PTHrP promotes development of mouse preimplantation embryos through the AKT/cyclin D1 pathway and nuclear translocation of HDAC4.
Parathyroid hormone-related protein (PTHrP), the main cause of humoral hypercalcemia in malignancies, promotes cell proliferation and delays terminal cell maturation during embryonic development. Our previous study reported that PTHrP plays important roles in blastocyst formation, pluripotency gene expression, and histone acetylation during mouse preimplantation embryonic development. In this study, we further investigated the mechanism of preimplantation embryonic development regulated by PTHrP. Our results showed that Pthrp depletion decreased both the developmental rate of embryos at the cleavage stage and the cell number of morula-stage embryos. Pthrp-depleted embryos had significantly decreased levels of cyclin D1, phospho (p)-AKT (Thr308) and E2F1. However, Pthrp depletion did not cause significant changes in CDK4, β-catenin or RUNX2 expression. In addition, our results indicated that Pthrp depletion promoted HDAC4 translocation from the cytoplasm to the nucleus in cleavage-stage embryos by stimulating the activity of protein phosphatase 2A (PP2A), which resulted in dephosphorylation of HDAC4. Taken together, these results suggest that PTHrP regulates cleavage division progression and blastocyst formation through the AKT/cyclin D1 pathway and that PTHrP modulates histone acetylation patterns through nuclear translocation of HDAC4 via PP2A-dependent HDAC4 dephosphorylation during preimplantation embryonic development in mice.


Long duration x-ray source development for x-ray diffraction at the National Ignition Facility.
We present the results of experiments to produce a 10 ns-long, quasi-monochromatic x-ray source. This effort is needed to support time-resolved x-ray diffraction (XRDt) measurements of phase transitions during laser-driven dynamic compression experiments at the National Ignition Facility. To record XRDt of phase transitions as they occur, we use high-speed (∼1 ns) gated hybrid CMOS detectors, which record multiple frames of data over a timescale of a few to tens of ns. Consequently, to make effective use of these imagers, XRDt needs the x-ray source to be narrow in energy and uniform in time as long as the sensors are active. The x-ray source is produced by a laser irradiated Ge foil. Our results indicate that the x-ray source lasts during the whole duration of the main laser pulse. Both time-resolved and time-integrated spectral data indicate that the line emission is dominated by the He-α complex over higher energy emission lines. Time-integrated spectra agree well with a one-dimensional Cartesian simulation using HYDRA that predicts a conversion efficiency of 0.56% when the incident intensity is 2 × 1015 W/cm2 on a Ge backlighter.


Note: A SMA wire actuated extremely long-lifetime release actuator using two ball-lock mechanisms.
A shape memory alloy (SMA)-wire actuated release actuator with an extremely long lifetime was designed and validated. To ensure the ability of repeated actuation, two stages of ball-lock mechanisms were adopted to reduce the load in the SMA wire. In addition, a length-increasing design of the SMA wire was employed. Validation tests, including function tests, vibration tests, shock tests, and thermal vacuum tests were conducted on prototypes. According to the test results, the actuator can release a maximum preload of 15 kN and has a lifetime of more than 693 cycles. Furthermore, the actuator can function well, even under severe thermal and vibration environments.


Inflammatory cells in the lungs of premature infants on the first day of life: perinatal risk factors and origin of cells.
Neither the origin of leucocytes in the premature newborn airway nor their relationship to perinatal factors has been adequately determined. In order to sample airway cells, modified bronchoalveolar lavage was performed on 74 intubated infants of < 32 weeks' gestation and < 24 hours of age. Cells were counted, stained and, in a small separate group of six infants, four boys and two girls, probed for the Y chromosome with suitable control samples. Perinatal risk factors for increased airway cellularity were analysed by multiple regression. Premature rupture of membranes of more than 24 hours' duration was independently associated with increased numbers of airway leucocytes (n = 74). More than 90% of airway leucocytes from four boys with pulmonary inflammation were positive for the Y chromosome indicating that the cells were of fetal rather than maternal origin.


Active immunization of patients with HIV infection: a study of the effect of VaxSyn, a recombinant HIV envelope subunit vaccine, on progression of immunodeficiency.
Infection with the human immunodeficiency virus (HIV) leads to a progressive immunodeficiency characterized by decreasing levels of CD4+ T lymphocytes. VaxSyn, a vaccine based on the recombinant envelope glycoprotein subunit (rgp160) of HIV-1IIIB, was used to immunize HIV-infected patients to determine whether its administration was beneficial with respect to slowing disease progression. A 3-year multicenter, randomized, placebo-controlled, double-blinded, efficacy and safety trial of repeated immunization with VaxSyn was used to evaluate the long-term impact on the progression of immunodeficiency. VaxSyn in alum, or alum alone, was given to 278 HIV-infected asymptomatic individuals with initial CD4 counts of > or =500 cells/mm3. Clinical findings, the CD4 count, and both virological and immunological parameters were followed. No significant differences were observed between the treatment and placebo control groups in rate of CD4 T cell decline, time to initiation of antiretroviral therapy, incidence of opportunistic infections, HIV RNA plasma viremia, HIV viral infectivity as measured by quantitative HIV coculture assay, and death. This study revealed no effect on either clinical or laboratory virological parameters from the administration of VaxSyn.


[Responses of rabbit's visual cortex neurons to changes in intensity and orientation of visual stimuli].
Changes in the number of spikes in the early phasic discharge (50-90 ms from stimuli replacement) of neurons in the rabbit's primary visual cortex were studied under conditions of an instant change in a flashing-line pattern. We used three type of stimulation: lines with different orientations (0-90 degrees) but constant intensity; lines with constant orientation but different intensities; complex stimuli with different intensities and different orientations of lines. Factor analysis made it possible to reconstruct two-dimensional sensory spaces of orientations in 13 of 43 analyzed neurons (30%). In 5 of 30 analyzed neurons (16.6%), both two-dimensional spaces of orientations and two-dimensional spaces of intensities were revealed. Achromatic spaces were reconstructed during changes in the lines of varying intensities but constant orientation. In experiments with complex stimuli, the intensity of lines with orientations varying from 0 to 38.58 degree was 5 cd/m2. The intensity of lines with orientations varying from 51.44 to 90 degrees was 15 cd/m2. In the sensorial space, stimuli with different intensities were located on the plane formed by the first and second significant factors in opposite quadrants, whereas within each quadrant, the stimuli were arranged closely to their orientation from minimum to maximum. We suggest that this type of sensory space reflects the interaction between intensity and orientation attributes of visual stimuli with the factor of intensity prevailing over the factor of orientation. Only 7 (12%) neurons with such complex spaces were found.


[Facial palsy as the first syndrome of multiple sclerosis in 16 years old girl].
Multiple sclerosis (MS) is demyelinating disease characterized by scattered neurologic deficits the central nervous system. The large number of scattered lessions produce many clinical symptoms. Facial palsy is rarely ascribed to multiple sclerosis as first syndrome. 16-years old girl with sequence of features: 1. facial palsy, 2. transitional sudden hearing loss 3. transitory vertigo is presented. In audiologic examination pure tone audiogram, impedance audiometry, ABR and ENG were done. Air and bone thresholds were normal, stapedial reflex was absent and ABR suggested retrocochlear involvement in affected ear. In this case after MRI examination multiple sclerosis was diagnosed. ENT specialists should considered MS like a reason of facial palsy.


The prevention of diabetes-associated birth defects.
Birth defects among infants of diabetic mothers convey a major financial and sociologic burden to society notwithstanding the psychologic impact to the patients and families. Epidemiologic, clinical, and experimental studies indicate that these malformations occur in early pregnancy, are influenced by the abnormal maternal metabolic milieu, and seem to result from a combination of more than one factor. Clinical and experimental studies, however, have demonstrated that optimal metabolic control achieved in the periconceptual period and maintained throughout the first trimester of pregnancy results in a significant reduction in the malformation rate among offspring of diabetic mothers. In this light, diabetic women contemplating pregnancy should be encouraged to delay conception until satisfactory metabolic control is achieved so that embryogenesis may occur in an optimal metabolic milieu. The experimental use of arachidonic acid in the prevention of diabetes-related embryopathy is a new and potentially valuable tool. It extends the spectrum of available methods for prevention and deserves further study as a potential agent for pharmacologic prophylaxis.


12 minute consultation: An evidence-based approach to the management of a child with speech and language delay.
Speech and language delay is a common developmental disorder. Persistent delay may lead to adverse effects on literacy, educational achievement and psychosocial development. Affected children are commonly referred to the otolaryngologist; hence, a structured management approach is required to facilitate diagnosis and allow for early intervention and improved outcomes. A literature search was performed on 05 November 2012 using the MEDLINE, EMBASE and Cochrane databases with the search terms paediatric, children, speech, language, delay, disorder, investigation and management. Relevant references from selected articles were reviewed after reading the abstract. Speech and language delay may be primary, meaning there is no associated comorbidity to account for the delay, or secondary, where it can be attributed to another condition or syndrome. Secondary causes include hearing loss and syndromes such as Down syndrome amongst many others. Speech and language therapy has been shown to be effective for primary disorders. If the delay is found to be secondary in nature, onward referral to an appropriate healthcare professional is required. The outpatient consultation for a child with speech and language delay should consist of a structured history and examination with the aim of identifying whether the delay is primary or secondary in nature. Relevant targeted investigations should lead to a correct diagnosis of the delay and enable appropriate treatment. This often requires a multidisciplinary approach and always requires full cooperation from the child's parents.


Ten-year experience with percutaneous bone-anchored hearing aids: a 3- to 10-year follow-up Markham Stouffville Hospital, 1990 to 2000.
Patients with bilateral conductive hearing losses continue to be a source of frustration for both otologists and audiologists. Efforts to rehabilitate their hearing have included medical and surgical treatment, as well as the use of conventional hearing aids and, less frequently, conventional bone-conduction hearing aids. In the late 1980s, a percutaneous bone-anchored hearing aid (BAHA) developed by Dr. A. Tjellström, as an offshoot of Dr. P. I. Brånemark's work on osseointegration of titanium and bone, became commercially available. The BAHA has become a high-performing, comfortable, and aesthetically pleasing sound processor. The results of a 10-year BAHA program based at Markham Stouffville Hospital are summarized. In particular, a retrospective review of the 76 patients implanted between 1990 and 1997 is reported (i.e., a 3- to 10-year follow-up). Recent innovations to the design of the BAHA will be described that will further improve the quality of life for these patients.


