals and humans. Trichothecenes are classified as gastrointestinal toxins, dermatotoxins, immunotoxins, hematotoxins, and gene toxins.T-2 and HT-2 toxin, and diacetoxyscirpenol (DAS, anguidine) are the most toxic mycotoxins among the trichothecene group. Deoxynivalenol (DON, vomitoxin) and nivalenol although less toxic are important because they frequently occur at levels high enough to cause adverse effects.The presence of mycotoxins in the animal diet can produce significant production losses. Any considerable presence of mycotoxins, in major dietary components,confirms the need to adopt a continuous prevention and control program. Such programs are usually based on several common approaches to minimize mycotoxin contamination in the food chain. Major strategies include preventing fungal growth and therefore mycotoxin formation, reducing or eliminating mycotoxins from contaminated feedstuffs, or diverting contaminated products to low risk uses. Because of the complexity of their chemical structures, mycotoxins also present a major analytical challenge. They are also found in a vast array of feed matrices. Analysis is essential for determining the extent of mycotoxin contamination, for risk analysis, confirming the diagnosis of a mycotoxicosis and for monitoring mycotoxin mitigation strategies.For the future, adequately controlling the mycotoxin problem in the livestock economy will depend on implementing appropriate agricultural management policies,as well as augmenting production and storage systems and analysis methods.Only such policies offer the opportunity to bring solid and long-lasting economical results to the livestock industry that is afflicted with the mycotoxin problem.


Changes in adiposity and fat tissue distribution among preschool children from Kraków, Poland, from 2008 to 2018.
In the light of changes in the living conditions of populations, excess adiposity is currently a serious public health problem worldwide. The aim of this study was to assess the changes in the body fat ratio among preschool children aged 3-7 years from Kraków, Poland, between 2008 and 2018. The study group consisted of children examined in two cross-sectional studies. Analysed characteristics included triceps, calf, subscapular, abdominal and suprailiac skinfold thicknesses, and adiposity calculated according to Slaughter's equations. The trunk adiposity index and limbs-to-trunk fat ratio were also calculated. Statistical significance was obtained using two-way ANOVA and Tukey's tests. Lower-limb adiposity was largest in the 2008 cohort and trunk adiposity was greater in the 2018 cohort. The mean values of the trunk adiposity index and limbs-to-trunk fat ratio were lower in the 2018 cohort than in the 2008 cohort. The 2018 cohort was also characterized by a lower overall adiposity. Regardless of the lower body adiposity percentage, in 2018 there was a tendency towards the central allocation of fat tissue. This is a negative phenomenon because, especially when co-existing with reduced lower-limb adiposity, it is associated with an increased risk of metabolic and cardiovascular diseases, even in young children.


Analysis of the effects of finite element type within a 3D biomechanical model of a human optic nerve head and posterior pole.
Biomechanical stresses and strains can be simulated in the optic nerve head (ONH) using the finite element (FE) method, and various element types have been used. This study aims to investigate the effects of element type on the resulting ONH stresses and strains. A single eye-specific model was constructed using 3D delineations of anatomic surfaces in a high-resolution, fluorescent, 3D reconstruction of a human posterior eye, then meshed using our simple meshing algorithm at various densities using 4- and 10-noded tetrahedral elements, as well as 8- and 20-noded hexahedral elements. A mesh-free approach was used to assign heterogeneous, anisotropic, hyperelastic material properties to the lamina cribrosa, sclera and pia. The models were subjected to elevated IOP of 45 mmHg after pre-stressing from 0 to 10 mmHg, and solved in the open-source FE package Calculix; results were then interpreted in relation to computational time and simulation accuracy, using the quadratic hexahedral model as the reference standard. The 10-noded tetrahedral and 20R-noded hexahedral elements exhibited similar scleral canal and laminar deformations, as well as laminar and scleral stress and strain distributions; the quadratic tetrahedral models ran significantly faster than the quadratic hexahedral models. The linear tetrahedral and hexahedral elements were stiffer compared to the quadratic element types, yielding much lower stresses and strains in the lamina cribrosa. Prior studies have shown that 20-noded hexahedral elements yield the most accurate results in complex models. Results show that 10-noded tetrahedral elements yield very similar results to 20-noded hexahedral elements and so they can be used interchangeably, with significantly lower computational time. Linear element types did not yield acceptable results.


[Relationship between blood pressure and serum insulin in Yi and Han people in Liangshan, Sichuan Province].
To explore the relationship between blood pressure and serum insulin level in different nationalities and whether there is difference in the effects of insulin on raising blood pressure. Study subjects were selected with cluster sampling from urban and rural areas in Xichang City, Butuo County and Zhaojue County, Liangshan Yi Autonomous Prefecture, Sichuan Province during October to December 1996, including Yi farmers, Yi migrants and local Han residents. Their systolic and diastolic blood pressure, body height and weight, and serum insulin were measured. Systolic and diastolic blood pressure in Yi farmers were significantly lower than those in Yi migrants and local Han residents. There was no significant difference in systolic and diastolic blood pressure between Yi migrants and local Han residents and in serum insulin level between Yi farmers and Yi migrants, with the means of 9.078 microIU/ml and 8.892 microIU/ml, respectively. But, serum insulin level in Yi farmers and migrants was significantly higher than that in local Han residents (6.577 microIU/ml). Multivariate regression analysis showed that there was no significant relationship between serum insulin level and systolic and diastolic blood pressure in different populations, except for that there was a weaker relationship between serum insulin and systolic blood pressure in Yi migrants. The association between serum insulin and blood pressure was uncertainty, which suggested that blood pressure was little affected by serum insulin.


Reliability and feasibility of physical fitness tests in female fibromyalgia patients.
The aim of the present study was to determine the reliability and feasibility of physical fitness tests in female fibromyalgia patients. 100 female fibromyalgia patients (aged 50.6±8.6 years) performed the following tests twice (7 days interval test-retest): chair sit and reach, back scratch, handgrip strength, arm curl, chair stand, 8 feet up and go, and 6-min walk. Significant differences between test and retest were found in the arm curl (mean difference: 1.25±2.16 repetitions, Cohen d=0.251), chair stand (0.99±1.7 repetitions, Cohen d=0.254) and 8 feet up and go (-0.38±1.09 s, Cohen d=0.111) tests. Intraclass correlation coefficients (ICC) range from 0.92 in the arm curl test to 0.96 in the back scratch test. The feasibility of the tests (patients able to complete the test) ranged from 89% in the arm curl test to 100% in the handgrip strength test. Therefore, the reliability and feasibility of the physical fitness tests examined is acceptable for female fibromyalgia patients.


Modeling Dr. Dynasaur 2.0 Coverage and Finance Proposals: Effects of the Expansion of Vermont's Dr. Dynasaur Program to All Individuals Through Age 25.
The authors assessed an expansion of Vermont's Dr. Dynasaur program that would cover all residents age 25 and younger. The current Dr. Dynasaur program combines Vermont's Medicaid program and Child Health Insurance Program for children ages 0 through 18 to provide a seamless insurance program for those with family incomes below 317 percent of the federal poverty level. The authors used RAND's COMPARE-VT microsimulation model with Vermont-specific demographic, economic, and actuarial data to estimate the effects on health insurance coverage, costs, and premiums. They also identified the new revenues required to fund the program expansion and explored three alternative financing strategies to raise those funds: (1) an increase in the Vermont income tax, (2) a Vermont payroll tax, and (3) a Vermont business enterprise tax. The authors found that enrollment would increase by more than 260 percent under the 100-percent enrollment scenario and by nearly 200 percent under the 70-percent enrollment scenario by 2019. Not surprisingly, the children and young adults who move off employer-sponsored insurance (ESI) and into Dr. Dynasaur 2.0 have considerably lower expected health care costs than those who remain on ESI, increasing the per-person premiums by nearly $1,000 for those remaining enrolled in ESI. Annual health care expenditures per person for children and young adults in 2019 are estimated at $4,325 with Medicare prices. The combination of increased reimbursement rates, large increases in enrollment, and relatively low Dr. Dynasaur premiums (no more than $720 per year) will require significant new tax revenues to meet program obligations.


