Epstein-Barr virus: the spectrum of its manifestations in human beings.
Epstein-Barr virus (EBV) infects virtually everyone by adulthood, and a lifelong latency is maintained. It infects children silently, whereas the majority of adolescents have infectious mononucleosis (IM). Children who have IM before 5 years of age are often heterophil negative; EBV-specific antibodies are required for diagnosis. On rare occasions the symptoms of IM may persist in a chronic or recurrent form, and fatal infectious mononucleosis occurs rarely. Depending on the type and degree of immune deficiency and the time the EBV infection occurs in the life cycle, various atypical outcomes can occur. Children with primary immune deficiency can have fatal or chronic IM, malignant B cell lymphoma, virus-associated hemophagocytic syndrome, aplastic anemia, or acquired hypogammaglobulinemia. The various outcomes of the EBV infections are likely governed by the immune response of the individual. The increased frequency of B cell neoplasms in immunodeficient patients is likely due, in part, to EBV. Individuals with acquired immune deficiency disorders such as AIDS or allograft recipients may develop malignant B cell lymphomas which tend to be polyclonal, but which may progress through stages of oligoclonality to monoclonality. This conversion likely results from specific reciprocal chromosomal translocations such as t(8;14), which is seen in Burkitt's lymphoma. Detection of EBV in immunodeficient patients is achieved by EBV-specific antibody studies or isolation of virus by obtaining spontaneous lymphoblastoid cell lines from peripheral blood, isolating virus from throat washings, or identifying EBV genome by molecular hybridization techniques. Prevention of primary immune deficiency by early detection and genetic counseling and monitoring of patients for occurrence of EBV infection may lead to early treatment. Acyclovir and immunoglobulin therapy can be of value in some patients with active EBV infection.


Chiral Bidentate Boryl Ligand Enabled Iridium-Catalyzed Enantioselective C(sp3)-H Borylation of Cyclopropanes.
We herein report an Ir-catalyzed enantioselective C(sp3)-H borylation of cyclopropanecarboxamides using a chiral bidentate boryl ligand for the first time. A variety of substrates with α-quaternary carbon centers could be compatible in this reaction to provide β-borylated products with good to excellent enantioselectivities. We have also demonstrated that the borylated products can be used as versatile precursors engaging in stereospecific transformations of C-B bonds, including the synthesis of a bioactive compound Levomilnacipran.


Incidental detection of thyroid nodules at magnetic resonance imaging of the cervical spine.
The incidental detection of thyroid lesions in patients undergoing magnetic resonance (MR) imaging of the cervical spine was prospectively evaluated on 389 MR images. Sagittal images extended from the cranio-cervical junction to the upper thoracic level, and axial images from C3-4 to C7-T1 intervertebral levels. Twenty patients (5.1%) had a total of 26 thyroid nodules. Eighteen patients presented with a single dominant nodule, of whom 2 had a multinodular gland with a single dominant nodule (one had 3 and the other had 5 nodules). Two patients had diffusely enlarged gland without a dominant nodule. The mean size of the nodules was 11.6 mm. One thyroid nodule was detected at the C5-6 intervertebral level, 14 at the C6-7, and 11 at the C7-T1. T(2)-weighted imaging was more useful than T(1)-weighted imaging for the detection of thyroid nodules because of the hyperintense versus isointense appearance of the lesions. Thyroid carcinoma was identified at surgery in one patient. The detection rate was low compared with computed tomography with contrast medium and ultrasonography. Our results suggest that MR imaging has limited value for the detection of thyroid lesions and that the presence of such lesions cannot be denied based only on MR imaging of the cervical spine. However, asymptomatic thyroid lesions, including thyroid cancer, can be identified on MR images of the cervical spine, so we recommend that evaluation of these images should consider such lesions.


Pressure Controlled Chemical Gardens.
The dissolution of metal salts in silicate solution can result in the growth of hollow precipitate tubes. These "chemical gardens" are a model of self-organization far from the equilibrium and create permanent macroscopic structures. The reproducibility of the growth process is greatly improved if the solid salt seed is replaced by a salt solution that is steadily injected by a pump; however, this modification of the original experiment eliminates the membrane-based osmotic pump at the base of conventional chemical gardens and does not allow for analyses in terms of the involved pressure. Here we describe a new experimental method that delivers the salt solution according to a controlled hydrostatic pressure. In one form of the experiment, this pressure slowly decreases as zinc sulfate solution flows into the silicate-containing reaction vessel, whereas a second version holds the respective solution heights constant. In addition to three known growth regimes (jetting, popping, budding), we observe single tubes that fill the vessel in a horizontally undulating but vertically layered fashion (crowding). The resulting, dried product has a cylindrical shape, very low density, and one continuous connection from top to bottom. We also present phase diagrams of these growth modes and show that the flow characteristics of our experiments follow a reaction-independent Hagen-Poiseuille equation.


Enhanced differentiation of human pluripotent stem cells into pancreatic progenitors co-expressing PDX1 and NKX6.1.
Pancreatic progenitors (PPs) co-expressing the two transcription factors (TFs) PDX1 and NKX6.1 are recognized as the indispensable precursors of functional pancreatic β cells. Here, we aimed to establish an efficient protocol for maximizing generation of PDX1+/NKX6.1+ PPs from human pluripotent stem cells (hPSCs). In order to enhance the PDX1+/NKX6.1+ population, we manipulated in vitro culture conditions during differentiation by dissociating densely formed endodermal cells and re-plating them at different densities. These dissociated cells were subjected to an augmented duration of retinoid and fibroblast growth factor (FGF)10 signaling to induce higher PDX1 and NKX6.1 expression. Our optimized protocol dramatically increased the expression of NKX6.1, leading to an increase in the proportion of PDX1+/NKX6.1+ progenitors (~90%) in monolayer, higher than the previously published protocols, as well as upregulated key TFs controlling pancreatic development. The improved efficiency of pancreatic differentiation was complemented by an inhibited hepatic specification and an increased proliferation of NKX6.1+ cells. Interestingly, we were able to enrich a novel PDX1-/NKX6.1+ population by manipulating the re-plating density; these oriented themselves in three-dimensional clusters. Further differentiation validated the ability of our PDX1+/NKX6.1+ progenitors to generate NGN3+ endocrine progenitors. We provide a novel technique that facilitates appropriate cellular rearrangement in monolayer culture to yield a high proportion of PDX1+/NKX6.1+ PPs with an elevated self-replicating capacity, thereby aiding scalable production of functional β cells from hPSCs in vitro. Our innovative method also enriches a novel NKX6.1+/PDX1- population, with characteristics of proposed endocrine precursors, allowing further studies on deciphering routes to β-cell development.


Transoral laser resection or radiotherapy? Patient choice in the treatment of early laryngeal cancer: a prospective observational cohort study.
The choices made by patients offered treatment for early laryngeal cancer with radiotherapy or transoral laser resection were reviewed. A prospective review was conducted of all patients diagnosed and treated for early laryngeal carcinoma from December 2002 to September 2009 at the Leeds Teaching Hospitals NHS Trust. A total of 209 patients with tumour stage T1 or T2 laryngeal cancer were treated; each new patient suitable for radiotherapy or transoral laser resection was seen jointly by the clinical (radiation) oncologist and head and neck surgeon, and offered the choice of treatment. Of the patients, 47.4 per cent were given a choice between radiotherapy and transoral laser resection; 51.2 per cent were advised to have radiotherapy, and there were no records for the remaining 1.4 per cent. From those given the choice, 59.6 per cent chose transoral laser resection (p < 0.02 (t-test)) and 35.4 per cent chose radiotherapy. When given the choice, a statistically significant majority of patients choose transoral laser resection rather than radiotherapy.


Transformation from Sinonasal Seromucinous Hamartoma to Adenocarcinoma: A Case Report.
Sinonasal hamartomas are benign neoplasms composed of disorganized mature tissue elements. Epithelial variants include respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SMH). Malignant transformation of REAH is rarely reported; however, the malignant transformation of SMH to adenocarcinoma has not been described. We report the first case of a transformation from SMH to adenocarcinoma. The medical records of a patient presenting with sinonasal SMH with malignant transformation to adenocarcinoma were reviewed. The NCBI database was queried for the literature regarding SMH and malignant transformation of sinonasal hamartomas. A 39-year-old man presented with a left nasal mass, nasal obstruction, and epistaxis. Computed tomography and magnetic resonance imaging demonstrated a nonaggressive and heterogeneous left nasal mass with involvement of the middle turbinate and posterior ethmoid sinuses. He underwent endoscopic sinus surgery with complete excision of the mass. Pathology revealed SMH with focal areas of transition to low-grade adenocarcinoma characterized by stromal invasion but no bony, perineural, or lymphovascular invasion. Adjuvant treatment was not recommended. Literature review revealed no reported cases of malignant transformation of SMH. We report the first case of malignant transformation of SMH. Patients with SMH must be counseled that there is an extremely rare and potentially unrecognized risk of malignancy that may influence treatment and postoperative monitoring.


Urinary incontinence in the elderly: a review.
About 20% of the aging population of Canada is incontinent of urine, at a minimum annual cost of $150 million for incontinence pads alone. The inability of the individual or the family to cope with the problem is often the sole reason for placing the individual in an institution. Until recently, the subject received only sporadic attention from groups of urologists, gynaecologists and internists. The physiology and pathophysiology of micturition and urinary incontinence in the elderly are reviewed as the basis for appropriate management strategies. Geriatric urinary incontinence can be adequately evaluated, in most cases, by a clinical history in combination with a neurologic and urologic examination and cystometry.


Testicular torsion in the dog: a review of 13 cases.
The clinical and pathological features of testicular torsion in 13 dogs are reviewed. The affected gonads were intra-abdominal in 11 animals, and inguinal and scrotal respectively in two others. In most cases, the torsion appeared to result from neoplastic enlargement of the testis.