[How do nurses in psychiatric institutions assess suicide risk? A survey in the German-speaking part of Switzerland].
In the interdisciplinary treatment process nurses play an important role, assessing suicide risk. To cope with this responsibility, the use of assessment instruments is recommended. Although a lot of instruments exist to assess the risk of suicide, nurses do not use them consistently. This cross-sectional study seeks to answer the following questions: How do nurses assess the suicidality of patients of psychiatric hospitals in the German speaking part of Switzerland? Do they use assessment instruments and if so, which ones? Ward nurses in every psychiatric hospital (n = 32) were asked about the state of the nursing practice in assessing the suicide risk by means of an electronic questionnaire. The following results emerged: Nurses use instruments to assess suicide risk on about half of the wards (n = 119, 50.63%). 13% of the mentioned instruments are research-based. Nurses mostly assess suicide endangerment in the case of a presumed danger, less often at admission and least often during the discharge process. As suicidality is assessed mostly when nurses assume a danger in this study, and due to the fact that suicides most frequently occur shortly prior to or during the discharge process, an expansion of or the introduction of the assessment is recommended before the discharge process.


Effect of norepinephrine infusion on plasma vasopressin levels in normal human subjects.
Norepinephrine was continuously infused for 30 minutes at a rate of 0.2 and 0.3 mug/kg/min into 3 normal human subjects, and plasma vasopressin levels, plasma osmolality, hematocrit value, blood pressure, and heart rate were determined simultaneously. In norepinephrine infusion, an elevation of mean blood pressure and a decrease in heart rate was seen, and the degree of these changes was greater with the infusion at a rate of 0.3 mug/kg/min. Plasma vasopressin levels were suppressed by the infusion, and a dose-response relationship was recognized between the infusion at rates of 0.2 mug/kg/min and 0.3 mug/kg/min, while plasma osmolality did not change, and the hematocrit value rose slightly. These results suggest that norepinephrine-induced water diuresis is related to the suppression of the vasopressin release.


EPC-derived microvesicles protect cardiomyocytes from Ang II-induced hypertrophy and apoptosis.
Cell-released microvesicles (MVs) represent a novel way of cell-to-cell communication. Previous evidence indicates that endothelial progenitor cells (EPCs)-derived MVs can modulate endothelial cell survival and proliferation. In this study, we evaluated whether EPC-MVs protect cardiomyocytes (CMs) against angiotensin II (Ang II)-induced hypertrophy and apoptosis. The H9c2 CMs were exposed to Ang II in the presence or absence of EPC-MVs. Cell viability, apoptosis, surface area and β-myosin heavy chain (β-MHC) expression were analyzed. Meanwhile, reactive oxygen species (ROS), serine/threonine kinase (Akt), endothelial nitric oxide synthase (eNOS), and their phosphorylated proteins (p-Akt, p-eNOS) were measured. Phosphatidylinositol-3-kinase (PI3K) and NOS inhibitors were used for pathway verification. The role of MV-carried RNAs in mediating these effects was also explored. Results showed 1) EPC-MVs were able to protect CMs against Ang II-induced changes in cell viability, apoptosis, surface area, β-MHC expression and ROS over-production; 2) The effects were accompanied with the up-regulation of Akt/p-Akt and its downstream eNOS/p-eNOS, and were abolished by PI3K inhibition or partially blocked by NOS inhibition; 3) Depletion of RNAs from EPC-MVs partially or totally eliminated the effects of EPC-MVs. Our data indicate that EPC-MVs protect CMs from hypertrophy and apoptosis through activating the PI3K/Akt/eNOS pathway via the RNAs carried by EPC-MVs.


Evaluating long-term effectiveness of sleeping sickness control measures in Guinea.
Human African Trypanosomiasis threatens human health across Africa. The subspecies T.b. gambiense is responsible for the vast majority of reported HAT cases. Over the past decade, expanded control efforts accomplished a substantial reduction in HAT transmission, spurring the WHO to include Gambian HAT on its roadmap for 2020 elimination. To inform the implementation of this elimination goal, we evaluated the likelihood that current control interventions will achieve the 2020 target in Boffa prefecture in Guinea, which has one of the highest prevalences for HAT in the country, and where vector control measures have been implemented in combination with the traditional screen and treat strategy. We developed a three-species mathematical model of HAT and used a Bayesian melding approach to calibrate the model to epidemiological and entomological data from Boffa. From the calibrated model, we generated the probabilistic predictions regarding the likelihood that the current HAT control programs could achieve elimination by 2020 in Boffa. Our model projections indicate that if annual vector control is implemented in combination with annual or biennial active case detection and treatment, the probability of eliminating HAT as public health problem in Boffa by 2020 is over 90%. Annual implementation of vector control alone has a significant impact but a decreased chance of reaching the objective (77%). However, if the ongoing control efforts are interrupted, HAT will continue to remain a public health problem. In the presence of a non-human animal transmission reservoir, intervention strategies must be maintained at high coverage, even after 2020 elimination, to prevent HAT reemerging as a public health problem. Complementing active screening and treatment with vector control has the potential to achieve the elimination target before 2020 in the Boffa focus. However, surveillance must continue after elimination to prevent reemergence.


Comparison of the Effect of Acupressure and Pilates-Based Exercises on Sleep Quality of Postmenopausal Women: A Randomized Controlled Trial.
Postmenopausal women experience a variety of symptoms, among which sleep disorder is one of the most common problems. Acupressure and Pilates exercise programs are effective nonpharmaceutical treatments which can improve sleep quality. In the present study, we aimed to compare the effects of acupressure and Pilates-based exercises on the sleep quality of postmenopausal women referred to medical clinics. In this single-blinded randomized controlled clinical trial, we recruited 108 women aged 40-60 years who were randomly assigned into one control and two intervention groups using balanced block randomization method (three groups of 36 each). The patients in the Pilates exercise group participated in an exercise training program of three 1-hour sessions per week for 6 consecutive weeks. The participants of acupressure group received acupressure intervention three times a week for 6 weeks. The sleep quality of all participants was assessed and recorded using the Pittsburgh Sleep Quality Index (PSQI) once before and once after the intervention. The results showed no statistically significant difference among the three groups on the total scores of sleep quality after the intervention. The intragroup comparison revealed that the changes in the mean total scores were significant in both the intervention groups (P < 0.001) but not in the control group (P = 0.76). Pilates-based exercises and acupressure can effectively improve women's sleep quality. Both techniques can be applied as effective alternative and complementary methods for improving sleep quality during the postmenopausal period.


Association between the hsa-mir-27a variant and breast cancer risk: a meta-analysis.
Although a number of studies were published in the past several years on associations between hsa-mir-27a and cancer risk, the findings remain conflicting rather than conclusive. To derive a more precise effect on the association between SNP hsa-mir-27a rs895819 and breast cancer risk, we conducted a meta-analysis for the first time. Through retrieval from PubMed for the period up to August 2012, a total of four studies were identified with 3,287 cases and 4,298 controls for SNP hsa-mir-27a rs895819.We calculated summary odds ratio (ORs) and corresponding 95% confidence intervals (CIs) using a fixed effects model (when the heterogeneity was absent, P>0.10). Otherwise, the random-effects model was used. We found that hsa-mir-27a rs895819 polymorphism also did not reveal any relationship with breast cancer susceptibility (AG versus AA: OR = 0.98; 95%CI, 0.73-1.32; GG versus AA: OR = 0.86; 95% CI, 0.72-1.03; AG/GG versus AA: OR = 0.92; 95% CI, 0.74-1.14), while significantly decreased risk was found among Europeans in AG versus AA and AG/GG versus AA models tested (AG versus AA: OR = 0.83; 95%CI, 0.72-0.97; GG versus AA: OR = 0.86; 95% CI, 0.71-1.05; AG/GG versus AA: OR = 0.84; 95% CI, 0.75-0.94). These findings suggest that hsa-mir-27a rs895819 polymorphism may play an important role in breast cancer development.


Novel perspectives in clinical cardiology and cardiac surgery.
The International Conference on Clinical & Experimental Cardiology was held in San Antonio (TX, USA) on 14-16 April 2014. This was the fourth meeting and had the theme 'Novel Perspectives on Clinical Cardiology and Cardiac Surgery' with sessions in heart disease, congenital heart disease, cardiac therapeutic agents, biophysics and systems biology, current research, and interventional cardiology, providing an interactive forum for discussion of science and clinical practices. Presentations by delegates from Africa, Saudi Arabia, India, China, Japan, Australia, Europe, South America, in addition to Canada and the USA, provided an opportunity for collaboration but also an appreciation of the challenges for treatment in remote locations as well as distance between health facilities.


Prognostic importance of central thrombus in hemodynamically stable patients with pulmonary embolism.
The association between mortality and localization of central thrombus in hemodynamically stable patients with pulmonary embolism (PE) is unclear. Sufficient data are not available to help clinicians to select between low molecular weight heparin (LMWH), unfractionated heparin (UFH) and thrombolytics for the management of central thrombus. The present study aims to investigate whether central thrombus in the pulmonary artery affects 30-day mortality rate, and to compare the outcomes of different treatment approaches in patients with central thrombus. This multi-central, prospective, observational study included 874 hemodynamically stable patients with PE confirmed by multidetector computed tomography scan. The localization of the emboli was evaluated and categorized as central (saddle or at least one main pulmonary artery), lobar or distal. The primary study outcome was 30-day all-cause mortality. Localization of the emboli was central in 319 (36.5%) patients, lobar in 264 (30.2%) and distal in 291 (33.2%) patients. Seventy-four (8.5%) patients died during the 30-day follow-up period. All-cause mortality rate was 11.9%, 6.8% and 6.2% in patients with central, lobar, and distal emboli, respectively (p < 0.001). Multivariate analysis did not show that hemodynamically stable central thrombus was an independent predictor of mortality. Additionally, mortality rate was not significantly different between UFH, LMWH and thrombolytic therapy groups. The present study showed that central thrombus was not an independent predictor of mortality in hemodynamically stable PE patients. LMWH and UFH were similarly effective in the treatment of this patient group.


Trichiasis associated with prostaglandin analog use.
A previously unreported complication of the use of prostaglandin analog medications for glaucoma therapy is described. A patient with monocular open-angle glaucoma had trichiasis, a condition associated with the use of a prostaglandin analog. The patient was treated with radiofrequency cautery and is now asymptomatic. The unmedicated eye remains asymptomatic to date. Increased lash length, thickness, and pigmentation are well-documented side effects of prostaglandin analog glaucoma drops. Physicians must consider this when prescribing these medications for patients with misdirected eyelashes.