Delayed illness recognition and multiple referrals: a qualitative study exploring care-seeking trajectories contributing to maternal and newborn illnesses and death in southern Tanzania.
Maternal and neonatal mortality remain high in southern Tanzania despite an increasing number of births occurring in health facilities. In search for reasons for the persistently high mortality rates, we explored illness recognition, decision-making and care-seeking for cases of maternal and neonatal illness and death. We conducted 48 in-depth interviews (16 participants who experienced maternal illnesses, 16 mothers whose newborns experienced illness, eight mothers whose newborns died, and eight family members of a household with a maternal death), and five focus group discussions with community leaders in two districts of Mtwara region. Thematic analysis was used for interpretation of findings. Our data indicated relatively timely illness recognition and decision-making for maternal complications. In contrast, families reported difficulties interpreting newborn illnesses. Decisions on care-seeking involved both the mother and her partner or other family members. Delays in care-seeking were therefore also reported in absence of the husband, or at night. Primary-level facilities were first consulted. Most respondents had to consult more than one facility and described difficulties accessing and receiving appropriate care. Definitive treatment for maternal and newborn complications was largely only available in hospitals. Delays in reaching a facility that can provide appropriate care is influenced by multiple referrals from one facility to another. Referral and care-seeking advice should include direct care-seeking at hospitals in case of severe complications and primary facilities should facilitate prompt referral.


Cortical oscillations that underlie visual selective attention are abnormal in adolescents with cerebral palsy.
Adolescence is a critical period for the development and refinement of several higher-level cognitive functions, including visual selective attention. Clinically, it has been noted that adolescents with cerebral palsy (CP) may have deficits in selectively attending to objects within their visual field. This study aimed to evaluate the neural oscillatory activity in the ventral attention network while adolescents with CP performed a visual selective attention task. Adolescents with CP (N = 14; Age = 15.7 ± 4 years; MACS I-III; GMFCS I-IV) and neurotypical (NT) adolescents (N = 21; Age = 14.3 ± 2 years) performed the Eriksen flanker task while undergoing magnetoencephalographic (MEG) brain imaging. The participants reported the direction of a target arrow that was surrounded by congruent or incongruent flanking arrows. Compared with NT adolescents, adolescents with CP had slower responses and made more errors regarding the direction of the target arrow. The MEG results revealed that adolescents with CP had stronger alpha oscillations in the left insula when the flanking arrows were incongruent. Furthermore, participants that had more errors also tended to have stronger alpha oscillatory activity in this brain region. Altogether these results indicate that the aberrant activity seen in the left insula is associated with diminished visual selective attention function in adolescents with CP.


Effect of apoplastic solutes on water potential in elongating sugarcane leaves.
Solute concentration in the apoplast of growing sugarcane (Saccharum spp. hybrid) leaves was measured using one direct and several indirect methods. The osmotic potential of apoplast solution collected directly by centrifugation of noninfiltrated tissue segments ranged from -0.25 megapascal in mature tissue to -0.35 megapascal in tissue just outside the elongation zone. The presence of these solutes in the apoplast manifested itself as a tissue water potential equal to the apoplast osmotic potential. Since the tissue was not elongating, the measurements were not influenced by growth-induced water uptake and no significant tension was detected with the pressure chamber. Further evidence for a significant apoplast solute concentration was obtained from pressure exudation experiments and comparison of methods for estimating tissue apoplast water fraction. For elongating leaf tissue the centrifugation method could not be used to obtain direct measurements of apoplast solute concentration. However, several other observations suggested that the apoplast water potential of -0.35 to -0.45 megapascal in elongating tissue had a significant osmotic component and small, but significant tension component. Results of experiments in which exudate was collected from pressurized tissue segments of different ages suggested that a tissue age-dependent dynamic equilibrium existed between intra- and extracellular solutes.


Efficient quantum computing using coherent photon conversion.
Single photons are excellent quantum information carriers: they were used in the earliest demonstrations of entanglement and in the production of the highest-quality entanglement reported so far. However, current schemes for preparing, processing and measuring them are inefficient. For example, down-conversion provides heralded, but randomly timed, single photons, and linear optics gates are inherently probabilistic. Here we introduce a deterministic process--coherent photon conversion (CPC)--that provides a new way to generate and process complex, multiquanta states for photonic quantum information applications. The technique uses classically pumped nonlinearities to induce coherent oscillations between orthogonal states of multiple quantum excitations. One example of CPC, based on a pumped four-wave-mixing interaction, is shown to yield a single, versatile process that provides a full set of photonic quantum processing tools. This set satisfies the DiVincenzo criteria for a scalable quantum computing architecture, including deterministic multiqubit entanglement gates (based on a novel form of photon-photon interaction), high-quality heralded single- and multiphoton states free from higher-order imperfections, and robust, high-efficiency detection. It can also be used to produce heralded multiphoton entanglement, create optically switchable quantum circuits and implement an improved form of down-conversion with reduced higher-order effects. Such tools are valuable building blocks for many quantum-enabled technologies. Finally, using photonic crystal fibres we experimentally demonstrate quantum correlations arising from a four-colour nonlinear process suitable for CPC and use these measurements to study the feasibility of reaching the deterministic regime with current technology. Our scheme, which is based on interacting bosonic fields, is not restricted to optical systems but could also be implemented in optomechanical, electromechanical and superconducting systems with extremely strong intrinsic nonlinearities. Furthermore, exploiting higher-order nonlinearities with multiple pump fields yields a mechanism for multiparty mediation of the complex, coherent dynamics.


Selective inhibition of RecA functions by the Hc1 nucleoid condensation protein from Chlamydia trachomatis.
During the normal biphasic life cycle of Chlamydia trachomatis, the histone-like protein Hc1 promotes the condensation of nucleoids in elementary bodies, it may also displace nucleoproteins, including repair functions from chromatin. Hc1 was found to effectively inhibit the recombination and repair of the weak binding RecA430 mutant protein from Escherichia coli, but had minimal effects on the parental RecA(+) protein. Expression of Hc1 was also found to inhibit the repair activities of the C. trachomatis RecA protein but not recombination. These results suggest that chlamydial RecA may have evolved mechanisms to minimize Hc1 competition for recombinational activities.


Effect of umbilical cord length on early fetal biomechanics.
The umbilical cord suspends the fetus within the amniotic cavity, where fetal dynamics is one of its many functions. Hence, the umbilical cord is a viable index in determining fetal activity. Fetal movements result in mechanical loads that are fundamental for fetal growth. At present, mechanical environment during early human fetal development is still largely unknown. To determine early fetal movement dynamics at given physiological (0.060 m) and pathological umbilical cord lengths (0.030 m, 0.020 m, 0.017 m and 0.014 m) a 2D computational model was created to simulate dynamic movement conditions. Main findings of this computational model revealed the shortest umbilical cord length (0.014 m) with a 6(10-6)N, twitch force amplitude had a two-fold increase on linear velocity (0.12 m/s) in comparison with other lengths (0.05m/s). Moreover, umbilical cord length effect presented an increasing exponential tension on the fetus body wall from longest to shortest, from 0 N in the control length to 0.05 N for the shortest umbilical cord. Last, tension was always present over a period of time for the shortest cord (0.03 N to 0.08 N). Collectively, for all variables evaluated the shortest umbilical cord (0.014 m) presented remarkable differences with other lengths in particular with the second shortest umbilical cord (0.017 m), suggesting a 0.003 m difference represents a greater biomechanical effect. In conclusion, this computational model brings new insights required by clinicians, where the magnitude of these loads could be associated with different pathologies found in the clinic.


Maternal age at last birth and leukocyte telomere length in a nationally representative population of perimenopausal and postmenopausal women.
The primary aim of this study was to evaluate if maternal age at birth of last child is associated with leukocyte telomere length in a nationally representative population of perimenopausal and postmenopausal women. We conducted a cross-sectional analysis of 1,232 women from the National Health and Nutrition Examination Survey to examine maternal age at last birth and telomere length, surveyed between 1999 and 2002. We included perimenopausal and postmenopausal women age 40 years and older. Maternal age at last live birth was self-reported, and leukocyte telomere length was measured using quantitative polymerase chain reaction. We calculated least-squares geometric mean telomere length across categories of maternal age adjusted for age, race/ethnicity, number of live births, survey cycle, and history of hysterectomy or oophorectomy. P trend < 0.05 was considered statistically significant. For hypothesis-generation, we explored modification by reproductive and sociodemographic factors. Maternal age at last birth was positively associated with telomere length: the multivariable-adjusted least-squares geometric mean leukocyte telomere length across categories of age at last birth (<25, 25-29, 30-34, 35-39, ≥40 y) was 0.90, 0.93, 0.93, 0.95, and 0.96, respectively (P trend = 0.04). There was suggestive evidence this association may be restricted to those women with one or two live births or women who reported ever using oral contraceptives (P interaction <0.10 for both). Later maternal age was associated with longer telomere length in a nationally representative population of women. These data provide new insight into the biological relationship between reproductive history and long-term health. : Video Summary:http://links.lww.com/MENO/A662.