Use of leaching chambers for on-site sewage treatment.
An innovative chamber system was installed for on-site sewage treatment beneath an active parking lot at a restaurant near Cornwall, Ontario. The configuration of this prototype system used polyethylene leaching chambers over which wastewater was allowed to trickle. The chambers were vented to the surface to provide direct, passive air transfer. This demonstration project was examined as a cost-effective wastewater treatment alternative for a very constrained site. The leaching chambers were installed over a geotextile-covered sand filter bed. Chamber sidewall contact contributed an additional 50% to the total soil contact area hence justification for a footprint reduction. A labile carbon source (sawdust) was added into one half of the bed to encourage dissimilatory denitrification. Average hydraulic loading was 50 l m(-1) day(-1) (5 cm day(-1)). Treatment rates exceeded more than 4 orders of magnitude removal for E. coli; 90% biochemical oxygen demand; ammonium; and 99% total phosphorus. Nitrate-N on the carbon-amended side averaged 0.6 mg l(-1) compared with 8.6 mg l(-1) on the (non-carbon) control side. This project has demonstrated that effective on-site treatment can be accomplished. Flow and load equalization, pulse dosing, chamber venting, phosphorus precipitation, and denitrification were keys to treatment success. Applications include domestic and commercial sites.


[Pain control of bone and joint diseases in the elderly].
The decline of multiple physiological processes, even in the absence of disease, combined should logically influence treatment options. Decreased gastric secretions, intestinal motility, and vitamin D receptors lead to loss of appetite, malnutrition. Increased arterial thickening and rigidity elevate cardiac risk, while decreased elasticity in the lungs potentially exacerbates breathing disorders. Memory impairment and cognitive decline progress as neurons become less resilient to stress over time. Reduced hepatic and renal blood flow limit metabolism and filtration, increasing the risk for accumulation of toxic substances. Physiologic changes, drug-drug interactions resulting from polypharmacy, and drug-disease interactions combine to make elderly patients more sensitive to the AEs of medications. Effective pain management in the elderly is challenging. The purpose of this review is to highlight the use of several treatment options for elderly patients.


Effect of the combination treatment of high-intensity focused ultrasound and cryocare knife in advanced liver cancer.
To analyze the effect of the combination treatment of high-intensity focused ultrasound (HIFU) and cryocare knife in advanced liver cancer. 74 patients with advanced liver cancer were divided into the observation group (40 cases) and the control group (34 cases). Patients in the control group were treated with simple transcatheter arterial chemoembolization (TACE), while those in the observation group were given the combination treatment of HIFU and cryocare knife. Therapeutic effects were compared. The total effective rate of the observation group was significantly higher than that of the control group (p<0.05). After treatment, both groups showed decreased level of AFP and increased level of ALT. Besides, the observation group had significantly lower levels of AFP and ALT than the control group (p<0.05). Comparison of albumin levels before and after treatment revealed no difference between groups. After treatment, both groups showed increased percents of CD3+ and CD4+ T lymphocytes and natural killer (NK) cells with the observation group having obviously higher percents than the control group (p<0.05). After treatment, CD8+ T lymphocyte of the observation group reduced, while that of the control group increased (p<0.05). After treatment, both groups showed decreased levels of hyaluronic acid (HA), laminin (LN), collagen (IV-C) an III procollagen (PCIII), and the levels of the observation group were obviously lower than those of the control group (p<0.05). Both groups were followed with a median follow-up time of 25.0 months. The observation group had significantly more prolonged median survival time, decreased reccurrence rate and improved survival rate (p<0.05). The combination treatment of HIFU and cryocare knife can improve the short and long-term treatment outcome of advanced liver cancer.


Efficacy of direct-acting anti-viral therapy on chronic, naïve hepatitis C virus patients of Punjab, Pakistan: a cross-sectional study.
The success of interferon-free regimens using new direct-acting antiviral (DAA) is a revolution and major breakthrough in the development of new therapeutic options against hepatitis C virus (HCV). Accumulating evidence suggest sustained virological response (SVR) with DAA in 95% of patients. To date, however, there are very few data related to efficacy of DAA in the Pakistani population. We aimed to investigate the efficacy of sofosbuvir-based regimen among Pakistani population. A total of 1,913 patients who attained SVR24 after being treated with sofosbuvir and ribavirin from August 2015 to March 2017 were enrolled in this study. We analyzed the demographic, clinical and virological data and screened all patients for HCV in March 2017 to evaluate the response rate. We found an overall response rate of 92.8%. In addition, we also observed lower response rates among older patients. It can be inferred that a large proportion of patients achieved SVR after treatment with sofosbuvir-based regimen.


Use of the ERG and EOG in evaluating the effect of sleep deprivation on visual function in flying personnel.
The electroretinogram (ERG) and electrooculogram (EOG) are electrophysiological tests employed in ophthalmology to diagnose degeneration or injury to the outer half of the retina, including the rods and cones of the visual system. This pilot study was undertaken to determine if sleep deprivation of more than 24 h in rated flying personnel may show an abnormality in retinal function as measured by the ERG and/or EOG. This may give insight to the visual function in flying personnel on deployment or other long missions where uninterrupted sleep may be a problem. The results of this study showed that some subjects deprived of sleep exhibited a statistically significant variance in their EOG ratios as compared to a nondeprived control group. No significant changes in ERG were detected. Principles and theory of electrophysiological testing in ophthalmology are presented.


[Hemorrhagic fever with renal syndrome in Croatia: incidence of infection in human and wild animal reservoirs].
On the territory of Lika and Gorski Kotar a group of 300 forest workers and 260 persons from the general population were screened for Hantavirus antibodies (by the indirect immunofluorescence test). In the first group of examenees a mean of 1.6% were found positive, ranging from 0% (Gospić) to 3.2% (Ogulin). In the second groups a mean of 5.4% were positive, ranging from 4.4 to 8.9% (Delnice and Slunj, respectively). It is concluded that the Hantavirus infection rate in our natural foci of HFRS is higher than officially registered. Screening of micromammals for the presence of Hantavirus in their organs (lungs), using the direct immunofluorescence test, was undertaken on three locations: Planina Gornja (hillsides of the mountain Medvednica), a case of HFRS having been registered there previously, and Plitvicka Jezera and Velika Gorica (village of Kobilić) selected because of two previous epidemics of HFRS (1967 and 1989, respectively). On the first location, all 126 animals examined (10 different species) were Hantavirus negative. On the second location, 9 of the 165 animals examined (three species) were Hantavirus positive (5.4%), namely 6 bank voles (Clethrionomys glareolus) and three yellow-necked mice (Apodemus flavicollis). On the third location, where 141 animals was caught and examined (7 different species), 7 animals were positive (4.9%): 3 striped field mice (A. agrarius), 3 wood mice (A. sylvaticus) and 1 bank vole (Cl. glareolus). The findings suggest that in our natural foci of HFRS the circulation of the Hantavirus is sustained by several species of micromammals.


Atrioventricular nodal ablation in patients with resynchronization therapy and atrial fibrillation - long term results.
Atrioventricular nodal ablation (AVNA) is recommended for patients (pts) with cardiac resynchronization therapy (CRT) having atrial fibrillation (AF) and incomplete ventricular capture (Class IIa, level B). AVNA reduces mortality and improves the New York Heart Association (NYHA) functional class during intermediate term follow-up. The objectives were to study the long-term outcome regarding quality of life (QoL) and survival of our CRT pts after AVNA. 37 CRT-pts undergoing AVNA due to inadequate biventricular pacing were included in the study. Data were retrospectively obtained from clinical records and through telephone interviews. Twenty pts died during the follow-up period of average 30.6 ± 24 months. After AVNA the ventricular capture improved significantly from 68.4 ± 23% to 98.5 ± 2% (p < 0.001). A significant and sustained improvement of average 0.3 ± 0.5 (p = 0.001) in NYHA functional class was found. Additionally a large percentage of pts discontinued taking rate reducing drugs with potential severe side effects. AVNA in CRT pts was safe and effective. The treatment resulted in a sustained improvement in QoL, including long-term improvement in NYHA functional class.


Childbirth and breast cancer prognosis.
Although certain risk factors for breast cancer incidence may also effect survival, findings have been inconsistent and the long-term role of childbirth is unknown. We studied the influence of number and timing of births on breast cancer prognosis prospectively. From 1958 to 1997, altogether 32,003 women, born 1932 or later, were notified to the Swedish Cancer Registry due to a primary invasive breast cancer. We obtained information on dates of all childbirths and achieved complete follow-up through 1997 by means of linkage to other nation-wide databases. Proportional hazards analyses were used to compute crude and multivariate hazard ratios (HR) with 95% confidence intervals (CI) of dying from breast cancer. We found a successively worse prognosis for women with a shorter delay between their last birth and breast cancer diagnosis (p for trend <0.0001). Compared to women with their last birth more than 10 years before diagnosis, the multivariate HR of breast cancer death was 1.39 (95% CI 1.17-1.67) for those with breast cancer diagnosis in the 3rd year after last birth and 1.72 (CI 95% 1.42-2.09) for those with diagnosis within 1 year after last birth. This adverse effect on prognosis of childbirth persisted beyond 10 years among women with a first birth before the age of 20 years. A pregnancy has marked adverse effects on the prognosis of a breast cancer diagnosed within 10 years after delivery. These findings suggest that pregnancy influences tumor biology.


Remote monitoring of medication adherence and patient and industry responsibilities in a learning health system.
A learning health system (LHS) seeks to establish a closer connection between clinical care and research and establishes new responsibilities for healthcare providers as well as patients. A new set of technological approaches in medication adherence monitoring can potentially yield valuable data within an LHS, and raises the question of the scope and limitations of patients' responsibilities to use them. We argue here that, in principle, it is plausible to suggest that patients have a prima facie obligation to use novel adherence monitors. However, the strength of the obligations depends considerably on the extent to which data that adherence monitors generate are, in fact, used to further the goals of LHSs. The way in which data ownership is structured in the USA poses a considerable challenge here, while the European Union framework offers a more promising alternative.