Kisspeptin Stimulation of Prolactin Secretion Requires Kiss1 Receptor but Not in Tuberoinfundibular Dopaminergic Neurons.
Kisspeptin has been shown to stimulate prolactin secretion. We investigated whether kisspeptin acts through the Kiss1 receptor (Kiss1r) to regulate dopamine and prolactin. Initially, we evaluated prolactin response in a Kiss1r-deficient mouse line, in which Kiss1r had been knocked into GnRH neurons (Kiss1r-/-R). Intracerebroventricular kisspeptin-10 (Kp-10) increased prolactin release in wild-type but not in Kiss1r-/-R female mice. In ovariectomized, estradiol-treated rats, the Kiss1r antagonist kisspeptin-234 abolished the Kp-10-induced increase in prolactin release but failed to prevent the concomitant reduction in the activity of tuberoinfundibular dopaminergic (TIDA) neurons, as determined by the 3,4-dihydroxyphenylacetic acid/dopamine ratio in the median eminence. Using whole-cell patch clamp recordings in juvenile male rats, we found no direct effect of Kp-10 on the electrical activity of TIDA neurons. In addition, dual-label in situ hybridization in the hypothalamus of female rats showed that Kiss1r is expressed in the periventricular nucleus of the hypothalamus (Pe) and arcuate nucleus of the hypothalamus (ARC) but not in tyrosine hydroxylase (Th)-expressing neurons. Kisspeptin also has affinity for the neuropeptide FF receptor 1 (Npffr1), which was expressed in the majority of Pe dopaminergic neurons but only in a low proportion of TIDA neurons in the ARC. Our findings demonstrate that Kiss1r is necessary to the effect of kisspeptin on prolactin secretion, although TIDA neurons lack Kiss1r and are electrically unresponsive to kisspeptin. Thus, kisspeptin is likely to stimulate prolactin secretion via Kiss1r in nondopaminergic neurons, whereas the colocalization of Npffr1 and Th suggests that Pe dopaminergic neurons may play a role in the kisspeptin-induced inhibition of dopamine release.


Aggregation-Enhanced Energy Transfer for Mitochondria-Targeted ATP Ratiometric Imaging in Living Cells.
Förster resonance energy transfer (FRET) from fluorescent nanoparticles to fluorescent dyes is an attractive approach for bioanalysis in living cells. However, the luminescence of the nanoparticle donor/acceptor has not been effectively used to produce highly efficient FRET because the distance between the energy donor and energy acceptor is often larger than the effective FRET radius (about 10 nm) and the uncontrolled rotational and translational diffusion of luminophores. Here, we develop an aggregation-enhanced energy transfer strategy that can overcome the impedance for effective energy transfer. The functional nanoprobes, named TPP-CDs-FITC, are carbon dots (CDs) functionalized with triphenylphosphine (TPP) and ∼117 fluorescein 5-isothiocyanate (FITC) on the surface. In dispersed solution, the 3.8 nm TPP-CDs-FITC show weak FRET efficiency (15.4%). After TPP-instructed mitochondrial targeting, enhanced FRET efficiency (53.2%) is induced due to the aggregation of TPP-CDs-FITC selectively triggered by adenosine triphosphate (ATP) in the mitochondria. The enhanced FRET efficiency can be attributed to the joint effect of the augment of numbers of FITC acceptors within 10 nm from dispersed 117 to aggregated 5499 and the restricted rotational and translational motions of TPP-CDs donors and FITC acceptors. Ultimately, we successfully observe the fluctuations of ATP levels in the mitochondria using the aggregation-enhanced energy transfer strategy of the TPP-CDs-FITC nanodevice.


Examining and Improving Provider Adherence to the Primary Care Mental Health Integration Model.
The Veterans Health Administration (VHA) is a national leader in integrated care, known in the VHA as the Primary Care Mental Health Integration (PCMHI) model. This model is associated with improved quality of services and same-day access for veterans. There has been some recent development of PCMHI/integrated care competencies within VHA and across the nation. To fully implement these competencies, however, PCMHI providers must not only be trained, but their adherence to the PCMHI model must also be assessed. While there have been recent advances, there has been little research that has examined the adherence of PCMHI providers to the model or methods to improve adherence. The present study sought to examine and improve the clinical practice of a team of eight PCMHI providers to make practice more adherent to the PCMHI model. This study was conducted at a large Midwestern VA Medical Center using interventions based in assessment, feedback, and training-measured at three points in time. The Primary Care Behavioral Health Provider Adherence Questionnaire (PPAQ; Beehler GP, Funderburk JS, Possemato K, et al.: Psychometric assessment of the primary care behavioral health provider adherence questionnaire (PPAQ). Transl Behav Med 2013; 3: 379-91.) was used to assess provider adherence and the PPAQ toolkit was used to provide tailored recommendations for improving provider practice. In addition, the VHA "Foundations Manual" and Functional Tool outlined essential behavioral targets that are consistent with the PCMHI model and the "essential provider behaviors" from the PPAQ. A combination of individual and group interventions was presented and adherence, pre and post, was assessed with the PPAQ and with evaluation of clinical practice data. Results indicated that the behavior of PCMHI providers changed over time, with providers exhibiting more PCMHI consistent behaviors and fewer inconsistent behaviors. Adherence to the PCMHI model increased. Providing assessment, feedback, and training in the PCMHI model changed the clinical practice of PCMHI providers and resulted in improved adherence. Clinical and research implications are discussed.


Metabolic ratios and SNPs implicated in tramadol-related deaths.
Tramadol (TR) metabolism is performed by polymorphic enzymes that are influenced by genetic polymorphisms. Within this scope, the study presented here aimed to describe 41 genetic variants within CYP2D6, CYP2B6, and CYP3A4 genes in 48 cases of TR-related death that may be involved in the response to TR and to assess whether there is a correlation between these genetic variants and metabolic ratios (MRs). Blood samples from 48 victims of a TR-related death were analyzed to determine the concentrations of TR and its metabolites [O-desmethyltramadol (M1) & N-desmethyltramadol (M2)] using a LC-MS/MS method. All the samples were also genotyped for 41 common CYP2D6, CYP2B6, and CYP3A4 single nucleotide polymorphisms (SNPs) using the HaloPlex Target Enrichment system. Cases with the T/- genotype (rs35742686 in CYP2D6) had significantly higher M2/M1 ratio than cases with T/T genotype and cases with the G/A genotype (rs35599367 in CYP3A4) had significantly higher MR2 (TR/M2) ratio than cases with G/G genotype. The frequency of tested SNPs which belong to CYP2D6, CYP2B6, and CYP3A4 revealed the over-presentation of 2 SNPs (rs1058172 in CYP2D6 and rs4803419 in CYP2B6) in TR overdose group, which could have toxicological implications. These results indicate these polymorphisms in CYP2D6, CYP2B6, and CYP3A4 might influence the function and could increase the risk of toxicity. However, these findings should be supported in future studies with larger groups of cases.


Glucocorticoid receptor suppresses gene expression of Rev-erbα (Nr1d1) through interaction with the CLOCK complex.
Glucocorticoids have various medical uses but are accompanied by side effects. The glucocorticoid receptor (GR) has been reported to regulate the clock genes, but the underlying mechanisms are incompletely understood. In this study, we focused on the suppressive effect of the GR on the expression of Rev-erbα (Nr1d1), an important component of the clock regulatory circuits. Here we show that the GR suppresses Rev-erbα expression via the formation of a complex with CLOCK and BMAL1, which binds to the E-boxes in the Nr1d1 promoter. In this GR-CLOCK-BMAL1 complex, the GR does not directly bind to DNA, which is referred to as tethering. These findings provide new insights into the role of the GR in the control of circadian rhythm.


Metabolism of a novel antiangiogenic agent KR-31831 in rats using liquid chromatography-electrospray mass spectrometry.
KR-31831 ((2S,3R,4S)-4-(((1H-imidazol-2-yl)methyl)(4-chlorophenyl)amino)-6-amino-2-(dimethoxymethyl)-2-methyl-3,4-dihydro-2H-chromen-3-ol) is a novel antiangiogenic agent. In vitro and in vivo metabolism of KR-31831 in rats has been investigated using LC-MS and LC-MS/MS analysis. Incubation of rat liver microsomes and hepatocytes with KR-31831 produced three metabolites (M1-M3). M1, M2, and M3 were identified as N-((1H-imidazol-2-yl)methyl)-4-chlorobenzenamine, (2R,3R,4S)-4-(((1H-imidazol-2-yl)methyl)(4-chlorophenyl) amino)-6-amino-2-(hydroxymethyl)-2-methyl-3,4-dihydro-2H-chromen-3-ol, and N-((2S,3R,4S)-4- (((1H-imidazol-2-yl)methyl)(4-chlorophenyl)amino)-2-(dimethoxymethyl)-3-hydroxy-2-methyl-3,4-dihydro-2H-chromen-6yl)acetamide, respectively, by co-chromatography with the authentic standards and by comparison with product ion spectra of the authentic standards. Those in vitro metabolites were also detected in bile, plasma, or urine samples after an intravenous administration of KR-31831 to rats. The metabolic routes for KR-31381 included the metabolism of acetal group to hydroxymethyl group (M2), N-dealkylation to M1, and N-acetylation at the 6-amino group (M3).


Research as a visiting doctor in Afghanistan and Cambodia.
This paper describes research I conducted into health care and its difficulties while working as a visiting doctor in two developing countries. The research was conducted in the Departments of Medicine, University Hospital, Jalalabad, Afghanistan, in 1994 and 1995, and Calmette Hospital, Phnom Penh, Cambodia, in 1997 and 1998. In Afghanistan I did an observational study of medical practice and case studies at the Department of Medicine, and a survey of drugs sold in pharmacies in Jalalabad. In Cambodia I surveyed hemoglobin concentrations of medical patients, and did an observational study of medical practice and case studies at Calmette Hospital. I surveyed the body weight of medical patients in relation to drug doses, and used a questionnaire to survey prescribing practices of physicians. Each project was conducted by me alone and was completed within 1-3 months. The support by the hospital was good and there where no ethics committees that had to approve the projects. Only verbal consent from the patients had to be obtained and no national laws or regulations affected the research. Small clinical research projects in developing countries are relatively easy to perform, if conducted by one researcher working in a hospital and not relying on special equipment such as a computer.