Concentrations of oestradiol-17 beta in plasma and corpora lutea throughout pregnancy in the tammar, Macropus eugenii.
Oestradiol-17 beta concentrations were measured by radioimmunoassay in peripheral blood samples from 10 tammar wallabies after their pouch young were removed to terminate embryonic diapause. Oestradiol concentrations rose from 8.3 +/- 1.2 pg/ml on Days 3 and 4 to peak of 15.8 +/- 2.9 pg/ml on Day 5, coincident with an increase in 'progesterone' concentrations, and then fell to 10.5 +/- 2.7 pg/ml on Day 7. No changes in oestradiol concentrations were associated with parturition. Five females came into oestrus and mated 9.8 +/- 6.1 h post partum; peak concentrations of plasma oestradiol (20.9 +/- 2.1 pg/ml) occurred around the time of mating. None of the females that did not mate up to the end of the experiment at Day 30 had a rise in plasma oestradiol concentrations. Corpora lutea contained 20-100 pg oestradiol during pregnancy. The highest ovarian oestradiol content (greater than 1200 pg) was measured in whole ovaries containing Graafian follicles from full-term pregnant females. The rise in oestradiol concentrations at Day 5 may be important in the termination of diapause. The post-partum increase in plasma oestradiol concentrations coincides with oestrus. The source of this oestrogen appears to be the preovulatory follicle.


Evaluation of the tip-bending response in clinically used endoscopes.
Endoscopic interventions require accurate and precise control of the endoscope tip. The endoscope tip response depends on a cable pulling system, which is known to deliver a significantly nonlinear response that eventually reduces control. It is unknown whether the current technique of endoscope tip control is adequate for a future of high precision procedures, steerable accessories, and add-on robotics. The aim of this study was to determine the status of the tip response of endoscopes used in clinical practice. We evaluated 20 flexible colonoscopes and five gastroscopes, used in the endoscopy departments of a Dutch university hospital and two Dutch teaching hospitals, in a bench top setup. First, maximal tip bending was determined manually. Next, the endoscope navigation wheels were rotated individually in a motor setup. Tip angulation was recorded with a USB camera. Cable slackness was derived from the resulting hysteresis plot. Only two of the 20 colonoscopes (10 %) and none of the five gastroscopes reached the maximal tip angulation specified by the manufacturer. Four colonoscopes (20 %) and none of the gastroscopes demonstrated the recommended cable tension. Eight colonoscopes (40 %) had undergone a maintenance check 1 month before the measurements were made. The tip responses of these eight colonoscopies did not differ significantly from the tip responses of the other colonoscopes. This study suggests that the majority of clinically used endoscopes are not optimally tuned to reach maximal bending angles and demonstrate adequate tip responses. We suggest a brief check before procedures to predict difficulties with bending angles and tip responses.


[Parenteral administration of formic acid in alternative medicine].
Treatment of rheumatic and other diseases through immersion in an anthill is reported in German folk medicine. In the first half of the twentieth century, the physicians Eduard and Egon Krull (1842-1914 and 1879-1936, respectively) as well as Albrecht Reuter (1863-1937) recommended injections of diluted formic acid to treat tuberculosis, gout, arthritis, renal disorders and other complaints. Between 1930 and 1960, more than 15 different commercial preparations were marketed, and Egon Krull invented a drug series called "Myrmekan". Formic acid inhalations were recommended by Sigmund von Kapff (1864-1946) at a time when the acid was rarely used in homeopathy. In the 1950s, the injection of formic acid was regarded as one of the most important procedures in alternative medicine.


Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia.
The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3'5'-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3'5'-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves. Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted. Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall. Preemption of oxidative stress initiated by "consumptive" oxidation of nitric oxide stabilizes the vascular endothelium and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 3'5'-cyclic monphosphate offsets the extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented. One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician of impending fetal compromise. Fetal growth and vital organ maturation can continue. As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed. The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will help restore them fiscally.


Using protein design to dissect the effect of charged residues on metal binding and protein stability.
Ca2+ controls biological processes by interacting with proteins with different affinities, which are largely influenced by the electrostatic interaction from the local negatively charged ligand residues in the coordination sphere. We have developed a general strategy for rationally designing stable Ca2+- and Ln3+-binding proteins that retain the native folding of the host protein. Domain 1 of cluster differentiation 2 (CD2) is the host for the two designed proteins in this study. We investigate the effect of local charge on Ca2+-binding affinity based on the folding properties and metal-binding affinities of the two proteins that have similarly located Ca2+-binding sites with two shared ligand positions. While mutation and Ca2+ binding do not alter the native structure of the protein, Ca2+ binding specifically induced changes around the designed Ca2+-binding site. The designed protein with a -5 charge at the binding sphere displays a 14-, 20-, and 12-fold increase in the binding affinity for Ca2+, Tb3+, and La3+, respectively, compared to the designed protein with a -3 charge, which suggests that higher local charges are preferred for both Ca2+ and Ln3+ binding. The localized charged residues significantly decrease the thermal stability of the designed protein with a -5 charge, which has a T(m) of 41 degrees C. Wild-type CD2 has a T(m) of 61 degrees C, which is similar to the designed protein with a -3 charge. This decrease is partially restored by Ca2+ binding. The effect on the protein stability is modulated by the environment and the secondary structure locations of the charged mutations. Our study demonstrates the capability and power of protein design in unveiling key determinants to Ca2+-binding affinity without the complexities of the global conformational changes, cooperativity, and multibinding process found in most natural Ca2+-binding proteins.


Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE).
The implication of the receptor for advanced glycation end-products (RAGE) in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an inflammatory biomarker. In the context of investigating RAGE as a biomarker, there is interest in developing radiotracers that will enable quantification of RAGE using positron emission tomography (PET) imaging. We have synthesized potential small molecule radiotracers for both the intracellular ([18F]InRAGER) and extracellular ([18F]RAGER) domains of RAGE. Herein we report preclinical evaluation of both using in vitro (lead panel screens) and in vivo (rodent and nonhuman primate PET imaging) methods. Both radiotracers have high affinity for RAGE and show good brain uptake, but suffer from off-target binding. The source of the off-target PET signal is not attributable to binding to melatonin receptors, but remains unexplained. We have also investigated use of lipopolysaccharide (LPS)-treated mice as a possible animal model with upregulated RAGE for evaluation of new imaging agents. Immunoreactivity of the mouse brain sections revealed increases in RAGE in the male cohorts, but no difference in the female groups. However, it proves challenging to quantify the changes in RAGE due to off-target binding of the radiotracers. Nevertheless, they are appropriate lead scaffolds for future development of 2nd generation RAGE PET radiotracers because of their high affinity for the receptor and good CNS penetration.


Secretory patterns and rates of gonadotropin-releasing hormone, follicle-stimulating hormone, and luteinizing hormone revealed by intensive sampling of pituitary venous blood in the luteal phase mare.
We used our unique nonsurgical technique for collecting pituitary venous (pit) blood to study GnRH, FSH, and LH secretion patterns in midluteal phase mares. This method does not perturb endocrine function and allows continuous monitoring of GnRH and gonadotropin (Gn) secretion, determination of the amount of GnRH perfusing gonadotropes, and direct measurements of the amounts of Gn secreted. In a total of 80 h of 5-min sampling in four mares, eight Gn peaks occurred; however, more frequent sampling was needed to define secretory events precisely. Therefore, pit blood was collected continuously and split into 30-sec segments in six mares. To ensure a peak during sampling, the opioid antagonist naloxone was given after 4-6 h of sampling to try to replicate a physiological signal for GnRH release. Naloxone induced Gn peaks in jugular blood that were indistinguishable in amplitude from spontaneous peaks. Intensive sampling of pit blood showed that jugular peaks reflected major episodes of GnRH and Gn secretion lasting 30-55 min, which were similar in profile whether naloxone induced or spontaneous and consisted of a train of three to six peaks of diminishing amplitude. Peaks of GnRH and, less often, Gn also occurred outside major episodes. Despite markedly variable size, GnRH peak maxima were correlated with the amount of LH and FSH secreted in concurrent peaks. Likewise, cross-correlation analyses (n = 960 samples/mare) showed close correspondence between patterns of GnRH and secreted FSH and LH. The delay (+/- SEM) between GnRH and Gn maxima was 0.62 +/- 0.18 min for LH and 0.18 +/- 0.22 min for FSH. The majority of GnRH and Gn peaks were concurrent; however, 34.7% of GnRH peaks occurred without Gn peaks. These peaks had a lower amplitude than those with Gn peaks (P < 0.001). For Gn, secretion (i.e. ratio between pit and jugular concentrations, > 1.5) continued at a low level for 40 +/- 9% (LH) or 64 +/- 14% (FSH) of the time between Cluster-defined peaks during the basal period. We conclude that in the luteal phase 1) the predominant mode of GnRH and Gn secretion is as concurrent, large amplitude, prolonged episodes that appeared to be the summation of a train of peaks; and 2) a GnRH dose-Gn response relationship operates endogenously. This along with the synchronicity of secretion patterns of the three hormones suggest that GnRH is the major secretagogue for both LH and FSH.