Rates of Venous Thromboembolism and Central Line-Associated Bloodstream Infections Among Types of Central Venous Access Devices in Critically Ill Children.
Central venous access devices, including peripherally inserted central catheters and central venous catheters, are often needed in critically ill patients, but also are associated with complications, including central-line associated bloodstream infections and venous thromboembolism. We compared different central venous access device types and these complications in the PICU. Multicenter, cohort study. One hundred forty-eight participating Virtual PICU Systems, LLC, hospital PICU sites. Pediatric patients with central venous access placed from January 1, 2010, to December 31, 2015. None. Patient and central venous access device variables postulated to be associated with central-line associated bloodstream infection and venous thromboembolism were included. Data were analyzed using Pearson chi-square test or Fisher exact test for categorical variables, Mann-Whitney U test for continuous variables, and logistic regression and classification trees for multivariable analysis that examined significant predictors of venous thromboembolism or central-line associated bloodstream infection. Analysis included 74,196 first lines including 4,493 peripherally inserted central catheters and 66,194 central venous catheters. An increased rate of venous thromboembolism (peripherally inserted central catheter: 0.93%, central venous catheter: 0.52%; p = 0.001) (peripherally inserted central catheter: 8.65/1,000 line days, central venous catheter: 6.29/1,000 line days) and central-line associated bloodstream infection (peripherally inserted central catheter: 0.73%, central venous catheter: 0.24%; p = 0.001) (peripherally inserted central catheter: 10.82/1,000 line days, central venous catheter: 4.97/1,000 line days) occurred in peripherally inserted central catheters. In multivariable analysis, central venous catheters had decreased association with central-line associated bloodstream infection (odds ratio, 0.505; 95% CI, 0.336-0.759; p = 0.001) and venous thromboembolism (odds ratio, 0.569; 95% CI, 0.330-0.982; p = 0.043) compared with peripherally inserted central catheters. Peripherally inserted central catheters are associated with higher rates of central-line associated bloodstream infection and venous thromboembolism than central venous catheters in children admitted to the PICU.


Sensitive surface-enhanced Raman spectroscopy (SERS) detection of organochlorine pesticides by alkyl dithiol-functionalized metal nanoparticles-induced plasmonic hot spots.
In this work, we report the detection of the organochlorine pesticides aldrin, dieldrin, lindane, and α-endosulfan by using surface-enhanced Raman spectroscopy (SERS) and optimization of the SERS-sensing substrate. In order to overcome the inherent problem of the low affinity of the above pesticides, we have developed a strategy consisting of functionalization of the metal surface with alkyl dithiols in order to achieve two different goals: (i) to induce the nanoparticle linkage and create interparticle junctions where sensitive hot spots needed for SERS enhancement are present, and (ii) to create a specific environment in the nanogaps between silver and gold nanoparticles, making them suitable for the assembly and SERS detection of the analyzed pesticides. Afterward, an optimization of the sensing substrate was performed by varying the experimental conditions: type of metal nanoparticles, molecular linker (aromatic versus aliphatic dithiols and the length of the intermediate chain), surface coverage, laser excitation wavelength. From the adsorption isotherms, it was possible to deduce the corresponding adsorption constant and the limit of detection. The present results confirm the high sensitivity of SERS for the detection of the organochlorine pesticides with a limit of detection reaching 10(-8) M, thus providing a solid basis for the construction of suitable nanosensors for the identification and quantitative analysis of this type of chemical.


The synergistic effects of insecticidal essential oils and piperonyl butoxide on biotransformational enzyme activities in Aedes aegypti (Diptera: Culicidae).
The biochemical mechanisms underlying the increased toxicity of several plant essential oils (thymol, eugenol, pulegone, terpineol, and citronellal) against fourth instar of Aedes aegypti L. when exposed simultaneously with piperonyl butoxide (PBO) were examined. Whole body biotransformational enzyme activities including cytochrome P450-mediated oxidation (ethoxyresorufin O-dethylase [EROD]), glutathione S-transferase (GST), and beta-esterase activity were measured in control, essential oil-exposed only (single chemical), and essential oil + PBO (10 mg/liter) exposed larvae. At high concentrations, thymol, eugenol, pulegone, and citronellal alone reduced EROD activity by 5-25% 16 h postexposure. Terpineol at 10 mg/liter increased EROD activity by 5 +/- 1.8% over controls. The essential oils alone reduced GST activity by 3-20% but PBO exposure alone did not significantly affect the activity of any of the measured enzymes. All essential oils in combination with PBO reduced EROD activity by 58-76% and reduced GST activity by 3-85% at 16 h postexposure. This study indicates a synergistic interaction between essential oils and PBO in inhibiting the cytochrome P450 and GST detoxification enzymes in Ae. aegypti.


Osteoimmunology as an intrinsic part of immunology.
Osteoimmunology has emerged as a field linking immunology and bone biology, but it has yet to be recognized as belonging to mainstream immunology. However, the extent of the research fields immunology actually covers has been enormously widened, and it is now ready to include such an interdisciplinary subject. One of the most obvious examples of an interaction between the immune and bone systems is the pathogenesis of rheumatoid arthritis, where bone resorption is increased by the autoimmune response. Moreover, the regulation of the immune system by bone cells has been clearly demonstrated by the finding that osteoprogenitor cells contribute to hematopoietic stem cell maintenance as well as the suppression of hematopoietic malignancy. Thus, the bidirectional dialogue has been established and inevitably will lead to the union of bone and immunity. Here, I summarize the history and concept of osteoimmunology, providing a perspective on the future of immunology.


Molecular targeted therapy of BRAF-mutant colorectal cancer.
Over the past two decades, the molecular characterization of metastatic colorectal cancer (mCRC) has been revolutionized by the routine implementation of RAS and BRAF tests. As a result, it is now known that patients with mCRC harboring BRAF mutations experience a poor prognosis. Although it accounts for only 10% of mCRC, this group is heterogeneous; only the BRAF-V600E mutation, also observed in melanoma, is associated with a very poor prognosis. In terms of treatment, these patients do not benefit from therapeutics targeting the epidermal growth factor receptor (EGFR). In first-line chemotherapy, there are two main options; the first one is to use a triple chemotherapy combination of 5-fluorouracil, irinotecan, and oxaliplatin, with the addition of bevacizumab, because post hoc analysis of randomized trials have reported interesting results. The other option is to use double chemotherapy plus bevacizumab, since anti-EGFR seems to have modest activity in these patients. Only a small percentage of patients who experience failure of this first-line treatment receive second-line treatment. Monotherapy with BRAF inhibitors has failed in this setting, and different combinations have also been tested. Using the rationale that BRAF inhibitor monotherapy fails due to feedback activation of the EGFR pathway, BRAF inhibitors have been combined with anti-EGFR agents plus or minus MEK inhibitors; however, the results did not live up to the hopes raised by the concept. To date, the best results in second-line treatment have been obtained with a combination of vemurafenib, cetuximab, and irinotecan. Despite these advances, further improvements are needed.


[Design of software for fluorescence microscopy system to measure cytosolic free calcium in living cell].
To design software based on the double-wavelength fluorescence microscopy to measure cytosolic free calcium ([Ca2+]i) in living cell. Through analyzing the work principles of monochromator, the function relation between output wavelength and voltage was obtained. Based on the analysis results as the arithmetic of the software, the application was developed in the integration development environment of VC ++ 6.0, by using the framework of Microsoft Foundation Class Library (MFC) and multithread technology. The authors has realized the software and constructed a fluorescence microscopy system using the software, PC, monochromator, fluorescence microscope, MPT and data acquisition to measure the [Ca2+]i in single living beta cell. Using this software, the [Ca2+]i in living cell can be detected. It has been proved to be an effective tool for the research in cellular biophysics.


[Pneumatosis cystoides intestini caeci--a pseudotumor presented at autopsy].
A large focus of cystic intestinal pneumatosis appeared as an accidental finding in a 59-year-old man suffering from obstructive lung disease, with cor pulmonale as the cause of death. The gas pseudocysts were found in the submucosa, muscularis propria and in the subserosal space. The pseudocysts were lined by flattened cells of connective tissue origin with presence of occasional macrophages. We believe that the lesion started by focal damage of the mucosal membrane, which was followed by penetration of stool particles with microbes into the submucosa. E. coli and Morganella morgani are the probable producers of the gas bullets.


Selective electrosynthesis of platform chemicals from the electrocatalytic reforming of biomass-derived hexanediol.
6-Hydroxyhexanoic acid and adipic acid are platform chemicals and are widely used as building blocks for the synthesis of important polymers. Nevertheless, the industrial syntheses of these two chemicals are fossil fuel-based and involve the use of corrosive acid and emission of the NOx greenhouse gas. In this study, the electrosynthesis of 6-hydroxyhexanoic acid and adipic acid from the electrochemical oxidation of hexanediol at the nanoporous nickel oxyhydroxide modified electrode was explored as an environmentally-benign alternative to the industrial syntheses of 6-hydroxyhexanoic acid and adipic acid. The effects of electrolysis conditions, including the electrolyte pH and applied potentials, on faradaic efficiency and product distribution of the electrochemical oxidation of hexanediol, were thoroughly examined through a series of controlled-potential electrolyses. In addition, the scale-up electrosynthesis of 6-hydroxyhexanoic acid and adipic acid using a flow-type electrolyzer was also demonstrated.


Antibiotic resistance--action to promote new technologies: report of an EU Intergovernmental Conference held in Birmingham, UK, 12-13 December 2005.
The increase in microorganisms that have developed resistance to currently available antimicrobial agents has become a major cause for concern worldwide. These organisms are widespread in hospitals but also occur increasingly in the community. Some of these strains are multiresistant and the agents available to treat infections caused by them are few and dwindling. Over recent years there have been a number of responses by national, international and professional bodies to this situation, many aimed at curbing this unprecedented growth in resistance, but there is an increasing recognition that a major problem in the management of infections caused by such organisms is the paucity of new drugs, vaccines and diagnostic aids. A conference, organized by the Specialist Advisory Committee on Antimicrobial Resistance (SACAR) on behalf of the UK Department of Health and sponsored by the BSAC, was held in Birmingham in December 2005 with the aim of addressing these problems. Conference attendees included those from academia, industry, funding agencies, healthcare management, the European Medicines Agency (EMEA), the European Centre for Disease Prevention and Control (ECDC), European Directorates and representatives of EU governments. Following a number of keynote presentations which identified major issues, there were a series of workshops which addressed specific questions and produced a number of recommendations. These recommendations were discussed by all delegates. The lack of new anti-infectives and the reasons for this were discussed in some detail. Major pharmaceutical companies no longer find this area as financially rewarding as other therapeutic areas while smaller biotechnology companies, who are seen as more innovative, are hampered by a lack of funding. In spite of a few marked successes, the use of vaccines has had minimal impact in the field of bacterial infections, and progress in this field also suffers from a lack of funding. Diagnostics could aid in the better use of antibacterials but need greater acceptance in the healthcare system, which does not generally appreciate their cost-efficacy. The major recommendations were as follows: (i) Increased efforts are needed to reduce the spread of resistant strains both in the environment and in hospitals--these include improved hygiene and decreased use of some antimicrobials. (ii) Surveillance of resistance is a key factor and improved technology (e.g. IT systems) is needed to improve the potential for surveillance data to inform clinical practice. (iii) Rapid, sensitive and specific diagnostics are urgently needed and the issue of reimbursement needs to be addressed. (iv) More accurate estimates of the cost-efficacy of using anti-infectives and diagnostics are urgently needed. (v) Vaccine technology is available but is underused for the prevention of bacterial infections, particularly those caused by organisms resistant to antimicrobials. (vi) Incentives are required to encourage large pharmaceutical companies to partner small biotechnology companies, which are more innovative and have the potential to deliver the new drugs, diagnostics and vaccines. Modifications to the international regulatory requirements for drug licensing could have a major impact on the time and thus the costs of developing new agents.