Photodissociation dynamics of methyl formate at 193.3 nm: Branching ratios, kinetic-energy distributions, and angular anisotropies of products.
We investigated the photodissociation dynamics of methyl formate-d (CH(3)OC(O)D) at 193.3 nm in a molecular-beam apparatus using undulator radiation as an ionization source. We measured kinetic-energy distributions, spatial angular anisotropies, and branching ratios of all photofragments. Fractions of energy release into product translation were calculated from the kinetic-energy distributions. Four primary dissociation pathways to asymptotes CH(3)O(X (2)E)+DCO(X (2)A(')), CH(3)O(X (2)E)+DCO(A (2)A(")), CH(3)OCO(X (2)A('))+D((2)S), and CH(3)OD(X (1)A('))+CO(X (1)Sigma(+)) were identified; their branching ratios were determined to be 0.73, 0.06, 0.13, and 0.08, respectively. The former two dissociation paths were discernible in the time-of-flight spectra of fragment CH(3)O with a signal at m/z=29. Nominal products DCO (A (2)A(")) and CH(3)OCO (X (2)A(')) were unobservable as DCO in state A dissociated to D((2)S)+CO(X (1)Sigma(+)) and internally hot CH(3)OCO (X (2)A(')) decomposed to CH(3)(X (2)A(2) ("))+CO(2)(X (1)A(1g)). Products DCO and CH(3)O have angular anisotropy parameter beta approximately -0.37 but other products have nearly isotropic angular distributions with /beta/<0.1. Nonadiabatic transitions might play an important role in fragmentation of methyl formate irradiated at 193.3 nm.


Normal contractions triggered by I(Ca,L) in ventricular myocytes from rats with postinfarction CHF.
Attenuated L-type Ca(2+) current (I(Ca,L)), or current-contraction gain have been proposed to explain impaired cardiac contractility in congestive heart failure (CHF). Six weeks after coronary artery ligation, which induced CHF, left ventricular myocytes from isoflurane-anesthetized rats were current or voltage clamped from -70 mV. In both cases, contraction and contractility were attenuated in CHF cells compared with cells from sham-operated rats when cells were only minimally dialyzed using high-resistance microelectrodes. With patch pipettes, cell dialysis caused attenuation of contractions in sham cells, but not CHF cells. Stepping from -50 mV, the following variables were not different between sham and CHF, respectively: peak I(Ca,L) (4.5 +/- 0.3 vs. 3.8 +/- 0.3 pApF(-1) at 23 degrees C and 9.4 +/- 0.5 vs. 8.4 +/- 0.5 pApF(-1) at 37 degrees C), the bell-shaped voltage-contraction relationship in Cs(+) solutions (fractional shortening, 15.2 +/- 1.0% vs. 14.3 +/- 0.7%, respectively, at 23 degrees C and 7.5 +/- 0.4% vs. 6.7 +/- 0.5% at 37 degrees C) and the sigmoidal voltage-contraction relationship in K(+) solutions. Caffeine-induced Ca(2+) release and sarcoplasmic reticulum Ca(2+)-ATPase-to-phospholamban ratio were not different. Thus CHF contractions triggered by I(Ca,L) were normal, and the contractile deficit was only seen in undialyzed cardiomyocytes stimulated from -70 mV.


Proteolytic cleavage of the disease-related lysosomal membrane glycoprotein CLN7.
CLN7 is a polytopic lysosomal membrane glycoprotein of unknown function and is deficient in variant late infantile neuronal ceroid lipofuscinosis. Here we show that full-length CLN7 is proteolytically cleaved twice, once proximal to the used N-glycosylation sites in lumenal loop L9 and once distal to these sites. Cleavage occurs by cysteine proteases in acidic compartments and disruption of lysosomal targeting of CLN7 results in inhibition of proteolytic cleavage. The apparent molecular masses of the CLN7 fragments suggest that both cleavage sites are located within lumenal loop L9. The known disease-causing mutations, p.T294K and p.P412L, localized in lumenal loops L7 and L9, respectively, did not interfere with correct lysosomal targeting of CLN7 but enhanced its proteolytic cleavage in lysosomes. Incubation of cells with selective cysteine protease inhibitors and expression of CLN7 in gene-targeted mouse embryonic fibroblasts revealed that cathepsin L is required for one of the two proteolytic cleavage events. Our findings suggest that CLN7 is inactivated by proteolytic cleavage and that enhanced CLN7 proteolysis caused by missense mutations in selected luminal loops is associated with disease.


[Familial amyloid polyneuropathy type IV (Finnish type)--a clinicopathological study].
Familial amyloid polyneuropathy type IV (Finnish type, FAP IV) is one form of hereditary generalized amyloidosis with autosomal dominant trait and is characterized clinically by a triad of corneal lattice dystrophy, caudal cranial neuropathy and various skin changes. The vast majority of the families with this disorder originated from Finland. We carried out a clinicopathological study of a large FAP IV kindred recently found in Japan. This family consisted of 73 members in 5 generations with 17 affected individuals and 7 of them (ages 45 to 73) were examined in detail. All patients showed typical clinical manifestations, lacking significant peripheral neuropathy in the limbs. However, autonomic dysfunctions including orthostatic fainting and dysuria were seen in 2 patients. Congophilic amyloid deposits were commonly observed in an aspiration biopsy of abdominal fat tissues, and noradrenergic nerve fibers of the rectal mucosa were reduced in one patient with autonomic symptoms. DNA analysis using PCR revealed a single base change (G to A) at nucleotide position 654 of the gelsolin gene in 7 patients and one asymptomatic individual. The clinical pictures and gene abnormality in this Japanese family are very similar to those reported in Finland. Moreover, this study added that autonomic nerves might be involved in FAP IV patients at the advanced stage.


The potential role of physical activity in the prevention of non-insulin-dependent diabetes mellitus: the epidemiological evidence.
Examining the epidemiological literature, a relationship between physical activity and the development of NIDDM seems not only plausible but likely. What is needed is a randomized clinical trial to confirm the metabolic and epidemiological research findings to date. To maximize success of a diabetes prevention trial, both diet and physical activity should be part of the intervention. The relative importance of diet or physical activity as components of the intervention will vary, depending upon the participant. However, it is critical that compliance with the physical activity and diet intervention be maintained, for this question to be answered. If the intervention is successful, the participants will have made lifestyle changes that have the potential of lasting beyond the closure of the clinical trial.


Combined treatment of vitamin K and teriparatide on bone metabolism and biomechanics in rats with osteoporosis.
Postmenopausal osteoporosis is a degenerative disease caused by lack of estrogen whereby bone degeneration exceeds bone formation, resulting in loss of bone mass. Various drugs have been utilized in an attempt to ameliorate bone strength in such patients. The aim of the present study was to compare the effects of vitamin K or teriparatide alone and combined on bone metabolism and biomechanics in rats with osteoporosis. The ovaries of rats were excised to construct a rat model of osteoporosis. Rats were subjected to oral intake of vitamin K or subcutaneous injection of teriparatide or both for 8 weeks. ELISA was used to detect the content of carboxylated-type of osteocalcin (Gla-OC) and C-telopeptide of type I collagen (CTX-I) in serum. Bone density of shaft of femur and metaphyseal bone was measured. Three-point bending test was performed to analyze the load-deformation curve of femur. Undecalcified sections of femur were stained with toluidine blue to measure bone histomorphometric static, dynamic and bone resorption parameters. Compared with monotherapy, vitamin K combined with teriparatide significantly increased serum Gla-OC level and the number of osteoblast, decreased serum CTX-I level, reduced the number of osteoclasts and increased bone density and strength. This study showed that the efficacy of vitamin K combined with teriparatide is better than that of monotherapy. This combined treatment can promote bone formation, inhibit bone degradation, and improve bone density and strength.


Elevated periprostatic venous testosterone correlates with prostate cancer progression after radical prostatectomy.
BACKGROUNDGenerally, clinical assessment of gonadal testosterone (T) in human physiology is determined using concentrations measured in peripheral blood. Prostatic T exposure is similarly thought to be determined from peripheral T exposure. Despite the fact that androgens drive prostate cancer, peripheral T has had no role in the clinical evaluation or treatment of men with localized prostate cancer.METHODSTo assess the role of local androgen delivery in prostate cancer, we obtained blood from the (periprostatic) prostatic dorsal venous complex in 266 men undergoing radical prostatectomy from July 2014 to August 2021 and compared dorsal T (DT) levels with those in circulating peripheral blood (PT) and prostatic tissue. Comprehensive targeted steroid analysis and unbiased metabolomics analyses were performed. The association between the DT/PT ratio and progression-free survival after prostatectomy was assessed.RESULTSSurprisingly, in some men, DT levels were enriched several-fold compared with PT levels. For example, 20% of men had local T concentrations that were at least 2-fold higher than peripheral T concentrations. Isocaproic acid, a byproduct of androgen biosynthesis, and 17-OH-progesterone, a marker of intratesticular T, were also enriched in the dorsal vein of these men, consistent with testicular shunting. Men with enriched DT had higher rates of prostate cancer recurrence. DT/PT concentration ratios predicted worse outcomes even when accounting for known clinical predictors.CONCLUSIONSThese data suggest that a large proportion of men have a previously unappreciated exposure to an undiluted and highly concentrated T supply. Elevated periprostatic T exposure was associated with worse clinical outcomes after radical prostatectomy.FUNDINGNational Cancer Institute (NCI), NIH grants R01CA172382, R01CA236780, R01CA261995, R01CA249279, and R50CA251961; US Army Medical Research and Development Command grants W81XWH2010137 and W81XWH-22-1-0082.


Non-sphenopalatine dominant arterial supply of the nasal cavity: an unusual anatomical variation.
We present a rare and clinically relevant anomaly of the sphenopalatine artery in relation to its blood supply of the nasal mucosa, with implications for the management of epistaxis. Case report and review of the world literature, using Medline through Pub Med (1950-2005), EMBASE (1980-2005) and Ovid (1958-2005), searching for papers using a combination of terms including 'spheno-palatine artery', 'anterior ethmoidal artery' and 'epistaxis'. In the presented case of refractory epistaxis, endoscopic and subsequent endovascular management failed to identify a significant supply from the sphenopalatine arteries bilaterally. The main supply was found to be from the anterior ethmoidal arteries. After a detailed search, the authors failed to locate any similar case in the English literature.