Early Lessons on Bundled Payment at an Academic Medical Center.
Orthopaedic care is shifting to alternative payment models. We examined whether New York University Langone Medical Center achieved savings under the Centers for Medicare and Medicaid Services Bundled Payments for Care Improvement initiative. This study was a difference-in-differences study of Medicare fee-for-service patients hospitalized from April 2011 to June 2012 and October 2013 to December 2014 for lower extremity joint arthroplasty, cardiac valve procedures, or spine surgery (intervention groups), or for congestive heart failure, major bowel procedures, medical peripheral vascular disorders, medical noninfectious orthopaedic care, or stroke (control group). We examined total episode costs and costs by service category. We included 2,940 intervention episodes and 1,474 control episodes. Relative to the trend in the control group, lower extremity joint arthroplasty episodes achieved the greatest savings: adjusted average episode cost during the intervention period decreased by $3,017 (95% confidence interval [CI], -$6,066 to $31). For cardiac procedures, the adjusted average episode cost decreased by $2,999 (95% CI, -$8,103 to $2,105), and for spinal fusion, it increased by $8,291 (95% CI, $2,879 to $13,703). Savings were driven predominantly by shifting postdischarge care from inpatient rehabilitation facilities to home. Spinal fusion index admission costs increased because of changes in surgical technique. Under bundled payment, New York University Langone Medical Center decreased total episode costs in patients undergoing lower extremity joint arthroplasty. For patients undergoing cardiac valve procedures, evidence of savings was not as strong, and for patients undergoing spinal fusion, total episode costs increased. For all three conditions, the proportion of patients referred to inpatient rehabilitation facilities upon discharge decreased. These changes were not associated with an increase in index hospital length of stay or readmission rate. Opportunities for savings under bundled payment may be greater for lower extremity joint arthroplasty than for other conditions.


Alveolar pentraxin 3 as an early marker of microbiologically confirmed pneumonia: a threshold-finding prospective observational study.
Timely diagnosis of pneumonia in intubated critically ill patients is rather challenging. Pentraxin 3 (PTX3) is an acute-phase mediator produced by various cell types in the lungs. Animal studies have shown that, during pneumonia, PTX3 participates in fine-tuning of inflammation (for example, microbial clearance and recruitment of neutrophils). We previously described an association between alveolar PTX3 and lung infection in a small group of intubated patients. The aim of the present study was to determine a threshold level of alveolar PTX3 with elevated sensitivity and specificity for microbiologically confirmed pneumonia. We recruited 82 intubated patients from two intensive care units (San Gerardo Hospital, Monza, Italy, and Massachusetts General Hospital, Boston, MA, USA) undergoing bronchoalveolar lavage (BAL) as per clinical decision. We collected BAL fluid and plasma samples, together with relevant clinical and microbiological data. We assayed PTX3 and soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in BAL fluid and PTX3, sTREM-1, C-reactive protein (CRP) and procalcitonin (PCT) in plasma. Two blinded independent physicians reviewed patient data to confirm pneumonia. We determined the PTX3 threshold in BAL fluid for pneumonia and compared it to other biomarkers. Microbiologically confirmed pneumonia of bacterial (n =12), viral (n =4) or fungal (n =8) etiology was diagnosed in 24 patients (29%). PTX3 levels in BAL fluid predicted pneumonia with an area under the receiving operator curve of 0.815 (95% CI =0.710 to 0.921, P <0.0001), whereas none of the other biomarkers were effective. In particular, PTX3 levels ≥1 ng/ml in BAL fluid predicted pneumonia in univariate analysis (β =2.784, SE =0.792, P <0.001) with elevated sensitivity (92%), specificity (60%) and negative predictive value (95%). Net reclassification index PTX3 values ≥1 ng/ml in BAL fluid for pneumonia indicated gain in sensitivity and/or specificity vs. all other mediators. These results did not change when we limited our analyses only to confirmed cases of bacterial pneumonia. Moreover, when we considered only the 70 patients who fulfilled the clinical criteria for the diagnosis of pneumonia at BAL fluid sampling, the diagnostic accuracy of PTX levels was confirmed in univariate and ROC curve analysis. In this hypothesis-generating convenience sample, a PTX3 level ≥1 ng/ml in BAL fluid was discriminative of microbiologically confirmed pneumonia in mechanically ventilated patients.


Relationship of red blood cell ion transport alterations and serum lipid abnormalities in Lyon genetically hypertensive rats.
Alterations of Na+ and K+ transport in erythrocytes of hypertensive humans or animals are often associated with abnormal lipid metabolism. The aim of the present study was to investigate red blood cell ion transport in Lyon inbred strains selected from Sprague-Dawley rats for different blood pressure levels. Lyon strains are characterized by important metabolic changes, including plasma lipid abnormalities. Serum triglycerides, cholesterol, and uric acid as well as red blood cell Na+ and K+ (Rb+) transport mediated by Na(+)-K+ pump or Na(+)-K+ cotransport and cation leaks were studied in hypertensive (LH), normotensive (LN), and low blood pressure (LL) Lyon rats aged 12 weeks. Increased erythrocyte Na+ content (Nai+) and higher levels of serum triglycerides, cholesterol, and uric acid were demonstrated in LH rats compared with LN animals. Nevertheless, at this age serum triglycerides and erythrocyte Nai+ of LL rats were even higher than those of LH animals. There were no significant differences between Lyon strains in either Na(+)-K+ pump activity or bumetanide-resistant (BR) cation leaks. The activity of bumetanide-sensitive (BS) Na(+)-K+ cotransport mediating inward Na+ movement was highest in LL rats and lowest in LH animals. In Lyon rats, Nai+ was positively related to serum triglycerides, whereas blood pressure correlated positively with BR Na+ leak and negatively with BS net Na+ uptake. A similar association of erythrocyte Nai+ with serum triglycerides was also observed in Prague hereditary hypertriglyceridemic rats (HTG) that were selected from Wistar rats for high plasma triglycerides. The major difference of the two forms of genetic hypertension associated with abnormal lipid metabolism was in BS net Na+ uptake, which was enhanced in HTG but reduced in LH rats. This was probably due to differences in plasma cholesterol, which was elevated in LH but not in HTG animals. Our study in Lyon rats confirmed the positive association of blood pressure with Na+ leak as a characteristic feature of genetic hypertension.


Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633.
The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study.


Contribution of serial and parallel microperfusion to spatial variability in pulmonary inter- and intra-acinar blood flow.
This study presents a theoretical model of combined series and parallel perfusion in the human pulmonary acinus that maintains computational simplicity while capturing some important features of acinar structure. The model provides a transition between existing models of perfusion in the large pulmonary blood vessels and the pulmonary microcirculation. Arterioles and venules are represented as distinct elastic vessels that follow the branching structure of the acinar airways. These vessels are assumed to be joined at each generation by capillary sheets that cover the alveoli present at that generation, forming a "ladderlike" structure. Compared with a model structure in which capillary beds connect only the most distal blood vessels in the acinus, the model with combined serial and parallel perfusion provides greater capacity for increased blood flow in the lung via capillary recruitment when the blood pressure is elevated. Stratification of acinar perfusion emerges in the model, with red blood cell transit time significantly larger in the distal portion of the acinus compared with the proximal portion. This proximal-to-distal pattern of perfusion may act in concert with diffusional screening to optimize the potential for gas exchange.


An anatomic study for the rectus abdominis myocutaneous flap combined with a vascularized rib.
The anatomy of the vascular connections between the eighth intercostal vessels and the deep epigastric vessels was studied in a series of 20 dissections in 10 preserved cadavers to develop the rectus abdominis myocutaneous flap combined with a vascularized rib. The distance between the point where the eighth intercostal vessels attached to the costal margin and the xiphoid process and the arcuate line, which become a good guide for design of the flap, was measured. The average length of the vascular pedicle of a vascularized rib was over 10 cm. Possible clinical uses of this compound flap for reconstruction of a composite maxillary or mandibular defect are described.