Novel pyrazolopyrimidines: Synthesis, in vitro cytotoxic activity and mechanistic investigation.
A series of novel pyrazolo[3,4-d]pyrimidines bearing benzenesulfonamide moiety 5a-f, 6 and 7 were synthesized. Cytotoxic screening was conducted against MCF-7 and HepG2. 6-(4-Methoxyphenyl)-4-oxopyrazolopyrimidine derivative 5e and 4-imino-6-oxopyrazolopyrimidine derivative 6 revealed potent cytotoxic activity with IC50 1.4 μM (MCF-7) and 0.4 μM (HepG2), respectively compared to that of doxorubicin, (IC50 = 1.02 μM and 0.9 μM, respectively). Compounds 5e and 6 were subjected to cell cycle analysis and apoptosis assay after 24 h and 48 h treatment. Compound 5e arrested cell at G1 phase, while 6 arrested cell at S and G2/M phases, respectively. The apoptotic effect of both compounds were evidenced by pre G1 apoptosis as its percentage increased by time (7.38%, 11.61%) and (13.92%, 16.71%), respectively. Apoptosis induction capability was confirmed by the effect on early and late apoptosis and augmentation of caspase-3 level. Furthermore, compound 6 inhibited CDK2 enzyme with IC50 = 0.19 μM and increased levels of its regulators, P21 and P27 by 10.06% and 8.5%, respectively. Moreover, a molecular docking study of compound 6 on CDK2 enzyme was adopted to explore binding interaction with amino acid residues of its active site.


Matrix-trapped viruses can prevent invasion of bacterial biofilms by colonizing cells.
Bacteriophages can be trapped in the matrix of bacterial biofilms, such that the cells inside them are protected. It is not known whether these phages are still infectious and whether they pose a threat to newly arriving bacteria. Here, we address these questions using Escherichia coli and its lytic phage T7. Prior work has demonstrated that T7 phages are bound in the outermost curli polymer layers of the E. coli biofilm matrix. We show that these phages do remain viable and can kill colonizing cells that are T7-susceptible. If cells colonize a resident biofilm before phages do, we find that they can still be killed by phage exposure if it occurs soon thereafter. However, if colonizing cells are present on the biofilm long enough before phage exposure, they gain phage protection via envelopment within curli-producing clusters of the resident biofilm cells.


Research partners: two teams, one study population.
Two large research projects funded by the National Institutes of Health, the Disease Management project and the Thrive study, which examine different phenomena in the chronically critically ill population, have combined research teams. Each study has its own project manager and maintains a separate database and budget. Operational tasks for both grants are streamlined through the collaboration and cross-training of all team members. The Disease Management project is a randomized clinical trial testing the effectiveness of a care program in improving outcomes for chronically critically ill patients and their caregivers during the first 2 months after discharge. The Thrive study is a prospective longitudinal investigation that aims to describe the weaning patterns of chronically critically ill patients as well as the patterns of illness-related variables. To date, many participants (n = 400) have been enrolled in each study. The results of both studies will be available through future publications. Although much information has been gleaned from gathering longitudinal data across one study population and examining two rich data sets, there are some limitations to this collaboration.


Population variation at the polymorphic ApaLI restriction enzyme site in intron 5 of the WT1 gene.
We examined 63 unrelated individuals from the United States for the Apa-LI polymorphism in intron 5 of the WT1 gene. Allele frequencies of 0.13 and 0.87 for the A and B alleles, respectively, and a heterozygosity index of 24% contrast sharply with previous data obtained in the Japanese population where allele frequencies of 0.55 and 0.45 for the A and B alleles and a heterozygosity index of 59% were reported. These data suggest genetic heterogeneity at the WT1 locus, which may contribute to the differences in the incidence of Wilms tumor between the two population groups.


Subcutaneous sarcoidosis with plantar involvement.
Sarcoidosis is a multisystem granulomatous disorder of an unknown etiology. Subcutaneous sarcoidosis is a rare manifestation of sarcoidosis, and plantar involvement is extremely rare and there is only one such case report in the medical literature. Herein we present an interesting case of a patient who was diagnosed as having subcutaneous sarcoidosis at a plantar localization because plantar involvement is extremely rare and also because of the successful outcome after performing intralesional corticosteroid therapy.


Integrated metagenomics and molecular ecological network analysis of bacterial community composition during the phytoremediation of cadmium-contaminated soils by bioenergy crops.
Two energy crops (maize and soybean) were used in the remediation of cadmium-contaminated soils. These crops were used because they are fast growing, have a large biomass and are good sources for bioenergy production. The total accumulation of cadmium in maize and soybean plants was 393.01 and 263.24μg pot-1, respectively. The rhizosphere bacterial community composition was studied by MiSeq sequencing. Phylogenetic analysis was performed using 16S rRNA gene sequences. The rhizosphere bacteria were divided into 33 major phylogenetic groups according to phyla. The dominant phylogenetic groups included Proteobacteria, Acidobacteria, Actinobacteria, Gemmatimonadetes, and Bacteroidetes. Based on principal component analysis (PCA) and unweighted pair group with arithmetic mean (UPGMA) analysis, we found that the bacterial community was influenced by cadmium addition and bioenergy cropping. Three molecular ecological networks were constructed for the unplanted, soybean- and maize-planted bacterial communities grown in 50mgkg-1 cadmium-contaminated soils. The results indicated that bioenergy cropping increased the complexity of the bacterial community network as evidenced by a higher total number of nodes, the average geodesic distance (GD), the modularity and a shorter geodesic distance. Proteobacteria and Acidobacteria were the keystone bacteria connecting different co-expressed operational taxonomic units (OTUs). The results showed that bioenergy cropping altered the topological roles of individual OTUs and keystone populations. This is the first study to reveal the effects of bioenergy cropping on microbial interactions in the phytoremediation of cadmium-contaminated soils by network reconstruction. This method can greatly enhance our understanding of the mechanisms of plant-microbe-metal interactions in metal-polluted ecosystems.


Suppression of renal sympathetic activity with potassium supplement in DOCA-salt rats.
We studied the involvement of renal sympathetic nervous system activity in the antihypertensive and natriuretic effects of potassium supplement in DOCA-salt treated rats. Systolic blood pressure of DOCA-salt rats rose substantially, reaching 181 +/- 3 mmHg after 4 weeks of DOCA-salt administration. In contrast, the supplement of 1% KCl solution attenuated the development of the hypertension until the fourth week (120 +/- 1 mmHg). After the 4-week treatments, renal norepinephrine turnover rate was calculated from the decline in specific activity after the injection of dl-3H-norepinephrine. It was markedly accelerated in DOCA-salt rats as compared to control rats. In contrast, 1% KCl supplement significantly restored to normal the increased renal norepinephrine turnover rate in DOCA-salt rats. Taken together, evidence presented suggests that the normalization of the increased renal sympathetic tone may be involved in the natriuretic and antihypertensive effects of potassium supplement in DOCA-salt hypertensive rats.


Identifying the shifting sources to predict the dynamics of COVID-19 in the U.S.
Mobility restriction is a crucial measure to control the transmission of the COVID-19. Research has shown that effective distance measured by the number of travelers instead of physical distance can capture and predict the transmission of the deadly virus. However, these efforts have been limited mainly to a single source of disease. Also, they have not been tested on finer spatial scales. Based on prior work of effective distances on the country level, we propose the multiple-source effective distance, a metric that captures the distance for the virus to propagate through the mobility network on the county level in the U.S. Then, we estimate how the change in the number of sources impacts the global mobility rate. Based on the findings, a new method is proposed to locate sources and estimate the arrival time of the virus. The new metric outperforms the original single-source effective distance in predicting the arrival time. Last, we select two potential sources and quantify the arrival time delay caused by the national emergency declaration. In doing so, we provide quantitative answers on the effectiveness of the national emergency declaration.


Snail-like Particles from Compartmentalized Microfibers.
Electrohydrodynamic cojetting has been employed to synthesize compartmentalized microfibers from thermally responsive hydrogels. The synthesis of the hydrogels as well as their transformation into compartmentalized microcylinders is discussed. After programmable shape-shifting, snail-like particles are obtained that undergo functional and structural reconfiguration in response to a change in temperature.


Dual role of pericyte α6β1-integrin in tumour blood vessels.
The α6β1-integrin is a major laminin receptor, and formation of a laminin-rich basement membrane is a key feature in tumour blood vessel stabilisation and pericyte recruitment, processes that are important in the growth and maturation of tumour blood vessels. However, the role of pericyte α6β1-integrin in angiogenesis is largely unknown. We developed mice where the α6-integrin subunit is deleted in pericytes and examined tumour angiogenesis and growth. These mice had: (1) reduced pericyte coverage of tumour blood vessels; (2) reduced tumour blood vessel stability; (3) increased blood vessel diameter; (4) enhanced blood vessel leakiness, and (5) abnormal blood vessel basement membrane architecture. Surprisingly, tumour growth, blood vessel density and metastasis were not altered. Analysis of retinas revealed that deletion of pericyte α6-integrin did not affect physiological angiogenesis. At the molecular level, we provide evidence that pericyte α6-integrin controls PDGFRβ expression and AKT-mTOR signalling. Taken together, we show that pericyte α6β1-integrin regulates tumour blood vessels by both controlling PDGFRβ and basement membrane architecture. These data establish a novel dual role for pericyte α6-integrin as modulating the blood vessel phenotype during pathological angiogenesis.