Differentiation of mumps virus strains with monoclonal antibody to the HN glycoprotein.
A hybridoma cell line secreting antibody of the immunoglobulin G3 isotype with kappa light chains and with activity against the HN glycoprotein of the Kilham strain of mumps virus was established. The antibody exhibited structural homogeneity in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and had a microheterogeneous isoelectric spectrum characteristic of an antibody of monoclonal origin. The specificity of the monoclonal antibody, shown by immunoprecipitation performed with radiolabeled virus and infected cell lysates, was for the larger mumps virus glycoprotein. In functional assays the antibody inhibited the hemagglutinating and neuraminidase activities and neutralized the infectivity of the homologous Kilham strain of virus and clearly differentiated this strain from two heterologous strains, Enders and O'Take. The antibody was markedly less effective with the O'Take strain than with either the Kilham or Enders strain in inhibiting both hemagglutination and neuraminidase activity against the macromolecular substrate fetuin. The inhibition of the neuraminidase activity of the Kilham strain was independent of substrate size, the antibody inhibiting the hydrolysis of both fetuin and the trisaccharide neuraminlactose. By contrast, the antibody did not inhibit the hydrolysis of neuraminlactose by the two heterologous mumps strains. These results provide the first demonstration of antigenic differences between mumps virus strains and highlight the utility of monoclonal antibody in analyzing the structural basis underlying functional activities of the HN glycoproteins.


Total absorption of an electromagnetic wave by an overdense plasma.
We show both theoretically and experimentally that an electromagnetic wave can be totally absorbed by an overdense plasma when a subwavelength diffraction grating is placed in front of the plasma surface. The absorption is due to dissipation of surface plasma waves (plasmons polaritons) that have been resonantly excited by the evanescent component of the diffracted electromagnetic wave. The developed theoretical model allows one to determine the conditions for the total absorption.


Revolutionary and evolutionary change in emergency management.
The following paper acknowledges that disasters are on the rise and asserts that more must be done to counter their causes and minimise their adverse consequences. It reviews proposed shifts in thinking and suggests that recommendations to meet future challenges must be based on sound assumptions. The central finding of this study is that significant change in emergency management is needed, but may not be easily achieved because of numerous barriers that are inherent to the disaster problem. As such, preparedness measures and response operations will always be needed in spite of, and in addition to, further mitigation activities. Progress is therefore both likely and advantageous as long as emergency management policy is built on--but goes much further than--historical efforts.


[Assessment of pathological biopsy and safety margin of specimens from breast cancer patients with breast conversing surgery].
Breast-conserving surgery (BCS) has now become one of the optimal surgical choices for early invasive breast cancer. The pathological diagnosis of margin in breast-conserving specimen is very important. There is no acknowledge on the approaches of pathological biopsy and safety margin diagnosis of breast conserving surgery. This paper will compare the biopsy and diagnosis methods of breast-conserving surgery specimens between Tianjin Medical University Cancer Institute and Hospital in China and MD Anderson Cancer Center in the United States. We summarize our biopsy method and diagnostic criteria to explore how to accurately evaluate the margin of breast-conserving surgery specimen from a pathological point of view, and to escort a successful breast-conserving surgery.


Influence of morbid obesity on physical capacity, knee-related symptoms and overall quality of life: A cross-sectional study.
To evaluate the impact of morbid obesity on physical capacity, joint-related symptoms, and on the overall quality of life. Cross-sectional study carried out at a university hospital, enrolling 39 individuals admitted to a bariatric surgery service. Physical capacity was assessed by Six-Minute Walk Test (SMWT) and the Borg rating of perceived exertion (RPE). Knee-related symptoms were evaluated by Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Lysholm Score. Quality of life was evaluated by Short Form 36 Health Questionnaire (SF-36). On SMWT, the mean distance walked was 374.1±107.5 m. The mean Borg score was 12.9±2.4. KOOS questionnaire found the following scores: pain (64.3±24), other symptoms (67.2±25.5), function in daily living (60.4±26.8), function in sport and recreation (28.5±32.2), knee-related quality of life (35.9±33.5), mean Lysholm scale score (55.3±25.4). SF-36 provided the following scores: physical functioning (41±27.4), physical role functioning (34.6±39.2), bodily pain (45.7±23.6), general health perceptions (63.1±26.2), vitality (53.5±12.1), social role functioning (52.6±29.3), emotional role functioning (41±44.9), mental health (55±27.7). Obesity led to significant loss of physical capacity, gait impairment, knee-related symptoms, and a negative impact on the overall quality of life.


[Lymphocyte trafficking and immunesurveillance].
The homeostasis of the immune system is maintained by the recirculation of naive lymphocytes through the secondary lymphoid tissues, such as the lymph nodes, Peyer's patches and spleen. Upon antigen encounter in the secondary lymphoid tissues, lymphocytes become activated and undergo a reprogramming of their trafficking properties. Most antigen-experienced lymphocytes traffic through the secondary lymphoid organs, but they can also migrate to extralymphoid tissues, where they exert effector functions. Dendritic cells in the secondary lymphoid tissues are crucial for the reprogramming of trafficking properties of activated T-lymphocytes. The exquisite specificity of such lymphocyte trafficking is determined by tissue-specific guidance signals expressed by the vascular endothelial cells, combined with counter receptors expressed by circulating lymphocytes. The high endothelial venules can selectively recruit naive lymphocytes into the lymph nodes and Peyer's patches by expressing a unique combination of vascular addressins and chemoattractants. The inflamed postcapillary venules in extralymphoid tissues also use a distinct array of endothelial adhesion molecules and tissue selective chemokines to support the recruitment of effector and memory lymphocytes that express appropriate trafficking receptors. Exit of lymphocytes from lymphoid and extralymphoid tissues into circulation is actively regulated by signals through specific receptors for sphingosine-1-phosphate and a certain chemokine(s), respectively. This review summarizes the present understandings of the mechanisms regulating homeostatic recirculation of naive lymphocytes through the secondary lymphoid tissues and tissue-specific trafficking of antigen-experienced lymphocytes.


Interactions of cyclic adenosine 3',5'-monophosphate, protein kinase-C, and calcium in dopamine- and gonadotropin-releasing hormone-stimulated growth hormone release in the goldfish.
In the goldfish, GH release is under the stimulatory control of multiple neuroendocrine factors, including dopamine (DA) and GnRH. We have previously shown that DA-stimulated GH release in the goldfish is mediated via D1 receptors and is dependent on cAMP, whereas the GH response to GnRH involves protein kinase-C (PKC) and extracellular Ca2+ entry through voltage-sensitive Ca2+ channels (VSCC). In this study, the interactions of PKC, cAMP, and Ca2+ in the regulation of GH release responses to DA and GnRH were examined using dispersed goldfish pituitary cells. The GnRH-induced GH secretion was unaffected by a protein kinase-A (PKA) inhibitor, but was additive to the GH responses to 8-bromo-cAMP (8-Br-cAMP), the phosphodiesterase inhibitor isobutylmethylxanthine, or the D1 agonist SKF38393. Similarly, the GH responses to PKC activators were additive to those to 8-Br-cAMP, forskolin, SKF38393, or the general DA agonist apomorphine. In contrast, depletion of cellular PKC content inhibited the GH responses to GnRH and PKC activators, but not those to DA, SKF38393, 8-Br-cAMP, or forskolin. Furthermore, the GH response to 8-Br-cAMP or SKF38393 was unaffected by the selective PKC inhibitor H7. Taken together, these results suggest that GnRH and DA D1 mechanisms stimulate GH release in the goldfish independently via PKC- and cAMP-dependent intracellular signaling pathways, respectively. However, both the cAMP (D1) and PKC (GnRH) mechanisms also interacted with VSCC. The VSCC agonist Bay K8644 potentiated, whereas the VSCC blocker verapamil reduced, the GH responses to GnRH, PKC activators, SKF38393, and activators of the cAMP pathway. A hypothesis is proposed based on these findings. GnRH and DA initiate GH release independently by activation of PKC- and cAMP-dependent mechanisms. The secondary activation of VSCC by either PKC or cAMP/PKA further enhances the GH response.


Multiple Mechanisms for the Thermal Decomposition of Metallaisoxazolin-5-ones from Computational Investigations.
The thermal decompositions of metallaisoxazolin-5-ones containing Ir, Rh, or Co are investigated using density functional theory. The experimentally observed decarboxylations of these molecules are found to proceed through retro-(3+2)-cycloaddition reactions, generating the experimentally reported η2 side-bonded nitrile complexes. These intermediates can isomerize in situ to yield a η1 nitrile complex. A competitive alternative pathway is also found where the decarboxylation happens concertedly with an aryl migration process, producing a η1 isonitrile complex. Despite their comparable stability, these η1 bonded species were not detected experimentally. The experimentally detected η2 side bound species are likely involved in the subsequent C-H activation reactions with hydrocarbon solvents reported for some of these metallaisoxazolin-5-ones.


The presence of BRAF point mutation in adult papillary thyroid carcinomas from atomic bomb survivors correlates with radiation dose.
In papillary thyroid carcinogenesis, the constitutively activated mitogen-activated protein (MAP) kinase signaling pathway caused by a genetic alteration such as RET/PTC rearrangement or mutation of RAS and BRAF genes, is thought to be a major early event. Among these, the recently identified BRAF(V600E) mutation has been found at high frequency in adult patients with papillary thyroid carcinoma (PTC). However, the association between this mutation and radiation exposure in adult PTC is still unknown. In this study, we examined the BRAF(V600E) mutation in 64 PTCs among adult atomic bomb survivors in Hiroshima, Japan, comprising 17 nonexposed (0 mGy) and 47 exposed patients who developed the carcinoma after the bombing, and assessed the association of BRAF(V600E) mutation with clinico-pathological and epidemiological variables. The median radiation dose in PTCs with the BRAF(V600E) mutation was significantly lower than that without the mutation (18.5 vs.156.9 mGy, Wilcoxon rank-sum test, P=0.022). A significant difference was found in the median latency period (years elapsed from atomic bombing to diagnosis) between exposed patients with and without BRAF(V600E) mutation (29 vs. 21 yr, Wilcoxon rank-sum test, P=0.014). These findings were further confirmed by logistic regression analysis with BRAF(V600E) mutation status as a dependent variable and taking into account possible interactions between the variables. We found that the log-transformed radiation dose and latency period were independently associated with the BRAF(V600E) mutation (P=0.039 and P=0.010, respectively). These results suggest that involvement of BRAF mutation in thyroid carcinogenesis in exposed people may differ from that in the nonexposed people.