Proteolytic activity of Staphylococcus aureus strains isolated from the colonized skin of patients with acute-phase atopic dermatitis.
Staphylococcus aureus strains isolated from the colonized skin lesions of 26 patients with acute-phase atopic dermatitis were reported to produce various extracellular proteolytic enzymes. Using the skim-milk-agar culture plating method, it was shown that 97% of the strains (65 of 67 examined) produced proteolytic activity, with 61% (42 strains) producing activity comparable to that of the proteolytically hyperactive reference strain Staphylococcus aureus V8. This observation was confirmed by azocasein degradation with culture supernatants, which indicated that 91% of the strains produced extracellular proteinases and 43% exceeded the 2% activity threshold of the reference strain. Control strains were isolated from the nose vestibules of 18 healthy carriers; the proteolytic activity of these strains never exceeded 2.5% of the activity of the reference strain. In 54% of the patients examined ( n=14), the activity of the strains was higher than that determined for the isolates from the control group. The combined use of assays incorporating azocasein and a synthetic chromogenic substrate, N-CBZ-Phe-Leu-Glu- pNA, showed that two staphylococcal enzymes, Staphylococcus aureus metalloproteinase (SAMP) and Staphylococcus aureus serine proteinase (SASP), contributed to the total proteolytic activity released by the strains examined. The contribution of each of the two enzymes varied greatly between different isolates. The undamaged skin of the patients was not colonized with Staphylococcus aureus. The presence of several strains with atypical proteinase characteristics was also reported, suggesting the possible involvement of enzymes other than serine- and metallo-proteinases in the proteolytic activity of Staphylococcus aureus. Taken together, the results of the study imply that staphylococcal proteinases may contribute to the pathogenicity of atopic dermatitis.


Variance calculations for identity-by-descent estimation.
Nonparametric linkage strategies often involve estimation of identity by descent (IBD) with the use of affected sibling pairs. Methods for IBD estimation are well established and have been successful for mapping complex traits. However, the majority of linkage approaches involving IBD have focused on statistical testing, rather than on the effect estimates themselves. Through a bootstrap procedure developed for linkage-scan data sets, we provide standard errors for the estimated mean IBD that are broadly applicable. Applications that benefit from the availability of standard errors include effect-size estimates and confidence intervals; meta-analyses, including tests for heterogeneity; and discordant-sibling-pair evaluation. We demonstrate the use of estimated mean IBD and its standard errors in the National Institute of Mental Health Human Genetics Initiative linkage samples for bipolar disorder and Alzheimer disease. Mean IBD and its standard errors are valuable tools for the further assessment and evaluation of linkage-scan samples involving complex disease.


Using spectroscopy to probe relaxation, decoherence, and localization of photoexcited states in π-conjugated polymers.
We use the coarse-grained Frenkel-Holstein model to simulate the relaxation, decoherence, and localization of photoexcited states in conformationally disordered π-conjugated polymers. The dynamics are computed via wave-packet propagation using matrix product states and the time evolution block decimation method. The ultrafast (i.e., t < 10 fs) coupling of an exciton to C-C bond vibrations creates an exciton-polaron. The relatively short (ca. 10 monomers) exciton-phonon correlation length causes ultrafast exciton-site decoherence, which is observable on conformationally disordered chains as fluorescence depolarization. Dissipative coupling to the environment (modelled via quantum jumps) causes the localization of quasi-extended exciton states (QEESs) onto local exciton ground states (LEGSs, i.e., chromophores). This is observable as lifetime broadening of the 0-0 transition (and vibronic satellites) of the QEES in two-dimensional electronic coherence spectroscopy. However, as this process is incoherent, neither population increases of the LEGSs nor coherences with LEGSs are observable.


HMO consolidation: a threat to network integration?
The ongoing wave of consolidations among major health plans and insurers across the country is creating anxiety and challenges for integrated networks and for providers in general. The federal government's recent action in intervening in the Aetna U.S. Healthcare/Prudential Health Plans merger offers some hope, say provider executives, that some providers may see some policy relief in the future. But integrated providers in highly managed care-penetrated markets like those of the large urban markets on the West Coast are already operating in an environment of high tension and consolidation.


A novel forensic panel of 186-plex SNPs and 123-plex STR loci based on massively parallel sequencing.
The MiSeq® FGX Forensic system and the HID-Ion AmpliSeq Panel were previously developed for massively parallel sequencing (MPS) for forensic casework. Among the three major sequencing platforms, BGISEQ-500TM, which is based on multiple PCRs, is still lacking in forensics. Here, a novel forensic panel was constructed to detect 186 single-nucleotide polymorphisms (SNPs) and 123 short tandem repeats (STRs) with MPS technology on the BGISEQ-500™ platform. First, the library preparation, sequencing process, and data analysis were performed, focusing on the average depth of coverage and heterozygote balance. We calculated the allelic frequencies and forensic parameters of STR and SNP loci in 73 unrelated Chinese Han individuals. In addition, performance was evaluated with accuracy, uniformity, sensitivity, PCR inhibitor, repeatability and reproducibility, mixtures, degraded samples, case-type samples, and pedigree analyses. The results showed that 100% accurate and concordant genotypes can be obtained, and the loci with an abundance in the interquartile range accounted for 92.90% of the total, suggesting reliable uniformity in this panel. We obtained a locus detection rate that was higher than 98.78% from 78 pg of input DNA, and the optimal amount was 1.25-10 ng. The maximum concentrations of hematin and humic acid were 200 and 100 μM, respectively (the ratios of detected loci were 96.52% and 92.41%), in this panel. As a mixture, compared with those of SNPs, minor-contributor alleles of STRs could be detected at higher levels. For the degraded sample, the ratio of detected loci was 98.41%, and most profiles from case-type samples were not significantly different in abundance in our studies. As a whole, this panel showed high-performance, reliable, robust, repeatable, and reproducible results, which are sufficient for paternity testing, individual identification, and use for potentially degraded samples in forensic science.


Infants' localization of sounds within hemifields: estimates of minimum audible angle.
Infants' acuity in localizing sounds within hemifields was examined by determining the smallest sound shift off 60 degrees and along the horizontal axis that infants could discriminate reliably, that is, minimum audible angle (MAA). Infants 6, 12, and 18 months of age were tested using a Go/No-Go conditioned head-turn procedure in which infants received an equal number of no-change (control) trials and sound-shift (experimental) trials. A correct response (i.e., a head turn toward the loud-speakers) on an experimental trial resulted in visual reinforcement. Localization acuity for sounds within hemifields was fairly poor and improved systematically with increasing age. MAA estimates at each age were significantly higher, indicating poorer localization acuity, in comparison to those obtained previously in research examining infants' resolution of auditory space near midline. These findings are consistent with adult data and demonstrate a finer partitioning of auditory space near midline than within hemifields. The implications of these findings for our understanding of the development of auditory processing mechanisms in sound localization are discussed.


A Study of Shuttlecock's Trajectory in Badminton.
The main purpose of this study was to construct and validate a motion equation for the flight of the badminton and to find the relationship between the air resistance force and a shuttlecock's speed. This research method was based on motion laws of aerodynamics. It applied aerodynamic theories to construct motion equation of a shuttlecock's flying trajectory under the effects of gravitational force and air resistance force. The result showed that the motion equation of a shuttlecock's flight trajectory could be constructed by determining the terminal velocity. The predicted shuttlecock trajectory fitted the measured data fairly well. The results also revealed that the drag force was proportional to the square of a shuttlecock velocity. Furthermore, the angle and strength of a stroke could influence trajectory. Finally, this study suggested that we could use a scientific approach to measure a shuttlecock's velocity objectively when testing the quality of shuttlecocks. And could be used to replace the traditional subjective method of the Badminton World Federation based on players' striking shuttlecocks, as well as applying research findings to improve professional knowledge of badminton player training. Key pointsThe motion equation of a shuttlecock's flying trajectory could be constructed by determining the terminal velocity in aerodynamics.Air drag force is proportional to the square of a shuttlecock velocity. Furthermore, the angle and strength of a stroke could influence trajectory.