Nanoporous Structure Formation in GaSb, InSb, and Ge by Ion Beam Irradiation under Controlled Point Defect Creation Conditions.
Ion beam irradiation-induced nanoporous structure formation was investigated on GaSb, InSb, and Ge surfaces via controlled point defect creation using a focused ion beam (FIB). This paper compares the nanoporous structure formation under the same extent of point defect creation while changing the accelerating voltage and ion dose. Although the same number of point defects were created in each case, different structures were formed on the different surfaces. The depth direction density of the point defects was an important factor in this trend. The number of point defects required for nanoporous structure formation was 4 × 1022 vacancies/m² at a depth of 18 nm under the surface, based on a comparison of similar nanoporous structure features in GaSb. The nanoporous structure formation by ion beam irradiation on GaSb, InSb, and Ge surfaces was controlled by the number and areal distribution of the created point defects.


Acute effects of static stretching on peak torque and mean power output in National Collegiate Athletic Association Division I women's basketball players.
The purpose of this study was to examine the acute effects of static stretching on peak torque (PT) and mean power output (MP) during maximal, voluntary concentric isokinetic leg extensions at 60 and 300 degrees .s(-1) in National Collegiate Athletic Association Division I Women's Basketball players. Eleven members of a women's basketball team volunteered to perform maximal concentric isokinetic leg extensions at 60 and 300 degrees .s(-1) on a calibrated Biodex System 3 dynamometer. After the initial isokinetic testing, the dominant leg extensors were stretched using 1 unassisted and 3 assisted static stretching exercises. The poststretching isokinetic assessments were repeated at 5, 15, 30, and 45 minutes after the static stretching (post-5, post-15, post-30, and post-45). PT (N.m) and MP (W) were recorded by dynamometer software. The results indicated no stretching-related changes in PT (p = 0.161) or MP (p = 0.088) from pre- to poststretching for any of the testing intervals (post-5, post-15, post-30, and post-45). These findings indicated that the static stretching had no impact on PT or MP during maximal, voluntary concentric isokinetic muscle actions in collegiate women's basketball players. In conjunction with previous studies, these findings suggested that trained athletes may be less susceptible to the stretching-induced force deficit than untrained, nonathletes.


Development of a Family Support Scale for Diet Therapy for Male Workers with type 2 diabetes.
Dietary self-care for patients with type 2 diabetes can be improved with family support. The purpose of this study was to develop a scale to assess family support for diet therapy for male workers with type 2 diabetes and to examine its reliability and validity. In this cross-sectional study, we collected data from 110 Japanese male workers with type 2 diabetes. Data were analyzed using exploratory factor analysis, reliability testing, and validity testing. The resultant Family Support Scale for Diet Therapy for Male Workers (FSS-DMW) with type 2 diabetes consisted of 31 items and a six-factor structure. The six factors explained 72.9% of the variance, and Cronbach's alpha for the total scale was .964. The scale correlated as expected with the Social Support Scale for Chronic Illness and the dietary subscale of the Japanese version of the Summary of Diabetes Self-Care Activities Measure. The FSS-DMW is a reliable and valid measure which can be used to assess family support for diet therapy for male workers with type 2 diabetes and has the potential to be used as a clinical instrument for family guidance.


[About Clinical Applicatoin of Local Rotation Plasty].
Local rotation plasty is a well-known and well-accepted plastic surgery tool for the body surface defects treatment. Because of some new theoretical streams in the literature, authors performed their own researches among oncological, non-oncological cases in which the method was performed as a part of surgical treatment. The aim of this study is a clinical analysis of local plasty application in different anatomical regions of the human body. A retrospective study was performed among 54 consecutives local plasty surgical cases. Between 01.2010 and 01.2015 54 consecutive patients were treated with local plasty surgical approach. 39 of them were man and 15 - women. The median age of the participants was 62,5 years for the man and 57.5 years for the women. In the 24,07 % of all cases the rotation angle chosen was 90°, and in the other 75,93% of all cases this one was lower 90°. Postoperative complication were established in 9,26 % ±4,25 % mainly in the greater angle rotation group. All of them were conservatively managed without reconstructive failure. We discuss our results with those obtained in the literature focused on some new streams in the local plasty applications.


Differences in Bacterial Colonization and Mucosal Responses Between High and Low SES Children in Indonesia.
Increased nasopharyngeal carriage of pathogenic bacteria is found in low socioeconomic status (SES) settings. How SES affects local immune responses, important for controlling colonization, is currently unknown. Examining bacterial colonization and cytokine response in the nasal mucosa of children from high and low SES. Nasosorption samples were collected in October 2019 from 48 high SES and 50 low SES schoolchildren, in a cross-sectional study in Makassar, Indonesia. Twenty-five cytokines were measured in nasal fluid. Quantitative polymerase chain reaction was performed to determine carriage and density of Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis and Staphylococcus aureus. Data were analyzed using multivariate regression. H. influenzae and S. pneumoniae densities were increased in low SES settings compared to the high SES settings (P = 0.006, P = 0.026), with 6 and 67 times higher median densities, respectively. Densities of H. influenzae and S. pneumoniae were positively associated with levels of IL-1beta and IL-6. After correcting for bacterial density, IL-6 levels were higher in colonized children from high SES than low SES for H. influenzae and S. pneumoniae (both P = 0.039). Increased densities of H. influenzae and S. pneumoniae were observed in low SES children, whereas IL-6 levels associated with colonization were reduced in these children, indicating that immune responses to bacterial colonization were altered by SES.


Phenotypic and Molecular Investigations on Hypovirulent Cryphonectria parasitica in Italy.
Chestnut blight is caused by the fungus Cryphonectria parasitica. As one of the most ecologically important diseases of Castanea spp., C. parasitica can rapidly kill trees. In Europe, mitigation of disease severity took place spontaneously through colonization of C. parasitica by mycoviruses, which reduced the virulence of the fungus. In the framework of a survey, 138 C. parasitica isolates were identified, and virulent/hypovirulent phenotypes were determined through morphological properties and pathogenicity tests. For a pool of four hypovirulent isolates, dsRNA was extracted, cDNA synthesized, and a library subjected to next-generation sequencing. The bioinformatics analysis allowed detecting and reconstructing the complete genome of Cryphonectria hypovirus 1 (CHV-1), denoted as CHV-1 Marche. When compared with the available genomes of other hypoviruses that affected the virulence of C. parasitica, available in databases, CHV-1 Marche showed some nucleotide diversity. The approach used in this study was effective to explore the virome inside a pool of hypovirulent C. parasitica isolates. Next-generation sequencing allowed us to exclude the presence of any other ssRNA and dsRNA viruses infecting the fungus and determine CHV-1 as the only responsible of hypovirulence of C. parasitica in the analyzed samples.


Entrapped appendicitis in post TAPP mesh repair.
Transabdominal preperitoneal (TAPP) repair is a common laparoscopic inguinal hernia repair technique performed worldwide. A rare long-term complication of TAPP is mesh-induced appendicitis, of which only four cases have been described in the literature to date. We report a case of appendicitis due to appendix entrapped in the TAPP mesh.


Periodic lateralized EEG abnormality in a case of Neuro-Behcet syndrome.
A thirty-six year old male with a sixteen month history of a progressive neurological disorder had Behcet's disease. His initial electroencephalogram showed periodic lateralizing epileptiform discharges (PLEDs). The electroencephalographic changes in this disorder have not been described in detail in the American literature. The review of world publications in this matter disclosed that there is no specific EEG pattern in this condition, and that electroencephalographic changes are mainly related to the side of the lesion and have no prognostic value.


Identifying talented health administration students: a look at academic criteria.
The objective of this study was to examine the relationships of undergraduate academic and admission test performance with graduate academic performance. Results could aid in selecting health service administration students in the future. The sample included 139 students (40 women and 99 men) entering seven health services administration programs during the fall of 1975 and graduating during the spring and summer of 1977. Participating programs were located in the Midwest, Northeast, South, and West Coast. Independent variables included undergraduate academic performance and admission test scores, while the dependent variable was graduate academic performance. Correlation analyses revealed that: (a) the verbal and quantitative subtest scores of the GRE were related to most aspects of graduate academic performance for men but only to selected aspects for women, (b) performance on the MAT was related to women's graduate academic performance in quantitative courses, and (c) men's and women's composite undergraduate grade point average was not related to composite graduate grade point average. These findings suggest that some of the standardized tests presently employed as admission screening devices should be used judiciously.


Transjugular intrahepatic portosystemic shunts compared with endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage. A randomized, controlled trial.
Transjugular intrahepatic portosystemic shunts (TIPS) have widened the use of portal decompression as therapy for variceal hemorrhage. However, no controlled studies have examined the efficacy of TIPS compared with that of other treatments. To compare the efficacy and safety of TIPS with those of endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage. Randomized, controlled trial. Tertiary-care academic medical center. 100 patients with cirrhosis were evaluated a mean of approximately 10 days after an episode of acute variceal bleeding; 20 patients were excluded because of portal venous thrombosis (n = 6), hepatoma (n = 3), florid alcoholic hepatitis (n = 6), and refusal to give consent (n = 5). TIPS (n = 41) or sclerotherapy (n = 39). The latter was performed by freehand injections of 5% Na morrhuate at 2- to 3-week intervals. Recurrent variceal hemorrhage was managed by sclerotherapy followed by angiographic assessment of TIPS and dilatation of the stents (TIPS group) or crossover to TIPS (sclerotherapy group). Rebleeding and survival were the primary end points. Complications and rates of rehospitalization were secondary end points. During a mean follow-up of approximately 1000 days, recurrent gastrointestinal bleeding resulted from variceal hemorrhage (9 patients in the TIPS group and 8 in the sclerotherapy group), portal gastropathy (1 patient in each group), and gastric lipoma (0 and 1 patients, respectively). A higher mortality rate was seen with TIPS (P = 0.03). Death resulted from variceal bleeding (5 patients in the TIPS group and 3 in the sclerotherapy group), sepsis (3 and 2 patients, respectively), liver failure (2 patients in each group), hepatoma (1 and 0 patients, respectively), and hemoperitoneum (1 and 0 patients, respectively). Encephalopathy was the most common complication in the TIPS group (n = 12), and pain developing after sclerotherapy was the most common in the sclerotherapy group (n = 10). The two groups had similar rates of rehospitalization. Endoscopic sclerotherapy and TIPS are equivalent with respect to rebleeding developing over the long term. However, sclerotherapy may be superior to TIPS with respect to survival.