Evaluation of the Physician Global Assessment and Body Surface Area Composite Tool for Assessing Psoriasis Response to Apremilast Therapy: Results from ESTEEM 1 and ESTEEM 2.
The Physician Global Assessment and Body Surface Area (PGAxBSA) composite tool is a simple, effective alternative for measuring psoriasis severity. To evaluate the product of PGAxBSA as a sensitive alternative to the Psoriasis Area and Severity Index (PASI) for assessing disease severity and therapeutic response with data collected from the phase 3 ESTEEM 1 and 2 trials. This post hoc analysis included 836 patients randomized to apremilast 30 mg BID at baseline (ESTEEM 1, n=562; ESTEEM 2, n=274). Spearman correlation coefficients were used to compare PGAxBSA, PASI, and the Dermatology Life Quality Index (DLQI). Concordance between PGAxBSA and PASI was evaluated for 50%/75%/90% improvement from baseline at week 16. In ESTEEM 1 and 2, PGAxBSA and PASI exhibited significant positive correlations for measuring disease severity at baseline (r≥0.757) and week 16 (r≥0.807). At week 16, ≥79% concordance was observed between PGAxBSA and PASI for 75% and 90% improvement from baseline; greater concordance (>88.0%) was observed using 50% improvement from baseline. At week 16, PGAxBSA and PASI were moderately correlated with DLQI. Analysis was limited to patients with baseline BSA ≥10% and static PGA ≥3. In patients with moderate to severe psoriasis, PGAxBSA is correlated with PASI and sensitive to therapeutic response.
J Drugs Dermatol. 2017;16(2):147-153.
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Gestures modulate speech processing early in utterances.
Electroencephalogram was recorded as healthy adults viewed short videos of spontaneous discourse in which a speaker used depictive gestures to complement information expressed through speech. Event-related potentials were computed time-locked to content words in the speech stream and to subsequent related and unrelated picture probes. Gestures modulated event-related potentials to content words co-timed with the first gesture in a discourse segment, relative to the same words presented with static freeze frames of the speaker. Effects were observed 200-550 ms after speech onset, a time interval associated with semantic processing. Gestures also increased sensitivity to picture probe relatedness. Effects of gestures on picture probe and spoken word analysis were inversely correlated, suggesting that gestures differentially impact verbal and image-based processes.


Palladium-Catalyzed Fluoroalkylative Cyclization of Olefins.
A palladium-catalyzed fluoroalkylative cyclization of olefins with readily available Rf-I reagents to afford the corresponding fluoroalkylated 2,3-dihydrobenzofuran and indolin derivatives with moderate to excellent yields is reported. This novel procedure provides an efficient method for the construction of Csp3-CF2 and C-O/N bonds in one step. A wide range of functional groups are tolerated. It is proposed that a radical/SET (single electron transfer) pathway proceeding via the fluoroalkyl radical may be involved in the catalytic cycle.


Cutting Edge: Distinct NK receptor profiles are imprinted on CD8 T cells in the mucosa and periphery during the same antigen challenge: role of tissue-specific factors.
NK cell receptors (NKRs) modulate T lymphocyte responses by modifying the Ag activation threshold. However, what governs their expression on T cells remains unclear. In this study we show that different NKRs are imprinted on CD8 T cells in the gut mucosa and periphery during the same Ag challenge. After a viral, bacterial, and tumor challenge, most CD8 peritoneal exudate lymphocytes expressed NKG2A but not 2B4. In contrast, most CD8 intraepithelial lymphocytes exhibited 2B4 but not NKG2A. Our data suggest that tissue-specific factors may determine the pattern of NKR expression. In the gut, CD70 licensing appears to promote 2B4 induction on mucosal CD8 T cells. Conversely, retinoic acid produced by the intestinal dendritic cells may suppress NKG2A expression. Thus, tissue-specific factors regulate NKR expression and may confer T cells with differing effector functions in a tissue and site-specific manner.


Management of the hearing impaired infant.
With the advent of new testing methods for screening and confirmation of hearing loss in the newborn and setting up neonatal screening programs across the country, significant number of children with hearing loss are being diagnosed very early. Although still considered as one of the best behavioural tests in the competent hands, distraction testing is becoming superseded by more refined and controlled techniques such as visual reinforcement audiometry which is capable of determining a more complete audiometric profile of an infant from about the age of 6 months. A combination of these methods has allowed audiologists to bring down the average age of diagnosis of permanent congenital hearing impairment (PCHI) from over 2 years to well below 12 months. At the same time, increasingly complex and sophisticated hearing instruments are being developed to address traditional problems and also to deliver better amplified speech. Habilitating a neonate with a hearing loss is often challenging and requires a significant amount of resources, expertise and experience. Determining the infant's amplification needs could be difficult, as often the audiometric information is not complete. Further, selecting a suitable hearing instrument for an infant from a vast range is not easy and measuring the outcome after fitting hearing aids, especially in a few months old infant, can be extremely hard. With professionals becoming more confident in implanting younger children and realizing the benefits of early implantation, especially for speech & language development, there is a growing demand for referring infants as early as possible to the implant teams. Providing amplification is only the beginning of the process of habilitation. A multidisciplinary team approach is extremely important in this process and inclusion of the parents in the multidisciplinary team managing the infant often leads to a much improved outcome. There is growing evidence that early diagnosis and habilitation of PCHI leads to better speech and language development and more children being educated in the mainstream setting.


Treatment of malignant ascites with a second cycle of catumaxomab in gastric signet cell carcinoma--a report of 2 cases.
Malignant ascites is a frequent complication in gastrointestinal malignancy and is unresponsive to systemic therapies. Therapeutic options are limited, and repeated paracentesis is associated with increased loss of fluids and proteins, and impaired quality of life. The bi-specific trifunctional antibody catumaxomab has been approved for the treatment of refractory ascites. It has been proposed that repeated application leads to formation of human anti-mouse antibodies with a decrease in effectiveness and potentially hypersensitivity reactions. Here we report on the repeated application of catumaxomab in 2 patients with advanced signet cell gastric cancer. Repeated application was safe and effective in decreasing the frequency of paracentesis in 1 patient. No hypersensitivity reactions beyond the immune-mediated side effects were observed with the application of catumaxomab. 1 patient experienced an inflammatory response with acute deterioration of kidney function during the first cycle but recovered quickly. Re-challenge with catumaxomab did not produce an inflammatory reaction in the 2 cases. Overall, the repeated treatment was associated with a beneficial effect on puncture-free survival in 1 patient, and appears to be a treatment option in selected patients with gastrointestinal malignancy.


People, Process and Technology: Strategies for Assuring Sustainable Implementation of EMRs at Public-Sector Health Facilities in Kenya.
The Ministry of Health (MoH) rollout of electronic medical record systems (EMRs) has continuously been embraced across health facilities in Kenya since 2012. This has been driven by a government led process supported by PEPFAR that recommended standardized systems for facilities. Various strategies were deployed to assure meaningful and sustainable EMRs implementation: sensitization of leadership; user training, formation of health facility-level multi-disciplinary teams; formation of county-level Technical Working Groups; data migration; routine data quality assessments; point of care adoption; successive release of software upgrades; and power provision. Successes recorded include goodwill and leadership from the county management (22 counties), growth in the number of EMR trained users (2561 health care workers), collaboration in among other things, data migration(90 health facilities completed) and establishment of county TWGs (13 TWGs). Sustenance of EMRs demand across facilities is possible through; county TWGs oversight, timely resolution of users' issues and provision of reliable power.


Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination.
The innate immune system recognizes influenza A virus via TLR 7 or retinoic acid-inducible gene I in a cell-type specific manner in vitro, however, physiological function(s) of the MyD88- or interferon-beta promoter stimulator 1 (IPS-1)-dependent signaling pathways in antiviral responses in vivo remain unclear. In this study, we show that although either MyD88- or IPS-1-signaling pathway was sufficient to control initial antiviral responses to intranasal influenza A virus infection, mice lacking both pathways failed to show antiviral responses, resulting in increased viral load in the lung. By contrast, induction of B cells or CD4 T cells specific to the dominant hemagglutinin or nuclear protein Ags respectively, was strictly dependent on MyD88 signaling, but not IPS-1 signaling, whereas induction of nuclear protein Ag-specific CD8 T cells was not impaired in the absence of either MyD88 or IPS-1. Moreover, vaccination of TLR7- and MyD88-deficient mice with inactivated virus failed to confer protection against a lethal live virus challenge. These results strongly suggest that either the MyD88 or IPS-1 signaling pathway is sufficient for initial antiviral responses, whereas the protective adaptive immune responses to influenza A virus are governed by the TLR7-MyD88 pathway.


Serious adverse effects of amiodarone.
Amiodarone is an effective antiarrhythmic drug which has been used successfully to treat a variety of cardiac arrhythmias. Early reports emphasized both the striking efficacy of this agent and the relative paucity of side effects necessitating discontinuing treatment with this drug. As amiodarone has been used more widely and in more diverse patient populations, reports of serious thyroid, pulmonary, cardiovascular, and other adverse reactions have appeared in the literature. In this paper, we review the serious adverse effects that have been reported to date. The incidence of these reactions varies considerably in different series, and cannot be explained solely by different doses employed or by varying methods of drug administration. The final role of amiodarone in the therapy of cardiac arrhythmias cannot be determined until the long-term toxicity has been more thoroughly investigated.


Mitigation strategies for excessive cadmium in rice.
Cadmium (Cd)-contaminated rice is a human food safety problem that lacks a clear solution. A large amount of rice having an excessive Cd content is processed yearly, but it cannot be discarded and placed in landfills because it will cause secondary pollution. How do we best cope with this toxic rice? From the perspectives of food safety, food waste prevention, and human hunger eradication, the use of contemporary physical, chemical, and biological techniques to lower the Cd content in postharvest Cd-contaminated rice so that it can be used safely is the best course of action. In this review, the contamination, chemical speciation, and distribution of Cd in rice are analyzed and discussed, as are the methods of Cd removal from rice, including a comparison of the advantages and disadvantages of various techniques. Owing to the limitations of current technology, research and technological development recommendations for removing Cd from rice grain are presented. The chemical and biological methods produce higher Cd-removal rates than physical methods. However, they are limited to small-scale laboratory applications and cannot be applied on a large industrial scale. For the efficient safe removal of Cd from food, mixed fermentation with lactic acid bacteria and yeast has good application prospects. However, limited strains having high Cd-removal rates have been screened. In addition, modern biotechnology has rarely been applied to reduce rice Cd levels. Therefore, applying genetic engineering techniques to rapidly obtain microorganisms with high Cd-removal rates in rice should be the focus of future research.