Developmental dissociation of T cells from B, NK, and myeloid cells revealed by MHC class II-specific chimeric immune receptors bearing TCR-zeta or FcR-gamma chain signaling domains.
The T-cell receptor zeta (TCR-zeta) and FcR-gamma chains play a critical role in mediating signal transduction. We have previously described HIV glycoprotein 120 (gp120)-specific chimeric immune receptors (CIRs) in which the extracellular domain of CD4 is linked to the signaling domain of zeta (CD4zeta) or gamma (CD4gamma). Such CIRs are efficiently expressed following retroviral transduction of mature T cells and specifically redirect effector functions toward HIV-infected targets. In this report, we examine development of CD4zeta- or CD4gamma-expressing T cells from retrovirally transduced hematopoietic stem cells following bone marrow transplantation. Although CD4zeta/gamma-expressing myeloid, NK, and B cells were efficiently reconstituted, parallel development of CD4zeta/gamma-expressing T cells was blocked prior to the CD25(+)CD44(+) prothymocyte stage. In contrast, T cells expressing a signaling-defective CIR were efficiently generated. When major histocompatibility complex (MHC) class II-deficient mice were used as transplant recipients, development of CD4zeta/gamma-expressing T cells was restored. We conclude that CD4zeta/gamma signaling generated following engagement of MHC class II selectively arrests T-lineage development.


Sympathetic and parasympathetic baroreflex dysfunction in familial dysautonomia.
To assess the possible abnormalities in the baroreflex modulation of both the heart and the arterial vasculature, in order to better evaluate the role of baroreflex abnormalities in the generation of the cardiovascular symptoms and complications affecting the familial dysautonomia (FD) patient. Twenty-one FD patients and 22 controls underwent 3 minutes of passive head-up tilt (HUT) and baroreceptor stimulation by means of sinusoidal neck suction (NS; 0 to -30 mm Hg; 0.1 Hz [LF] and 0.2 Hz [HF]). Respiration was maintained constant during NS at 15 breaths/minute. The authors monitored RR-intervals (RRI), blood pressure (BP) (Colin), and respiration. NS induced changes of RRI and BP were determined by spectral analysis. HUT showed orthostatic hypotension without compensatory tachycardia in FD patients but not in controls. LF-NS increased LF power of RRI and BP and HF-NS increased HF power of RRI in controls, but not in FD patients. Familial dysautonomia patients have a widespread baroreflex abnormality, involving both the efferent sympathetic arm on the resistance vessels, and the sympathetic and parasympathetic efferent arms on the heart. Therefore, the abnormalities in the control of blood pressure-i.e., supine hypertension, orthostatic hypotension, blood pressure lability-and heart rate-i.e., bradyarrhythmias-are likely due to baroreflex abnormalities.


Attenuation by butalbital of capsaicin-induced c-fos-like immunoreactivity in trigeminal nucleus caudalis.
We examined the effects of butalbital (30, 100, and 1000 micrograms/kg) on the number of cells expressing c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, within lamina I, IIo of the trigeminal nucleus caudalis and the nucleus of the solitary tract 2 hours after the intracisternal injection of capsaicin (0.1 mL; 15.25 mg/mL) or vehicle in urethane-anesthetized guinea pigs (N = 45). Robust c-fos-LI was observed within nuclei of cells in the trigeminal nucleus caudalis after capsaicin (329 +/- 35). Butalbital dose-dependently reduced the number of labeled cells to a maximum of 66% (1000 micrograms/kg intraperitoneally [i.p.], P < .01) in lamina I, IIo but not within area postrema, medial reticular nucleus, or the nucleus of the solitary tract. Pretreatment with bicuculline (30 micrograms/kg i.p.) blocked the effect of butalbital, thereby suggesting the importance of the GABAA receptor to activation involved in the transmission of nociceptive information. Our studies suggest the possibility that GABAA receptors might provide an important therapeutic target in migraine and related headache disorders.


Prevalence of and factors associated with burnout in midwifery: A scoping review.
Midwifery care meets the triple aims of health system improvement, i.e. good health outcomes, high client satisfaction, and low per capita costs. Scaling up access to midwifery care is a global priority yet the growth and sustainability of the profession is threatened by high levels of burnout and attrition. This scoping review provides a comprehensive review of the existing literature on burnout in midwifery, with a focus on prevalence, associated factors and potential solutions. Four electronic databases were searched to locate relevant literature up to July 2019. A total of 1034 articles were identified and reduced to 27 articles that met inclusion criteria. We summarize sample sizes, settings, study designs, burnout measures, prevalence of burnout, associated factors and potential solutions, and recommendations. Prevalence of burnout was highest among Australian, Western Canadian and Senegalese midwives and lowest among Dutch and Norwegian midwives. Midwives working in caseload/continuity models reported significantly lower burnout compared to midwives working in other models. We identified 26 organizational and personal factors that were significantly associated with burnout, such as high workload, exposure to traumatic events, and fewer years in practices. Organizational support to improve work-life balance and emotional well-being, as well as more continuing education to raise awareness about burnout and how to cope with it, emerged as common strategies to prevent and address burnout. Burnout is a serious and complex occupational phenomenon. More qualitative research is needed in this area, to better understand the lived experience of burnout.


Miniaturized sample preparation on a digital microfluidics device for sensitive bottom-up microproteomics of mammalian cells using magnetic beads and mass spectrometry-compatible surfactants.
While LC-MS-based proteomics with high nanograms to micrograms of total protein has become routine, the analysis of samples derived from low cell numbers is challenged by factors such as sample losses, or difficulties encountered with the manual manipulation of small liquid volumes. Digital microfluidics (DMF) is an emerging technique for miniaturized and automated droplet manipulation, which has been proposed as a promising tool for proteomic sample preparation. However, proteome analysis of samples prepared on-chip by DMF has previously been unfeasible, due to incompatibility with down-stream LC-MS instrumentation. To overcome these limitations, we here developed protocols for bottom-up LC-MS based proteomics sample preparation of as little as 100 mammalian cells on a commercially available digital microfluidics device. To this end, we developed effective cell lysis conditions optimized for DMF, as well as detergent-buffer systems compatible with downstream proteolytic digestion on DMF chips and subsequent LC-MS analysis. A major step was the introduction of the single-pot, solid-phase-enhanced sample preparation (SP3) approach on-chip, which allowed the removal of salts and anti-fouling polymeric detergents, thus rendering sample preparation by DMF compatible with LC-MS-based proteome analysis. Application of DMF-SP3 to the proteome analysis of Jurkat T cells led to the identification of up to 2500 proteins from approximately 500 cells, and up to 1200 proteins from approximately 100 cells on an Orbitrap mass spectrometer, emphasizing the high compatibility of DMF-SP3 with low protein input and minute volumes handled by DMF. Taken together, we demonstrate the first sample preparation workflow for proteomics on a DMF chip device reported so far, allowing the sensitive analysis of limited biological material.


Vascular emergencies of the thorax after blunt and iatrogenic trauma: multi-detector row CT and three-dimensional imaging.
Multi-detector row computed tomographic (CT) angiography is an effective modality for vascular imaging in the thorax. It allows acquisition of high-resolution data sets during a single breath hold, making it the preferred method for evaluation of patients with acute vascular disease. In contrast to conventional angiography, multirow CT angiography not only depicts the vessels but also allows assessment of adjacent structures. Multirow CT angiography with two- and three-dimensional reformation can be used to diagnose vascular emergencies of the thorax after blunt and iatrogenic trauma. These include incomplete and complete aortic rupture; traumatic aortic dissection; arterial dissection and rupture after minor trauma in patients with Ehlers-Danlos syndrome; traumatic intramural hematoma; pseudoaneurysm after endovascular repair; injuries due to Swan-Ganz catheters; complications of central venous cannulation, pacemaker implantation, and percutaneous pericardial drainage; and foreign-body embolism. The diagnoses can be established with multirow CT angiography in the emergency department. Thus, the time to diagnosis can be considerably decreased by obviating conventional angiography. Knowledge of the CT findings in various vascular conditions is essential to make use of multirow CT angiography in combination with two- and three-dimensional reformation as an efficient and accurate diagnostic tool in emergency radiology.


Fermentation strategies to improve propionic acid production with propionibacterium ssp.: a review.
Propionic acid (PA) is a carboxylic acid applied in a variety of processes, such as food and feed preservative, and as a chemical intermediate in the production of polymers, pesticides and drugs. PA production is predominantly performed by petrochemical routes, but environmental issues are making it necessary to use sustainable processes based on renewable materials. PA production by fermentation with the Propionibacterium genus is a promising option in this scenario, due to the ability of this genus to consume a variety of renewable carbon sources with higher productivity than other native microorganisms. However, Propionibacterium fermentation processes present important challenges that must be faced to make this route competitive, such as: a high fermentation time, product inhibition and low PA final titer, which increase the cost of product recovery. This article summarizes the state of the art regarding strategies to improve PA production by fermentation with the Propionibacterium genus. Firstly, strategies associated with environmental fermentation conditions and nutrition requirements are discussed. Subsequently, advantages and disadvantages of various strategies proposed to improve process performance (high cell concentration by immobilization or recycle, co-culture fermentation, genome shuffling, evolutive and metabolic engineering, and in situ recovery) are evaluated.