The replication checkpoint control in Bacillus subtilis: identification of a novel RTP-binding sequence essential for the replication fork arrest after induction of the stringent response.
We have shown previously that induction of the stringent response in Bacillus subtilis resulted in the arrest of chromosomal replication between 100 and 200 kb either side of oriC at distinct stop sites, designated LSTer and RSTer, left and right stringent terminators respectively. This replication checkpoint was also shown to involve the RTP protein, normally active at the chromosomal terminus. In this study, we show that the replication block is absolutely dependent upon RelA, correlated with high levels of ppGpp, but that efficient arrest at STer sites also requires RTP. DNA-DNA hybridization data indicated that one or more such LSTer sites mapped to gene yxcC (-128 kb from oriC). A 7.75 kb fragment containing this gene was cloned into a theta replicating plasmid, and plasmid replication arrest, requiring both RelA and RTP, was demonstrated. This effect was polar, with plasmid arrest only detected when the fragment was orientated in the same direction with respect to replication, as in the chromosome. This LSTer2 site was further mapped to a 3.65 kb fragment overlapping the next40 probe. Remarkably, this fragment contains a 17 bp sequence (B'-1) showing 76% identity with an RTP binding site (B sequence) present at the chromosomal terminus. This B'-1 sequence, located in the gene yxcC, efficiently binds RTP in vitro, as shown by DNA gel retardation studies and DNase I footprinting. Importantly, precise deletion of this sequence abolished the replication arrest. We propose that this modified B site is an essential constituent of the LSTer2 site. The differences between arrest at the normal chromosomal terminus and arrest at LSTer site are discussed.


Overexpression of microRNA‑21 inhibits the growth and metastasis of melanoma cells by targeting MKK3.
Melanoma is an aggressive skin carcinoma with poor prognosis, and is prevalent worldwide. It was demonstrated that microRNA (miR)‑21 and mitogen‑activated protein kinase kinase 3 (MKK3) both participated in the occurrence and development of various tumors; however, their detailed roles in the progression of melanoma remain unclear. Reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analyses were conducted to examine the expression levels of miR‑21 and MKK3 in clinical specimens of patients with melanoma and melanoma cell lines. A dual‑luciferase reporter assay was performed to verify the target interaction between miR‑21 and MKK3. The mRNA and protein expressions of MKK3 were measured using RT‑qPCR and western blot analysis, respectively, following transfection with miR‑21 mimics and inhibitor. Subsequently, Cell Counting Kit‑8 and colony formation assays, and flow cytometry were conducted to assess the effects of miR‑21 and MKK3 on the cell growth of melanoma. Cell migration and invasion experiments were performed to evaluate the effects of miR‑21 and MKK3 on the cell metastasis of melanoma. It was revealed that MKK3 was upregulated, and miR‑21 was downregulated in patients with melanoma and melanoma cell lines. MKK3 was demonstrated to be a direct target of miR‑21. Furthermore, it was demonstrated that upregulated miR‑21 expression and downregulated MKK3 expression suppressed cell proliferation and colony formation, promoted apoptosis, delayed the cell cycle, and inhibited cell migration and invasion. The present findings suggested that miR‑21 could inhibit the cell growth and metastasis of melanoma by negatively regulating MKK3.


Comparison of phased-array 3.0-T and endorectal 1.5-T magnetic resonance imaging in the evaluation of local staging accuracy for prostate cancer.
To retrospectively evaluate local staging accuracy for prostate cancer at 3.0-T magnetic resonance imaging (MRI) by comparing with that at 1.5-T MRI. Two groups, each consisting of 54 patients, were included by matching for age, prostate specific antigen, and Gleason score. Before radical prostatectomy, 1 group underwent 3.0-T MRI using a phased-array coil, and the other 1.5-T MRI using an endorectal coil. T2-weighted MR images at 3.0 and 1.5 T were analyzed in consensus by 2 radiologists, and their staging accuracy was compared with histology. Artifact and overall image quality were compared at both 3.0 and 1.5 T. Accuracy for T3 stage at 3.0 and 1.5 T were 72% (39/54) and 70% (38/54), respectively (P > 0.05). The 3.0-T MRI had a lower incidence of MR artifacts than the 1.5-T MRI (P < 0.05). However, overall imaging quality at both 3.0 and 1.5 T had no significant difference (P > 0.05). The 3.0-T phased-array MRI is equivalent to the 1.5-T endorectal MRI in evaluating local staging accuracy for prostate cancer without significant loss of imaging quality.


Toward flexibility-activity relationships by NMR spectroscopy: dynamics of Pin1 ligands.
Drug design involves iterative ligand modifications. For flexible ligands, these modifications often entail restricting conformational flexibility. However, defining optimal restriction strategies can be challenging if the relationship between ligand flexibility and biological activity is unclear. Here, we describe an approach for ligand flexibility-activity studies using Nuclear Magnetic Resonance (NMR) spin relaxation. Specifically, we use (13)C relaxation dispersion measurements to compare site-specific changes in ligand flexibility for a series of related ligands that bind a common macromolecular receptor. The flexibility changes reflect conformational reorganization resulting from formation of the receptor-ligand complex. We demonstrate this approach on three structurally similar but flexibly differentiated ligands of human Pin1, a peptidyl-prolyl isomerase. The approach is able to map the ligand dynamics relevant for activity and expose changes in those dynamics caused by conformational locking. Thus, NMR flexibility-activity studies can provide information to guide strategic ligand rigidification. As such, they help establish an experimental basis for developing flexibility-activity relationships (FAR) to complement traditional structure-activity relationships (SAR) in molecular design.


Egress route of emulsified 20 centistokes silicone oil from anterior chamber of rabbit.
Silicone oil is used in recent clinical practice, however, it may cause adverse reactions in the eyes. When the high viscosity silicone oil is contaminated with low molecular weight silicone oil, the contamination may cause ocular toxicity or elevation of the intraocular pressure. To obtain information on the distribution of this preparation, emulsified 20 centistokes silicone oil was injected into the anterior chamber of rabbit eyes. The silicone oil droplets were visualized by light and electron microscopy by using oil soluble phthalocyanine blue. This copper containing dye remains in the tissue after removal of the silicone oil by organic solvents. Two and 4 weeks after an injection, the silicone emulsion was observed as numerous small vacuoles with blue precipitate at the margin of vacuoles within elongated trabecular endothelial cells, fibroblasts along the route of uveoscleral outflow and cells of the iris. Three hours after the injection, only a few vacuoles were present in these cells. These results demonstrated that the emulsified silicone oil leaves the anterior chamber through the conventional and unconventional routes. Phagocytosis by the trabecular endothelial cells and fibroblasts along the uveoscleral route caused an accumulation of the emulsified silicone oil in these cells. With chronic exposure to emulsified silicone oil, changes in the trabecular meshwork may lead to a reduction in the outflow of aqueous humor and cause glaucoma.


Venous dysfunction and the change of blood viscosity during head-up tilt.
The precise stimulus that induces vasovagal syncope is still unclear. We have previously demonstrated that the peripheral distribution of blood volume (venous pooling) is a strong predictor of tilt induced vasovagal reaction. We hypothesized that an increase in venous pooling during tilt accentuates the measured increase in blood viscosity. This hypothesis is based on the previously demonstrated increase in venous pressure and subsequent increase in transcapillary fluid transudation during tilt. The increased blood viscosity, in turn, increases vascular shear rate, which may alter the vasoconstrictive and other cardiovascular responses to decreased preload. We measured blood viscosity (supine and tilt) in 56 patients with a history of orthostatic intolerance (37 with venous pooling [VP] and 19 without venous pooling [non-VP]). VP and non-VP were separated into subgroups based on blood pressure and heart rate response to tilt. There was a positive correlation between blood viscosity and plasma aldosterone in the supine. In the group as a whole, neither supine blood viscosity nor its increase during tilt differed between VP and non-VP. However, the tilt induced increase of blood viscosity was significant only in patients with tilt provoked tachycardia plus normal blood pressure response in VP group. We suggest that the increase of blood viscosity in this group led to the normal blood pressure response. The positive correlation between supine blood viscosity and supine plasma aldosterone indicates that the normal blood pressure response in this group possibly was via stimulation of the renin-angiotensin-aldosterone system.


Phosphaturic effect of dopamine in dogs. Possible role of intrarenally produced dopamine in phosphate regulation.
A possible role for dopamine in phosphate handling by the dog kidney was investigated by intrarenal artery infusions of dopamine. Dopamine increased fractional phosphate excretion both in the presence and absence of control of parathyroid hormone and calcitonin. In addition, dopamine increased both renal blood flow and sodium excretion, however, the phosphaturia was independent of these changes; since 30 min after completion of dopamine infusion, renal blood flow and sodium excretion returned to control levels and phosphate excretion remained elevated. For comparison, the vasodilator isoproterenol increased renal blood flow and sodium excretion without a significant change in fractional phosphate excretion. Thus, the phosphaturic effect of dopamine is probably independent of its vasodilator effect. The phosphaturic effect of dopamine could not be accounted for by subsequent conversion to norepinephrine, since norepinephrine was antiphosphaturic in the dog. The effect of endogenous dopamine on renal phosphate excretion was investigated by intrarenal infusion of the precursor dopa. Dopa was phosphaturic both in the presence and absence of parathyroid hormone and calcitonin. In dogs pretreated with carbidopa, which blocks conversion of dopa to dopamine, dopa was no longer phosphaturic, although the kidney remained responsive to dopamine. It is postulated that dopamine may play a role in the intrarenal regulation of phosphate excretion.