Improving lip aesthetics in the face profile after treatment of class II, division 2 malocclusion.
The aims of our research were as follows: 1) Description of changes in the position of the upper and lower lips, as a result of the change in the position of upper and lower incisors after orthodontic treatment of malocclusion of Class II, division 2 type. 2) Determination of correlation between changes in the position of lips and incisors in the profile of the face after orthodontic treatment of malocclusion of Class II, division 2 type.MATERIALS AND METHODS: Our study analyses the documentation of 115 patients with malocclusion of Class II, division 2 type treated with a fixed orthodontic appliance in the upper and lower dental arches at the Orthodontic Department of the Clinic of Dentistry in Olomouc from January 1, 1996 to December 31, 2017. There were 78 women and 37 men aged 11 to 36 years included in the database. Cephalometric images of patients from the group taken before and after the treatment were used for the purpose of cephalometric analysis according to Kamínek (1) and Burstone's analysis (2) of soft tissues. Subsequently, all output data were processed statistically. While the protrusion of the incisors after treatment of malocclusion of Class II, division 2 type was 3 mm, the facial profile showed statistically significant changes in soft tissues in the ventral direction by 1 mm on average just in the area of the upper and lower lips, which means a shift corresponding to one third of teeth movement. A statistically significant change in the position of incisors, soft tissues as well as correlation between changes in hard and soft tissues in the face profile after orthodontic treatment of malocclusion of Class II, division 2 type were demonstrated. The more the incisors were inclined, the more the lips moved forward, and the patient's profile turned out to be aesthetically improved (Tab. 2, Fig. 3, Ref. 39).


[A case of renal perivascular epithelioid cell tumor (PEComa)].
A 44-year-old woman was admitted with acute hepatic dysfunction. Screening computed tomography showed an enhancing mass of about 9 cm in the right renal upper pole. An open right nephrectomy was performed for the pre-operative diagnosis of renal cell carcinoma. Pathological examination revealed a perivascular epithelioid cell tumor (PEComa). PEComa is a rare tumor, which includes angiomyolipoma and lymphangiomyomatosis. It is sometimes associated with aggressive clinical behavior such as local recurrence and metastasis. She had no evidence of recurrence at 34 months follow up.


The Impact of an Emergency Department Upgrade to Level I Trauma Status on the Timeliness of Nontrauma Computed Tomography Scans.
Resources such as computed tomography (CT) scanners are sometimes shared when separate adult and pediatric emergency departments (EDs) exist in proximity. To assess the impact of American College of Surgeons Level I trauma verification of an adult ED on the timeliness of nontrauma CT scans in a pediatric and adult ED that share a CT scanner. ED patient records were retrospectively reviewed to determine the time from order to completion of nontrauma CT scans. We compared the timeliness of CT scan completion between the year leading up to the adult ED being verified as a Level I Trauma Center (2015), and the 2 subsequent years (2016-2017). The median time for nontrauma CT completion in the adult ED prior to Level I verification was 39 min, compared with 50 min and 49 min for the subsequent 2 years (p < 0.001). Similarly, the median time for completion of nontrauma CT scans in the pediatric ED increased from 33 min to 41 min and 39 min (p < 0.001). The proportion of patients who received CT scans within 30 min from order decreased after adult ED trauma upgrade, from 40% in 2015 to 30% and 32% (p < 0.001) in the 2 subsequent years. The pediatric ED showed similar results, with 48% of patients receiving CT scans within 30 min in 2015, compared with 34% in 2016 and 35% in 2017 (p < 0.001). Level I trauma verification of the adult ED adversely affected the timeliness of nontrauma CT scans in the EDs.


Effect of brivaracetam (400 mg/day) on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive in healthy women.
Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in Phase III clinical development for epilepsy. This study assessed the effect of brivaracetam 400 mg/day on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive (OC) containing 30 µg ethinylestradiol and 150 µg levonorgestrel, in healthy pre-menopausal women. This open-label, single-center, randomized, two-way crossover, multiple oral dose study (N01080) included two consecutive 28-day cycles without (control) or with brivaracetam (test), and a 28-day follow-up. OC was taken on Days 1–21 of every cycle and brivaracetam 200 mg twice daily was administered on Days 1–20 of the test cycle. Ethinylestradiol and levonorgestrel pharmacokinetics were determined on Day 20 and endogenous hormones were measured frequently during both control and test cycles. Overall, 23/24 participants (age: 19–39 years) completed the study. AUC ratio (90% confidence interval) for brivaracetam versus control was 0.73 (0.69, 0.78) for ethinylestradiol and 0.78 (0.72, 0.83) for levonorgestrel, outside pre-defined bioequivalence limits (0.80–1.25). Levels of endogenous hormones were similar and normal during brivaracetam and control cycles. Brivaracetam in combination with OC was well tolerated. Brivaracetam 400 mg/day co-administered with a combination OC in healthy women reduced ethinylestradiol and levonorgestrel plasma levels but did not result in ovulation.


Normalized Index of Synergy for Evaluating the Coordination of Motor Commands.
Humans perform various motor tasks by coordinating the redundant motor elements in their bodies. The coordination of motor outputs is produced by motor commands, as well properties of the musculoskeletal system. The aim of this study was to dissociate the coordination of motor commands from motor outputs. First, we conducted simulation experiments where the total elbow torque was generated by a model of a simple human right and left elbow with redundant muscles. The results demonstrated that muscle tension with signal-dependent noise formed a coordinated structure of trial-to-trial variability of muscle tension. Therefore, the removal of signal-dependent noise effects was required to evaluate the coordination of motor commands. We proposed a method to evaluate the coordination of motor commands, which removed signal-dependent noise from the measured variability of muscle tension. We used uncontrolled manifold analysis to calculate a normalized index of synergy. Simulation experiments confirmed that the proposed method could appropriately represent the coordinated structure of the variability of motor commands. We also conducted experiments in which subjects performed the same task as in the simulation experiments. The normalized index of synergy revealed that the subjects coordinated their motor commands to achieve the task. Finally, the normalized index of synergy was applied to a motor learning task to determine the utility of the proposed method. We hypothesized that a large part of the change in the coordination of motor outputs through learning was because of changes in motor commands. In a motor learning task, subjects tracked a target trajectory of the total torque. The change in the coordination of muscle tension through learning was dominated by that of motor commands, which supported the hypothesis. We conclude that the normalized index of synergy can be used to evaluate the coordination of motor commands independently from the properties of the musculoskeletal system.


State-and-rate friction in contact-line dynamics.
In order to probe the dynamics of contact-line motion, we study the macroscopic properties of sessile drops deposited on and then aspirated from carefully prepared horizontal surfaces. By measuring the contact angle and drop width simultaneously during droplet removal, we determine the changes in the shape of the drop as it depins and recedes. Our data indicate that there is a force which opposes the motion of the contact line that depends both on the amount of time that the drop has been in contact with the surface and on the withdrawal rate. For water on silanized glass, we capture the experimentally observed behavior with an overdamped dynamical model of contact-line motion in which the phenomenological drag coefficient and the assumed equilibrium contact angle are the only inputs. In this case, the damping coefficient decreases with increasing velocity of the contact line. For other liquid-substrate pairs, the observed contact-line motion suggests that a maximum static friction force is important in addition to damping. The dependence on time of contact and withdrawal rate, reminiscent of rate-and-state friction between solid surfaces, is qualitatively consistent across three substrate-liquid pairs.


Effect of electrocautery on endothelial integrity of the internal thoracic artery: ultrastructural analysis with transmission electron microscopy.
The internal thoracic artery (ITA) is typically harvested from the chest wall by means of conventional electrocautery. We investigated the effects of electrocautery on endothelial-cell and vessel-wall morphology at the ultrastructural level during ITA harvesting. Internal thoracic artery specimens from 20 patients who underwent elective coronary artery bypass grafting were investigated in 2 groups. The ITA grafts were sharply dissected with use of a scalpel and clips in the control group (n=10) and were harvested by means of electrocautery in the study group (n=10). Each sample was evaluated for intimal, elastic-tissue, muscular-layer, and adventitial changes. Free flow was measured intraoperatively. Light microscopic examinations were performed after hematoxylin-eosin and Masson's trichrome staining. Transmission electron microscopy was used to evaluate ultrastructural changes in the endothelial cells and vessel walls of each ITA. In the sharp-dissection group, the endothelial surfaces were lined with normal amounts of original endothelium, endothelial cells were distinctly attached to the basal lamina, cytoplasmic organelles were evident, and intercellular junctional complexes were intact. Conversely, in the electrocautery group, the morphologic integrity of endothelial cells was distorted, with some cell separations and splits, contracted cells, numerous large cytoplasmic vacuoles, and no visible cytoplasmic organelles. The subendothelial layer exhibited disintegration. Free ITA flow was higher in the sharp-dissection group (P=0.04). The integrity of endothelial cells can be better preserved when the ITA is mobilized by means of sharp dissection, rather than solely by electrocautery; we recommend a combined approach.


The varied beneficial effects of ivermectin (Mectizan) treatment, as observed within onchocerciasis foci in south-eastern Nigeria.
In the treatment of humans, ivermectin (Mectizan((R))), a semi-synthetic macrocyclic lactone, is now primarily used as a rapid microfilaricide. The drug has several other benefits, however, and these have recently been investigated in five states in south-eastern Nigeria, where there have been mass treatments with ivermectin, for the control of Onchocerca volvulus, for more than 10 years. Between the January and December of 2005, 3125 adult onchocerciasis patients (each aged >/=20 years and known to have at least one clinical sign of onchocerciasis) were enlisted, clinically examined and interviewed. Relevant data were collected in the interviews, using a structured, pre-tested questionnaire, and in personal and focus-group discussions. Overall, 612 (19.6%) of the subjects reported that they had had nodules that had disappeared following repeated doses of ivermectin, although only 83.8% of the 612 attributed their nodule clearance to ivermectin (the other 16.2% being unsure of the cause). A larger percentage of the subjects (24.6%) reported that they had expelled intestinal helminths following the last round of ivermectin treatment (i.e. been dewormed). Other side-benefits reported in the study were improved vision (11.7% of subjects), reversal of secondary amenorrhea (4.5%), increased appetite (22.3%), reduction in arthritic or other musculo-skeletal pain (7.9%), reductions in the severity of body itching (18.5%) and skin rash (17.3%), darkening of leopard skin (6.6%), improved libido in men (6.6%), and clearance of head lice (4.5%). If, via health education, the local communities could be made more aware of the side-benefits of ivermectin treatment, the sustainability of the on-going programme of community-directed treatment with ivermectin (CDTI) in south-eastern Nigeria would probably be improved.