Multiplex advantage in the detection of optical images in the photon noise limit.
This paper contains a theoretical comparison of the performance of a single, optically multiplexed detector with a set of independent scanned detectors in the measurement of optical images in the signal-dominated regime. The difference between the uncorrelated counts received in two channels-one corresponding to the required signal, the other to the background only-is analyzed as the signal estimator. Correlated counts, where identical photodetections are added to each channel, do not affect the accuracy of the signal that is described in terms of a SNR. The theory is confirmed by detailed experimental measurements of signal and noise. The results show a multiplex power advantage over a single scanned detector in the photon-noise limit of 1/4R, where R is the ratio of the mean signal per element over the entire image to the signal in the element under consideration. Thus, for instance, for a bright star in a dark field a 100 x 100 multiplex system would be equivalent to 2500 parallel detectors.


Monitoring histone deacetylase inhibition in vivo: noninvasive magnetic resonance spectroscopy method.
Histone deacetylase inhibitors (HDACis) are emerging as promising and selective antitumor agents. However, HDACis can lead to tumor stasis rather than shrinkage, in which case, traditional imaging methods are not adequate to monitor response. Consequently, novel approaches are needed. We have shown in cells that (19)F magnetic resonance spectroscopy (MRS)-detectable levels of the HDAC substrate Boc-Lys-TFA-OH (BLT) are inversely correlated with HDAC activity. We extended our investigations to a tumor xenograft model. Following intraperitoneal injection of BLT, its accumulation within the tumor was monitored by in vivo (19)F MRS. In animals treated with the HDACi suberoylanilide hydroxamic acid (SAHA), tumoral BLT levels were higher by 77% and 132% on days 2 and 7 of treatment compared with pretreatment levels (n = 6; p < .05). In contrast, tumoral BLT levels remained unchanged in control animals and in normal tissue. Thus, (19)F MRS of BLT detected the effect of HDACi treatment as early as day 2 of treatment. Importantly, tumor size confirmed that SAHA treatment leads to inhibition of tumor growth. However, difference in tumor size reached significance only on day 6 of treatment. Thus, this work identifies BLT as a potential molecular imaging agent for the early noninvasive MRS detection of HDAC inhibition in vivo.


Case report: Fluocinonide-induced perioral dermatitis in a patient with psoriasis.
Topical corticosteroids are the primary treatment for psoriasis. A patient with psoriasis being treated with topical fluocinonide for lesions on the extremities developed an erythematous facial eruption consistent with perioral dermatitis. When topical agents are applied, they often end up in unintended areas. The potential for drug-induced perioral dermatitis should be considered in psoriasis patients treated with potent topical corticosteroids.


Diffusion model in ion channel gating. Extension to agonist-activated ion channels.
Previously, we described a model which treats ion channel gating as a discrete diffusion problem. In the case of agonist-activated channels at high agonist concentration, the model predicts that the closed lifetime probability density function from single channel recording approximates a power law with an exponent of -3/2 (Millhauser, G. L., E. E. Salpeter, and R. E. Oswald. 1988a. Proc. Natl. Acad. Sci. USA. 85: 1503-1507). This prediction is consistent with distributions derived from a number of ligand-gated channels at high agonist concentration (Millhauser, G. L., E. E. Salpeter, and R. E. Oswald. 1988b. Biophys. J. 54: 1165-1168.) but does not describe the behavior of ion channels at low activator concentrations. We examine here an extension of this model to include an agonist binding step. This extended model is consistent with the closed time distributions generated from the BC3H-1 nicotinic acetylcholine receptor for agonist concentrations varying over three orders of magnitude.


Evaluation of an initiative to improve advance care planning for a home-based primary care service.
Advance care planning (ACP) is a process that enables individuals to describe, in advance, the kind of health care they would want in the future. There is evidence that ACP reduces hospital-based interventions, especially at the end of life. ACP for frail older adults is especially important as this population is more likely to use hospital services but less likely to benefit from resource intensive care. Our study goal was to evaluate whether an approach to ACP developed for frail older adults, known as the Palliative and Therapeutic Harmonization or PATH, demonstrated an improvement in ACP. The PATH approach was adapted to a primary care service for homebound older adults in Vancouver, Canada. This retrospective chart review collected surrogate measures related to ACP from 200 randomly selected patients enrolled in the service at baseline (prior to June 22, 2017), and 114 consecutive patients admitted to the program after implementation of the PATH ACP initiative (October 1, 2017 to May 1, 2018). We compared the following surrogate markers of ACP before and after implementation of the PATH model, chart documentation of: frailty stage, substitute decision-maker, resuscitation decision, and hospitalization decision. A composite ACP documentation score that ascribed one point for each of the above four measures (range 0 to 4) was also compared. For those with documented resuscitation and hospitalization decisions, the study examined patient/ substitute decision-maker expressed preferences for do-not-resuscitate and do-not-hospitalize, before and after implementation. We found the following changes in ACP-related documentation before and after implementation: frailty stage (27.0% versus 74.6%, p < .0001); substitute decision-maker (63.5% versus 71.9%, p = 0.128); resuscitation decision documented (79.5% versus 67.5%, p = 0.018); and hospitalization decision documented (61.5% versus 100.0%, p < .0001); mean (standard deviation) composite ACP documentation score (2.32 (1.16) versus 3.14 (1.11), p < .0001). The adjusted odds ratios (95% confidence intervals) for an expressed preference of do-not-resuscitate and do-not-hospitalize after implementation were 0.87 (0.35, 2.15) and 3.14 (1.78, 5.55), respectively. Results suggest partial success in implementing the PATH approach to ACP in home-based primary care. Key contextual enablers and barriers are important considerations for successful implementation.


[Giant cutaneous squamous cell carcinoma of the nose with subsequent brain extension].
Cutaneous squamous cell carcinoma is an invasive and destructive tumor, and may cause death by local extension or because of metastasis. We report the case of a patient with a giant squamous cell carcinoma of the nose and extension to the brain and discuss the main risk factors from this extension. Resection of a giant squamous cell carcinoma was performed of the nose in a 45 year-old man after debulking radiotherapy. Histological examination disclosed a well-differentiated tumor and perineural involvement, with at least a 6 mm margin. A first relapse occurred on the orbital edge of the initial resection, the lesion was removed revealing an involvement of the infra-orbital nerve. Whilst the patient was receiving chemotherapy, a second relapse occurred responsible for ophthalmoplegia and loss of vision, with involvement of the left orbital apex, cavernous sinus and temporal lobe. The patient died from grand mal seizures. Brain extension of cutaneous squamous cell carcinoma of the head is rare. It develops along the anatomic pathways, especially perineural spread. Main risk factors for such a poor course are discussed, including the size of tumor, the anatomic site, the depth and perineural invasion.


Murder-suicides involving children: a 29-year study.
Review was undertaken from February 1969 to January 1998 at the State forensic science center (Forensic Science) in Adelaide, South Australia, of all cases of murder-suicide involving children <16 years of age. A total of 13 separate cases were identified involving 30 victims, all of whom were related to the perpetrators. There were 7 male and 6 female perpetrators (age range, 23-41 years; average, 31 years) consisting of 6 mothers, 6 father/husbands, and 1 uncle/son-in-law. The 30 victims consisted of 11 daughters, 11 sons, 1 niece, 1 mother-in-law, and 6 wives of the assailants. The 23 children were aged from 10 months to 15 years (average, 6.0 years). The 6 mothers murdered 9 children and no spouses, with 3 child survivors. The 6 fathers murdered 13 children and 6 wives, with 1 child survivor. This study has demonstrated a higher percentage of female perpetrators than other studies of murder-suicide. The methods of homicide and suicide used were generally less violent among the female perpetrators compared with male perpetrators. Fathers killed not only their children but also their wives, whereas mothers murdered only their children. These results suggest differences between murder-suicides that involve children and adult-only cases, and between cases in which the mother rather than the father is the perpetrator.