Identification of Genes Involved in the Synthesis of the Fungal Cell Wall Component Nigeran and Regulation of Its Polymerization in Aspergillus luchuensis.
Certain Aspergillus and Penicillium spp. produce the fungal cell wall component nigeran, an unbranched d-glucan with alternating α-1,3- and α-1,4-glucoside linkages, under nitrogen starvation. The mechanism underlying nigeran biosynthesis and the physiological role of nigeran in fungal survival are not clear. We used RNA sequencing (RNA-seq) to identify genes involved in nigeran synthesis in the filamentous fungus Aspergillus luchuensis when grown under nitrogen-free conditions. agsB, which encodes a putative α-1,3-glucan synthase, and two adjacent genes (agtC and gnsA) were upregulated under conditions of nitrogen starvation. Disruption of agsB in A. luchuensis (ΔagsB) resulted in the complete loss of nigeran synthesis. Furthermore, the overexpression of agsB in an Aspergillus oryzae strain that cannot produce nigeran resulted in nigeran synthesis. These results indicated that agsB encodes a nigeran synthase. Therefore, we have renamed the A. luchuensis agsB gene the nigeran synthase gene (nisA). Nigeran synthesis in an agtC mutant (ΔagtC) increased to 121%; conversely, those in the ΔgnsA and ΔagtC ΔgnsA strains decreased to 64% and 63%, respectively, compared to that in the wild-type strain. Our results revealed that AgtC and GnsA play an important role in regulating not only the quantity of nigeran but also its polymerization. Collectively, our results demonstrated that nisA (agsB) is essential for nigeran synthesis in A. luchuensis, whereas agtC and gnsA contribute to the regulation of nigeran synthesis and its polymerization. This research provides insights into fungal cell wall biosynthesis, specifically the molecular evolution of fungal α-glucan synthase genes and the potential utilization of nigeran as a novel biopolymer. IMPORTANCE The fungal cell wall is composed mainly of polysaccharides. Under nitrogen-free conditions, some Aspergillus and Penicillium spp. produce significant levels of nigeran, a fungal cell wall polysaccharide composed of alternating α-1,3/1,4-glucosidic linkages. The mechanisms regulating the biosynthesis and function of nigeran are unknown. Here, we performed RNA sequencing of Aspergillus luchuensis cultured under nitrogen-free or low-nitrogen conditions. A putative α-1,3-glucan synthase gene, whose transcriptional level was upregulated under nitrogen-free conditions, was demonstrated to encode nigeran synthase. Furthermore, two genes encoding an α-glucanotransferase and a hypothetical protein were shown to be involved in controlling the nigeran content and molecular weight. This study reveals genes involved in the synthesis of nigeran, a potential biopolymer, and provides a deeper understanding of fungal cell wall biosynthesis.


Enhancing Patient Outcomes while Containing Costs after Complex Abdominal Operation: A Randomized Controlled Trial of the Whipple Accelerated Recovery Pathway.
This study was designed to determine whether a standardized recovery pathway could reduce post-pancreaticoduodenectomy hospital length of stay to 5 days without increasing complication or readmission rates. Pancreaticoduodenectomy patients (high-risk patients excluded) were enrolled in an IRB-approved, prospective, randomized controlled trial (NCT02517268) comparing a 5-day Whipple accelerated recovery pathway (WARP) with our traditional 7-day pathway (control). Whipple accelerated recovery pathway interventions included early discharge planning, shortened ICU stay, modified postoperative dietary and drain management algorithm, rigorous physical therapy with in-hospital gym visit, standardized rectal suppository administration, and close telehealth follow-up post discharge. The trial was powered to detect an increase in postoperative day 5 discharge from 10% to 30% (80% power, α = 0.05, 2-sided Fisher's exact test, target accrual: 142 patients). Seventy-six patients (37 WARP, 39 control) were randomized from June 2015 to September 2017. A planned interim analysis was conducted at 50% trial accrual resulting in mandatory early stoppage, as the predefined efficacy end point was met. Demographic variables between groups were similar. The WARP significantly increased the number of patients discharged to home by postoperative day 5 compared with controls (75.7% vs 12.8%; p < 0.001) without increasing readmission rates (8.1% vs 10.3%; p = 1.0). Overall complication rates did not differ between groups (29.7% vs 43.6%; p = 0.24), but the WARP significantly reduced the time from operation to adjuvant therapy initiation (51 days vs 66 days; p = 0.005) and hospital cost ($26,563 vs $31,845; p = 0.011). The WARP can safely reduce hospital length of stay, time to adjuvant therapy, and cost in selected pancreaticoduodenectomy patients without increasing readmission risk.


Retrospective study of posterior cervical fusions with rhBMP-2.
Posterior cervical decompression and fusion can be performed for various spinal conditions. Previous rates of pseudoarthrosis have been reported in up to 38% of patients. The use of bone morphogenic protein (BMP) has been approved for use in certain anterior lumbar interbody fusion techniques to decrease the incidence of pseudoarthrosis. Bone morphogenic protein in the anterior cervical spine carries a potential increased risk of airway complications; however, few data exist on the safety and efficacy of BMP in the posterior cervical spine. The purpose of this study was to evaluate fusion success, safety, and heterotopic bone formation using BMP in posterior cervical fusion.Twenty-nine patients who received posterior cervical fusion with BMP were followed for a minimum of 12 months. Computed tomography scans were obtained at a minimum of 12 months postoperatively to evaluate for solid arthrodesis and the presence of heterotopic bone formation. Patients' demographic data and adverse events were evaluated. All patients underwent posterior cervical decompression and instrumented fusion of at least 1 level between 2006 and 2008. Of 37 patients eligible for the study, 29 agreed to participate. Three (10.3%) of 29 patients developed pseudoarthrosis, as found on computed tomography scan. None of these went on to further surgery. No evidence existed of heterotopic bone formation outside of the lateral masses or bone growth over the spinal canal or neuroforamen. No adverse events were related to the use of BMP in this series of posterior cervical fusions. Bone morphogenic protein can be used safely in posterior cervical spine fusion, but additional larger studies are recommended. Even with the use of bone morphogenic protein, the possibility of pseudoarthrosis exists.


An Inexpensive, Single Use Carbon-Based Sensor for the Rapid and Early Detection of Hydrocarbon Leaks.
A novel fabrication process for a single use, low-cost organic solvent sensor has been developed. The process is simple, and the materials are readily available. Carbon nanomaterials are self-assembled at a water/hexane interface, where the hexane phase contains dissolved paraffin wax. Upon the controlled evaporation of hexane, the paraffin wax precipitates, trapping the carbon nanoparticles at the surface in a paraffin wax backbone, realizing a carbon-nanoparticle-decorated film. The film is hydrophobic and highly electrically conductive. When exposed to hydrocarbons or a mixture of hydrocarbons, the conductive carbon network deteriorates and an increase in film resistivity is monitored. The rate of change in resistivity is proportional to the concentration and composition of organic molecules in contact with the film.


Measuring quality of life: a new and practical survey instrument.
Despite increasing recognition of the importance of measuring the quality of life (QOL) of people with severe mental illness, such assessments are seldom carried out because of the lack of an efficient, easy-to-use, and valid measurement instrument. To facilitate the gathering of QOL information from clients in evaluation, program improvement, or other efforts, the authors present a new short (24-item) self-administered questionnaire called the Quality of Life Questionnaire (QLQ). The questionnaire assesses subjective QOL in seven areas. Evidence for the reliability and validity of the QLQ is based on data gathered from 971 clients with serious mental illness who were receiving publicly funded mental health services at the time of the study. The results of a confirmatory factor analysis using a random split-half procedure indicated that a seven-factor solution fit the data well. Scores on the QLQ also correlated significantly with the client's functioning and satisfaction with services, providing support for the validity of the QLQ. The advantages of the QLQ over existing measures include low-cost administration and some superior psychometric properties.


Skipping of Exon 1 in the KCNQ1 gene causes Jervell and Lange-Nielsen syndrome.
The Jervell and Lange-Nielsen syndrome (JLNS) is a rare autosomal recessive form of the long QT syndrome linked with a profound hearing loss caused by mutations affecting both alleles of either the KCNQ1 or the KCNE1 gene. We carried out a mutant screening of the KCNQ1 and KCNE1 genes in a clinical diagnosed German family with JLNS. Family members were examined by single strand conformation polymorphism analysis and PCR and amplified products were characterized by DNA sequence analysis. We identified a splice donor mutation of exon 1 in the KCNQ1 gene (G477+1A). Analysis of lymphocyte RNA by RT-PCR revealed that two symptomatic patients, homozygous for the mutant allele, exclusively produce KCNQ1 transcripts lacking exon 1 leading to a frameshift that introduced a premature termination codon at exon 4. Mutant subunits, functionally characterized in Xenpous oocytes, were unable to form homomeric channels but strongly reduced IKs (slowly activating delayed rectifier potassium current) in vitro (mutant isoforms 1 and 2 by 62 and 86%, respectively), a fact supposed to lead to severely affected heterozygous individuals. However, individuals heterozygous for the mutant allele exhibit an asymptomatic cardiac phenotype. Thus, the observed dominant-negative effect of mutant subunits in vitro is absent in vivo leaving heterozygous individuals unaffected. These data suggest mechanisms that prevent production of truncated KCNQ1 channel subunits in cardiomyocytes of individuals heterozygous for the mutant allele.


β2-adrenoceptor agonists and antagonists and risk of Parkinson's disease.
β2-adrenoreceptors have recently been identified as regulators of the α-synuclein gene, which is implicated in the pathogenesis of Parkinson's disease. The objectives of this study were to assess the association between use of β2-agonists and β-antagonists and the risk of developing PD. We conducted a nested case-control study in a cohort of 1,762,164 adults without a diagnosis of PD. They were identified on January, 1, 2004, from the electronic medical records of the largest health care provider in Israel. Participants were followed up until June 30, 2017, for the occurrence of PD. Ten randomly selected controls were matched to each case of PD on age, sex, ethnic group, and duration of follow-up. During follow-up 11,314 patients were newly diagnosed with PD and were matched with 113,140 controls. An increased risk of PD was seen with the use of nonselective β-antagonists (RR, 2.04 [1.90-2.20]) but not with the use of selective β1-antagonists (RR, 1.00 [0.95-1.05]). Use of β2-agonists was associated with reduced risk of PD (RR, 0.89 [0.82-0.96] for short-acting; RR, 0.84 [0.76-0.93] for long-acting; and RR, 0.49 [0.25-0.92] for ultra-long-acting β2-agonists). In an analysis of individual drugs, propranolol and salbutamol were significantly associated with PD risk, even when these drugs were ascertained 5 years prior to the index date, compared with nonusers (RR, 1.31 [1.08-1.58] and 1.89 {1.53-2.33]) in patients who filled <6 and ≥6 propranolol prescriptions, respectively; the corresponding RRs for salbutamol were 0.95 (0.83-1.08) and 0.65 (0.45-0.94), respectively. Use of propranolol appears to be associated with an increased risk of PD, whereas use of β2-agonists is associated with a decreased risk of PD. © 2018 International Parkinson and Movement Disorder Society.