Missed traumatic abdominal injury with challenging management: report of 12-year follow-up.
Despite well-established clinical guidelines and use of radiologic imaging for diagnosis, challenges are faced when accurate decisions must be made within seconds. Patients with life-threatening injuries represent 10-15% of all hospitalized trauma patients. In fact, 20% of abdominal injuries will require surgical intervention. In abdominal trauma, it is important to distinguish the difference between surgical intervention, which includes damage control procedures and definitive treatment. The main objective of damage control surgery is to control the bleeding, reduce the contamination and delay additional surgical stress at a time of physiological vulnerability of the patient, along with abdominal containment, visceral protection and avoiding aponeurotic retraction in situations where primary abdominal closure is not possible. However, this technique has high morbidity and comes with a myriad of complications, including development of catastrophic abdomen and formation of enterocutaneous fistulas.


Paleo-Wildfires and Their Paleoclimatic Effects in Early Permian Coal in the Southern North China Basin.
Paleo-wildfires can help elucidate the transition trends of Earth from "icehouse" to "greenhouse," thereby allowing us to forecast the current changes associated with wildfires of this era. In this study, the early Permian Shanxi Formation in the Pingdingshan coalfield, located south of the North China Basin, was selected as a study site. Based on data on inertinite content, inertinite reflectance, nine polycyclic aromatic hydrocarbons (PAHs), paleo-wildfires, and their paleoclimate effect during the early Permian coal formation were systematically analyzed. The inertinite content in coal in the study area ranged from 9.76 to 29.65%, with an average of 19.32%. Meanwhile, the average inertinite reflectance values ranged from 2.41-4.74%, with an average of 2.75%. PAHs in the study area were mainly tricyclic and tetracyclic; the contents of fluorene, phenanthrene, pyrene, bypyrene, benzo[b]fluoranthene, and benzo[e]pyrene were higher than those of other PAHs in the same stratum. The total concentration of PAHs varied widely between layers (3601-21,894 ng/g). The presence of paleo-wildfires was confirmed by the contents of inertinite and PAHs. It can be concluded that paleo-wildfires in the study area were dominated by surface fires at low and medium temperatures based on the combustion equation. The oxygen content in the paleo-atmosphere of the Early Permian Shanxi Formation in the study area was 24.29%, which provided the necessary conditions for the occurrence of wildfires.


A-ring nitro- and amino-substituted estradiol analogs produce a negative cooperative or noncooperative [3H]estradiol-estrogen receptor binding mechanism.
We have investigated the relation between ligand structure and binding mechanism between the calf uterine estrogen receptor. A series of structurally altered estradiol analogs was used in which either an amino- or a nitro group had been added to the 2 or 4 position on the phenolic A-ring. The binding affinity of both amino analogs and the 4-nitro analog for the estrogen receptor was reduced relative to that of estradiol, as measured by competitive binding assay; the values were between 0.008% and 8% of estradiol's affinity. The slope of the displacement curve for the 4-nitro analog was also significantly different from that of estradiol (p < 0.05), indicating that the binding mechanism of these two ligands was different. The affinity of the 2-nitroestradiol ligand for the receptor was too low to be measured. The binding mechanism was then further investigated by measuring the Hill coefficient of [3H]estradiol binding in the presence of the analog. The presence of a nitro group on C4 eliminated the positive cooperativity of the [3H]estradiol-estrogen receptor interaction; the Hill coefficient of [3H]estradiol binding in the presence of the analog was 0.99 compared with 1.7 for [3H]estradiol alone. Most interestingly, the presence of an amino group on either C2 or C4 brought about a switch from a positive to a negative cooperative binding interaction; the Hill coefficients of [3H]estradiol binding in the presence of the analogs were between 0.6 and 0.7. These results provide additional support for an induced-fit mechanism of ligand-estrogen receptor interactions.


Immunohistochemical demonstration of serotonin-containing nerve fibers in the mammalian hippocampal formation.
The distributional pattern of serotonin-immunoreactive nerve fibers in the hippocampal formation of six different mammalian species (rat, chipmunk, hamster, cat, dog and monkey) was studied in detail by means of a modified peroxidase-antiperoxidase immunohistochemical method, using a specific serotonin antiserum. Furthermore, the density of varicosities distributed in each layer of the hippocampus was semiquantitatively analyzed. In all species investigated, the routes of serotonin fibers entering the hippocampal formation were found to be almost the same. These fibers were extensively distributed throughout the hippocampal formation, and had a characteristic arrangement corresponding to the laminar structure of this region. A dense innervation by varicose serotonin fibers was found in the stratum lacunosum-moleculare, but a few serotonin fibers were also distributed in the stratum lucidum of the CA2 and CA3 fields. The stratum pyramidale and the granule cell layer of the dentate gyrus contained a small number of serotonin fibers. The concentration and the direction of serotonin fibers were different in each area of each animal. Two peculiar observations should be stressed: (1) in the rat, the strata oriens and radiatum of CA2 and CA3 as well as the stratum lacunosum-moleculare displayed abundant serotonin fibers; (2) in the dog, abundant serotonin fibers were diffusely distributed in the CA1 field except for the stratum pyramidale and the most dense concentration of serotonin fibers was seen in the stratum oriens of CA3. The present study provides a morphological basis for further study of the functional significance of serotonin in the limbic system.


[Characteristics of hearing loss in 299 high-risk neonates].
To compare the occurrence of hearing loss in neonates with hyperbilirubinemia, hypoxic-ischemic encephalopathy (HIE) and very low-birth weight infant (VLBW) body mass, and to provide evidence for early intervention. Totally 299 high-risk neonates (598 ears) were divided into six groups: pure hyperbilirubinemia group, pure HIE group, hyperbilirubinemia with HIE group, hyperbilirubinemia with VLBW group, HIE with LBWI group, hyperbilirubinemia with VLBW and HIE mass group. Auditory brainstem response (ABR) was detected in all groups. The hearing threshold of ABR and the abnormal rate of hyperbilirubinemia with LBWI and HIE were much higher than that of pure hyperbilirubinemia and pure HIE neonates. Of the three high-risk factors, hearing loss occurs more often and more serious in neonates with hyperbilirubinemia and with VLBW while as HIE body mass. So the babies should receive hearing screening with ABR and be treated in time or following up as early as possible.


Adaptation of non-technical skills behavioural markers for delivery room simulation.
Simulation in healthcare has proved to be a useful method in improving skills and increasing the safety of clinical operations. The debriefing session, after the simulated scenario, is the core of the simulation, since it allows participants to integrate the experience with the theoretical frameworks and the procedural guidelines. There is consistent evidence for the relevance of non-technical skills (NTS) for the safe and efficient accomplishment of operations. However, the observation, assessment and feedback on these skills is particularly complex, because the process needs expert observers and the feedback is often provided in judgmental and ineffective ways. The aim of this study was therefore to develop and test a set of observation and rating forms for the NTS behavioural markers of multi-professional teams involved in delivery room emergency simulations (MINTS-DR, Multi-professional Inventory for Non-Technical Skills in the Delivery Room). The MINTS-DR was developed by adapting the existing tools and, when needed, by designing new tools according to the literature. We followed a bottom-up process accompanied by interviews and co-design between practitioners and psychology experts. The forms were specific for anaesthetists, gynaecologists, nurses/midwives, assistants, plus a global team assessment tool. We administered the tools in five editions of a simulation training course that involved 48 practitioners. Ratings on usability and usefulness were collected. The mean ratings of the usability and usefulness of the tools were not statistically different to or higher than 4 on a 5-point rating scale. In either case no significant differences were found across professional categories. The MINTS-DR is quick and easy to administer. It is judged to be a useful asset in maximising the learning experience that is provided by the simulation.


The role of Fcγ receptors in atherosclerosis.
Atherosclerosis is widely considered to be an immune-mediated process. Fcγ receptors (Fcγ Rs) contribute to the regulation of a multitude of immune and inflammatory responses and are implicated in human atherosclerotic lesions. Major cell types involved in the pathogenesis of atherosclerosis express Fcγ Rs and their proatherogenic ligands such as immune complexes and C-reactive protein, which act to activate Fcγ R signaling pathways. This review summarizes recent significant progress addressing the multifaceted roles of Fcγ Rs in atherogenesis which comes from the studies of Fcγ R-deficient animal models, clinical investigations and in vitro molecular and cellular studies. These new findings help us appreciate the emerging role of Fcγ Rs in atherosclerosis, and suggest Fcγ Rs as a potential therapeutic target for atherosclerosis.


An anticholinergic burden score for German prescribers: score development.
Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.


Tangential hard x-ray diagnostic array on the EXL-50 spherical tokamak.
A tangential hard x-ray (HXR) diagnostic on the newly constructed ENN XuanLong-50 (EXL-50) spherical tokamak for fast electron emission studies is presented. The HXR detection system consists of a symmetrical CdZnTe semiconductor detector array with a spectral sensitivity range of 20-300 keV. 25 channels have been designed on the 270° horizontal vacuum port with 12 sight lines to observe the forward emission, 12 sight lines to observe the backward emission of fast electrons, and 1 for viewing the central. Currently, ten channels have been in operation in the EXL-50 experiments. The systems are designed to measure the x-ray spectra for the estimation of fast electron temperature and electron velocity distribution in the EXL-50 experiment, which will be useful for understanding the dynamics of fast electrons generated by electron cyclotron resonance heating, for plasma instability and transport studies and for the analysis of plasma heating efficiency.


[Expression of xenogeneic homologous epidermal growth factor receptor ectodomain in Pichia pastoris].
To develop a secreted expression system of xenogeneic homologous epidermal growth factor receptor (EGFR) ectodomain using Pichia pastoris (P. pastoris), thus providing a basis for subsequent antitumor immunological researches on EGFR subunit protein vaccine. In order to construct the secreted expression vector pPICZaA-mer and pPICZaA-her, we recombined the cDNA of xenogeneic (human) EGFR ectodomain (her) and the corresponding control mouse EGFR ectodomain (mer) with the empty plasmid pPICZaA, respectively. Then the recombinant plasmids were linearized by Sac I and transformed into P. pastoris strain GS115 by electroporation. The positive transformants were selected on YPDS plate including Zeocin and were induced to express by methanol. Consequently, the proteins in the culture supernatant were assayed with SDS-PAGE and Western-blot. So we could choose the high-level secreted expression recombinant strain to produce protein vaccine vastly. We got the secreted expression of mouse and human EGFR ectodomain in P. pastoris. The relative molecular mass of the two aimed proteins is about 95 x 10(3). The Western-blot analysis demonstrated that the expression proteins have much good antigenicity and specificity. The recombinant plasmids pPICZaA-mer and pPICZaA-her could be induced to express the EGFR aimed proteins by methanol in methanol-trophic yeast expression system.