The role of the amygdala in signaling prospective outcome of choice.
Can brain activity reveal a covert choice? Making a choice often evokes distinct emotions that accompany decision processes. Amygdala has been implicated in choice behavior that is guided by a prospective negative outcome. However, its specific involvement in emotional versus cognitive processing of choice behavior has been a subject of controversy. In this study, the human amygdala was monitored by functional magnetic resonance imaging (fMRI) while subjects were playing in a naturalistic choice paradigm against the experimenter. In order to win, players had to occasionally choose to bluff their opponent, risk "getting caught," and suffer a loss. A critical period, when choice has been made but outcome was still unknown, activated the amygdala preferentially following the choice that entailed risk of loss. Thus, the response of the amygdala differentiated between subject's covert choice of either playing fair or foul. These results support a role of the amygdala in choice behavior, both in the appraisal of inherent value of choice and the signaling of prospective negative outcomes.


Rapid weight gain in infliximab treated Crohn's disease patients is sustained over time: real-life data over 12 months.
Infliximab (IFX) is used in active Crohn's disease for induction and maintenance of remission. There are scanty data on weight gain in IBD-patients under anti-TNF treatment. We investigated changes in weight and blood chemistry in anti-TNF-naïve Crohn's disease patients during their first course of IFX. Retrospective analysis of 110 patients (77 men, 33 women) aged 34 years (range 14-73), 54 with luminal and 56 with fistulising disease, given at least 3 infusions of IFX (range 3-11). Data regarding body weight, height, C-reactive protein (CRP), haemoglobin and S-albumin at baseline, before the third infusion, at three months and at 12 months were collected. At 6 weeks, 65 (59%) increased in weight, 73% and 76% at three and 12 months, respectively. There was an increase in median weight (1.7 kg, IQR = 3.1 kg) and BMI (0.5 kg/m2, IQR = 1.2 kg/m2) at 6 weeks, which persisted at three and 12 months (all p < .001). There was no difference between men and women. Young patients, patients with underweight or fistulising disease increased most in weight. Disease activity assessed by PGA and SES-CD decreased at all time points (p < .05). Increases in weight and BMI correlated with an increase in serum albumin and a decrease in CRP. Approximately 60% of Crohn's disease patients experience weight gain within the first six weeks of infliximab treatment. The weight increment correlates with improvements in inflammatory markers and disease activity. The causes of weight gain may be related to treatment induced metabolic changes and reduced inflammatory burden.


Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent.
Mammalian thioredoxin reductase 1 (TrxR1) is considered to be an important anticancer drug target and to be involved in both carcinogenesis and cancer progression. Here, we report that ethaselen, a novel organoselenium compound with anticancer activity, specifically binds to the unique selenocysteine-cysteine redox pair in the C-terminal active site of mammalian TrxR1. Ethaselen was found to be a potent inhibitor rather than an efficient substrate of mammalian TrxR1. It effectively inhibits wild-type mammalian TrxR1 at submicromolar concentrations with an initial mixed-type inhibition pattern. By using recombinant human TrxR1 variants and human glutathione reductase, we prove that ethaselen specifically targets the C-terminal but not the N-terminal active site of mammalian TrxR1. In A549 human lung cancer cells, ethaselen significantly suppresses cell viability in parallel with direct inhibition of TrxR1 activity. It does not, however, alter either the disulfide-reduction capability of thioredoxin or the activity of glutathione reductase. As a downstream effect of TrxR1 inactivation, ethaselen causes a dose-dependent thioredoxin oxidation and enhances the levels of cellular reactive oxygen species in A549 cells. Thus, we propose ethaselen as the first selenium-containing inhibitor of mammalian TrxR1 and provide evidence that selenium compounds can act as anticancer agents based on mammalian TrxR1 inhibition.


Acquisition: it's all in how you look at it.
In the world of hospitals acquisitions, getting the hospital would seem to be the goal. But that's not always true. Sometimes an acquisition is just a means to another end. That has been the case with La Palma (Calif.) Intercommunity Hospital, near Los Angeles, which has had three owners in the past year and is in the midst of a deal to be sold to a fourth. Its current and previous owners acknowledge that ownership of La Palma was not the ultimate motive for any of the deals to date, and the hospital was quickly peddled after each sale. Officials from the company now trying to buy La Palma, however, say the hospital is worth having. Whether that is true seems to depend on who is doing the talking.


Public perceptions of natural resource damages and the resources that require restoration.
The public and health professionals are interested in restoring degraded ecosystem to provide goods and services. This study examined public perceptions in coastal New York and New Jersey about who is responsible for restoration of resources, which resources should be restored, by whom, and do they know the meaning of natural resource damage assessment (NRDA). More than 98% felt that resources should be restored; more (40%) thought the government should restore them, rather than the responsible party (23%). The highest rated resources were endangered wildlife, fish, mammals, and clams/crabs. Only 2% of respondents knew what NRDA meant. These data indicate that people felt strongly that resources should be restored and varied in who should restore them, suggesting that governmental agencies must clarify the relationship between chemical discharges, resource injury, NRDA, and restoration of those resources to produce clean air and water, fish and wildlife, and recreational opportunities.


Design of synthetic gene libraries encoding random sequence proteins with desired ensemble characteristics.
Libraries of random sequence polypeptides are useful as sources of unevolved proteins, novel ligands, and potential lead compounds for the development of vaccines and therapeutics. The expression of small random peptides has been achieved previously using DNA synthesized with equimolar mixtures of nucleotides. For many potential uses of random polypeptide libraries, concerns such as avoiding termination codons and matching target amino acid compositions make more complex designs necessary. In this study, three mixtures of nucleotides, corresponding to the three positions in the codon, were designed such that semirandom DNA synthesized by repeated cycles of the three mixtures created an open reading frame encoding random sequence polypeptides with desired ensemble characteristics. Two methods were used to design the nucleotide mixtures: the manual use of a spreadsheet and a refining grid search algorithm. Using design targets of less than or equal to 1% stop codons and an amino acid composition based on the average ratios observed in natural, globular proteins, the search methods yielded similar nucleotide ratios, Semirandom DNA, synthesized with a designed, three-residue repeat pattern, can encode libraries of very high diversity and represents an important tool for the construction of random polypeptide libraries.


Measuring B-Type Natriuretic Peptide From Capillary Blood or Venous Sample: Is It the Same?
In recent years, several systems have been implemented to achieve quick and non-invasive measurements of B-type natriuretic peptide (BNP). Among them, AlereTM Heart Check (AHC) BNP test represents the most recent advancement. It is a rapid point-of-care (POC) immunoassay, projected for measuring BNP directly from a capillary whole blood sample. This study aimed at comparing the analytical and clinical performances of this new POC to our reference method (Abbott Architect System). One hundred eleven patients with stable chronic heart failure (CHF) referring to one cardiac rehabilitation center were enrolled from December 2013 to May 2015. These patients were subjected to a simultaneous capillary (AHC) and plasma (Abbott) BNP measurements. Clinical and analytical performances of AHC were assessed and compared to the reference method. Capillary BNP showed a good correlation with the reference method (r = 0.94, P < 0.0001), although the values diverged when BNP was higher than 1,500 pg/mL. Indeed, the AHC had a relatively poor precision and the coefficient of variability was 10.1% and 18% for low and high controls, respectively. However, both methods showed similar diagnostic performances in discriminating the patients with heart failure in New York Heart Association (NYHA) class I from those belonging to NYHA classes II-III, with values of area under the curve (AUC) of 0.983 and 0.984, respectively, and equivalent sensitivity, specificity, and positive and negative likelihood ratios. The AHC BNP test is a good POC able to provide reliable information about the hemodynamic status of CHF patients, especially of those belonging to NYHA classes I-III.


[Immune deficiencies: diagnosis, management, some perspectives].
Severe primary immunodeficiencies (PID) are rare; their global incidence is comparable to that of childhood leukemia; they include more than 100 different entities. Clinical manifestations are: unusually severe or frequent infections or infections that do not respond to adequate treatment; an increased risk of certain malignancies; sometimes auto-immune manifestations. Delayed diagnosis and management of PID can lead to severe and irreversible complications or to death. PID can become manifest only in the adult; in common variable immune deficiency, the median age at diagnosis is between the 2nd and the 3rd decade of life. PID are often transmitted genetically; recent progresses in molecular biology have allowed more precise and earlier, including antenatal, diagnosis. Molecular treatment of 3 infants with a severe immunodeficiency has recently been achieved in April 2000. Those progresses were mostly based on the study of immunodeficiency databases. We present here the work of a Belgian group specialized in PID; meetings have started in June 1997. This group establishes guidelines for the diagnosis and treatment of PID, adapted to the local situation. The elaboration of a national register of PID is also underway; this has to provide all guaranties of anonymity to patients and families. Such a register already exists at the European level; it has provided the basis for new diagnostic and therapeutic possibilities. The inclusion of Belgian data in this register should allow essential progresses essential for our patients.