Quantifying TEMPO Redox Polymer Charge Transport toward the Organic Radical Battery.
To design new and better organic active battery materials in a rational fashion, fundamental parameters of the charge transport must be studied. Herein we report on the electronic conductivity by electron diffusion in a TEMPO-containing redox polymer, and the reorganization energy of the TEMPO self-exchange in an organic solvent is determined for the first time. The electronic conductivity was 8.5 μS/cm at E0 and corresponded to a redox hopping mechanism. The apparent electron diffusion coefficient was 1.9 × 10-9 cm2/s at room temperature, and at short times the ion diffusion was limiting with a diffusion coefficient of 6.5 × 10-10 cm2/s. The reorganization energy was determined to be 1.01 eV, indicating a rather polar chemical environment for the TEMPO groups. The implications for the usage of this type of materials in organic energy storage are discussed. As conductivity through 10 μm was demonstrated, we show that, if sufficient swellability can be ensured, charge can be transported through several micrometer thick layers in a battery electrode without any conducting additive.


Sensitivity of vertebral compressive strength to endplate loading distribution.
The sensitivity of vertebral body strength to the distribution of axial forces along the endplate has not been comprehensively evaluated. Using quantitative computed tomography-based finite element models of 13 vertebral bodies, an optimization analysis was performed to determine the endplate force distributions that minimized (lower bound) and maximized (upper bound) vertebral strength for a given set of externally applied axial compressive loads. Vertebral strength was also evaluated for three generic boundary conditions: uniform displacement, uniform force, and a nonuniform force distribution in which the interior of the endplate was loaded with a force that was 1.5 times greater than the periphery. Our results showed that the relative difference between the upper and lower bounds on vertebral strength was 14.2 +/- 7.0% (mean +/- SD). While there was a weak trend for the magnitude of the strength bounds to be inversely proportional to bone mineral density (R2 = 0.32, p = 0.02), both upper and lower bound vertebral strength measures were well predicted by the strength response under uniform displacement loading conditions (R2 = 0.91 and R2 = 0.99, respectively). All three generic boundary conditions resulted in vertebral strength values that were statistically indistinguishable from the loading condition that resulted in an upper bound on strength. The results of this study indicate that the uncertainty in strength arising from the unknown condition of the disc is dependent on the condition of the bone (whether it is osteoporotic or normal). Although bone mineral density is not a good predictor of strength sensitivity, vertebral strength under generic boundary conditions, i.e., uniform displacement or force, was strongly correlated with the relative magnitude of the strength bounds. Thus, explicit disc modeling may not be necessary.


Inference in functional mixed regression models with applications to Positron Emission Tomography imaging data.
In a function-on-scalar regression framework, we present some modeling strategies for functional mixed models and also some approaches for making inference about various aspects of the fixed effects. This is presented in the context of modeling positron emission tomography (PET) data in order to explore the density of various proteins of interest throughout the human brain. For this application, information about the density of the target protein in a given brain region is encapsulated in the impulse response function (IRF) of the region. Previous work on nonparametric estimation of the IRF is limited in that it is only able to model a single brain region at a time. We propose an extension, based on principles of functional data analysis, that will allow modeling of multiple brain regions simultaneously. Applicable more broadly to functional mixed regression modeling, we discuss two general approaches for permutation testing and describe valid strategies for identifying exchangeable units within the model and building corresponding permutation tests. We illustrate our methods with an application to PET data and explore the effects of depression and sex on the IRF.


Effects of left amygdala lesions on respiration, skin conductance, heart rate, anxiety, and activity of the right amygdala during anticipation of negative stimulus.
The present study reports the effects of lesions in the left amygdala on anxiety, respiration, skin conductance, heart rate, and electrical potentials in the right amygdala in two patients. Trait and anticipatory-state anxiety were measured before and after left amygdala resection to control medically intractable epilepsy in the patients. Lesions in the left amygdala resulted in decreases of trait and state anxiety, respiratory rate, and activity in the right amygdala in both patients; one patient also showed notable decreases in skin conductance and heart rate. The study also reports that activities in the right amygdala before the lesion were not observed after the lesion. We suggest that the activity of the right amygdala is dominantly activated in anxiety and anxiety-related physiological responses but needs excitatory inputs from the left amygdala.


Nursing students' experience bathing patients for the first time.
This study describes nursing students' experience bathing an adult patient for the first time. The students feared giving their first patient a bath and voiced concern about harming him or her. They discovered that it was easier when they were paired with another student and acknowledged being supported by fellow nursing students. Beginners were uncomfortable about exposing and touching the patient's private body parts and were surprised when patients helped them through the bath.


Pharmacokinetics of anidulafungin in critically ill patients with candidemia/invasive candidiasis.
The pharmacokinetics of intravenous anidulafungin in adult intensive care unit (ICU) patients were assessed in this study and compared with historical data from a general patient population and healthy subjects. Intensive plasma sampling was performed over a dosing interval at steady state from 21 ICU patients with candidemia/invasive candidiasis. All patients received the recommended dosing regimen (a 200-mg loading dose on day 1, followed by a daily 100-mg maintenance dose), except for a 54-year-old 240-kg female patient (who received a daily 150-mg maintenance dose instead). Plasma samples were assayed for anidulafungin using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters in ICU patients were calculated by a noncompartmental method. With the exclusion of the 240-kg patient, the median (minimum, maximum) age, weight, and body mass index (BMI) of 20 ICU patients were 57 (39, 78) years, 65 (48, 106) kg, and 23.3 (16.2, 33.8) kg/m(2), respectively. The average anidulafungin area under the curve over the 24-hour dosing interval (AUC(0-24)), maximum concentration (C(max)), and clearance (CL) in 20 ICU patients were 92.7 mg · h/liter, 7.7 mg/liter, and 1.3 liters/h, respectively. The exposure in the 240-kg patient at a daily 150-mg dose was within the range observed in ICU patients overall. The average AUC(0-24) and Cmax in the general patient population and healthy subjects were 110.3 and 105.9 mg · h/liter and 7.2 and 7.0 mg/liter, respectively. The pharmacokinetics of anidulafungin in ICU patients appeared to be comparable to those in the general patient population and healthy subjects at the same dosing regimen.


Hippo-YAP/TAZ signaling in angiogenesis.
Angiogenesis is a complex, multistep process involving dynamic changes in endothelial cell (EC) shapes and behaviors, especially in specialized cell types such as tip cells (with active filopodial extensions), stalk cells (with less motility) and phalanx cells (with stable junction connections). The Hippo-Yes-associated protein (YAP)/ transcription activator with PDZ binding motif (TAZ) signaling plays a critical role in development, regeneration and organ size by regulating cell-cell contact and actin cytoskeleton dynamics. Recently, with the finding that YAP is expressed in the front edge of the developing retinal vessels, Hippo-YAP/TAZ signaling has emerged as a new pathway for blood vessel development. Intriguingly, the LATS1/2-mediated angiomotin (AMOT) family and YAP/TAZ activities contribute to EC shapes and behaviors by spatiotemporally modulating actin cytoskeleton dynamics and EC junction stability. Herein, we summarize the recent understanding of the role of Hippo-YAP/TAZ signaling in the processes of EC sprouting and junction maturation in angiogenesis. [BMB Reports 2018; 51(3): 157-162].


Studies of phagocytosis in chronic granulomatous disease.
Abnormal phagocyte function in chronic granulomatous disease (CGD) is associated with decreased bactericidal activity. Ingestion of serum-opsonized organisms is reported to be normal in these patients. We previously showed that in CGD the expression of C3b receptors (CR1) on polymorphonuclear leukocytes (PMNs) is significantly depressed. In this study, we compared the phagocytic activity of the PMNs from normal healthy controls with that of CGD patients and one individual with myeloperoxidase (MPO) deficiency. The ingestion of sheep erythrocytes (E) by PMNs adherent to a glass surface was examined; the E were coated either with excess IgG (E-IgG) or with C3b plus limited IgG (EAC3b-IgG). The PMNs, both in CGD and in MPO deficiency, ingested E-IgG and EAC3b-IgG at levels markedly above normal. C3b-coated erythrocytes were not phagocytosed. Preincubating the PMNs with sodium azide, which blocks MPO, or catalase, a scavenger of H2O2, caused a marked increase in phagocytosis by normal PMNs. Azide had a variable effect on PMN activity in CGD and no effect on the activity in the subject with MPO deficiency. Even in the presence of azide, the ingestion of EAC3b-IgG by the PMNs from the CGD patients was significantly greater than that seen in paired normals [mean phagocytic index (PI), 2.13 for CGD vs. 1.48 for normals; P less than 0.05 by the paired sample t test]. Similar results were obtained with ingestion of E-IgG. Notably, ingestion of serum-opsonized Candida organisms (relatively nondegradable particles) was markedly above normal with CGD PMNs and, in normal PMNs, azide treatment also evoked an increase. In addition, rosette formation of the adhered PMNs with E-IgG was enhanced with CGD and the azide-treated normal PMNs. We demonstrated that this increased activity was not the result of increased Fc receptor (FcR) number, as determined from the binding of a monoclonal anti-FcR antibody. Both the E-IgG rosette formation and the ingestion by CGD PMNs were abrogated in the presence of an H2O2-generating system. In contrast, the phagocytic activity of MPO-deficient PMNs was not altered by exogenous H2O2. These findings suggest that cellular products generated by the H2O2-MPO-halide system down-regulate the rosette-forming and phagocytic activity of PMNs from normal healthy individuals, but not that from CGD and MPO-deficient patients.


Release of carbon nanotubes from an epoxy-based nanocomposite during an abrasion process.
The abrasion behavior of an epoxy/carbon nanotube (CNT) nanocomposite was investigated. An experimental setup has been established to perform abrasion, particle measurement, and collection all in one. The abraded particles were characterized by particle size distribution and by electron microscopy. The abrasion process was carried out with a Taber Abraser, and the released particles were collected by a tube for further investigation. The particle size distributions were measured with a scanning mobility particle sizer (SMPS) and an aerodynamic particle sizer (APS) and revealed four size modes for all measured samples. The mode corresponding to the smallest particle sizes of 300-400 nm was measured with the SMPS and showed a trend of increasing size with increasing nanofiller content. The three measured modes with particle sizes from 0.6 to 2.5 μm, measured with the APS, were similar for all samples. The measured particle concentrations were between 8000 and 20,000 particles/cm(3) for measurements with the SMPS and between 1000 and 3000 particles/cm(3) for measurements with the APS. Imaging by transmission electron microscopy (TEM) revealed that free-standing individual CNTs and agglomerates were emitted during abrasion.