Development and implementation of a centralized comprehensive refill authorization program in an academic health system.
The development and implementation of a centralized, comprehensive, refill authorization (CCRA) program within an academic health system are described. In order to improve continuity of care for our medically complicated patients, ambulatory pharmacy services developed and implemented a highly coordinated CCRA program for multiple community clinics within the system. To implement the CCRA program, we centralized the refill-request intake process to the Pharmacy Ambulatory Clinical Care Center (PAC3). PAC3 technicians were incorporated into the refill authorization process, and the collaborative practice agreement was updated to standardize the pharmacist refill approval process at the PAC3. We successfully standardized and centralized the medication refill process from 10 community clinics with 95 family practice and internal medicine providers and 26 medical residents. We handled an average of 12,000 refill requests each month, and pharmacists documented any interventions performed with each refill request. The cost savings associated with the CCRA program were attributed to the increased efficiency of the staff reviewing refill requests. The CCRA program increased the refill approval up to 10% compared with the previous decentralized refill authorization model. With the increased approval rate, the CCRA program saved 510 hours of our providers' time annually, which created time for an additional 1,530 clinic visits. We demonstrated a faster average turnaround time for refill authorization, from an average of 72 hours before implementation to about 1 business day. Implementation of an integrated refill authorization service standardized the method by which patients' refill requests were addressed, increased refill efficiency, and improved refill authorization turnaround time.


High quality clinical grade human embryonic stem cell lines derived from fresh discarded embryos.
Human embryonic stem cells (hESCs) hold tremendous promise for cell replacement therapies for a range of degenerative diseases. In order to provide cost-effective treatments affordable by public health systems, HLA-matched allogeneic tissue banks of the highest quality clinical-grade hESCs will be required. However only a small number of existing hESC lines are suitable for clinical use; they are limited by moral and ethical concerns and none of them apply Good Manufacturing Practice (GMP) standards to the earliest and critical stages of gamete and embryo procurement. We thus aimed to derive new clinical grade hESC lines of highest quality from fresh surplus GMP grade human embryos. A comprehensive screen was performed for suitable combinations of culture media with supporting feeder cells or feeder-free matrix, at different stages, to support expansion of the inner cell mass and to establish new hESC lines. We developed a novel two-step and sequential media system of clinical-grade hESC derivation and successfully generated seven new hESC lines of widely varying HLA type, carefully screened for genetic health, from human embryos donated under the highest ethical and moral standards under an integrated GMP system which extends from hESC banking all the way back to gamete and embryo procurement. The present study, for the first time, reports the successful derivation of highest-quality clinical-grade hESC lines from fresh poor-quality surplus human embryos generated in a GMP-grade IVF laboratory. The availability of hESC lines of this status represents an important step towards more widespread application of regenerative medicine therapies.


A proatherogenic role for C-reactive protein in vivo.
We have selectively reviewed some of the latest papers on the mechanistic role of C-reactive protein in atherosclerotic cardiovascular disease. C-reactive protein is known to activate the classic pathway of the complement system. One paper examined the role of C-reactive protein in complement activation by enzymatically remodeled LDL proteins. Enzymatically remodeled LDL was found to induce complement activation with or without C-reactive protein, but in the presence of C-reactive protein the activation of complement halted before its terminal sequence. Complement activation by C-reactive protein in atherogenesis remains controversial. Different laboratories have reported the multi-organ origin of C-reactive protein. The atherosclerotic lesion itself is another place where C-reactive protein could be produced. Numerous studies have continued to dissect the potential diverse proatherogenic actions of C-reactive protein on cultured vascular cells. Caution must be exercised in inadequately controlled studies that have unwittingly used commercial C-reactive protein preparations contaminated by other bioactive components. In contrast to in-vitro experiments, in-vivo studies that support a proatherogenic role of C-reactive protein are less likely to be subject to misinterpretation. Evidence suggests that C-reactive protein is a proatherogenic molecule that plays an active role. The amount of C-reactive protein in lesions is determined by its plasma levels and its local production. The biological effect of C-reactive protein on atherosclerosis development seems to encompass a complex network of interactions with other players in immunity and inflammation, such as the complement system, as well as a direct effect of C-reactive protein on the cells involved in lesion growth and development.


Three-dimensional structures of acidic and basic fibroblast growth factors.
Members of the fibroblast growth factor (FGF) family of proteins stimulate the proliferation and differentiation of a variety of cell types through receptor-mediated pathways. The three-dimensional structures of two members of this family, bovine acidic FGF and human basic FGF, have been crystallographically determined. These structures contain 12 antiparallel beta strands organized into a folding pattern with approximate threefold internal symmetry. Topologically equivalent folds have been previously observed for soybean trypsin inhibitor and interleukins-1 beta and -1 alpha. The locations of sequences implicated in receptor and heparin binding by FGF are presented. These sites include beta-sheet strand 10, which is adjacent to the site of an extended sequence insertion in several oncogene proteins of the FGF family, and which shows sequence conservation among the FGF family and interleukin-1 beta.


Decrease of trace elements in erythrocytes and plasma after removal of dental amalgam and other metal alloys.
The objective of this study was to determine the concentration changes of 13 elements in erythrocytes and plasma after the removal of dental amalgam and other metal alloys. Blood samples from 250 patients were collected, separated into erythrocytes and plasma, and analyzed by inductively coupled plasma-mass spectrometry. The 250 patients were divided into 3 groups (Negative, Zero, and Positive) depending on their estimation of quality of life in an earlier study. Magnesium in plasma, selenium and mercury in plasma, and erythrocytes showed decreased concentrations after amalgam removal in all groups (p < 0.05). Titanium in plasma, copper in plasma, and erythrocytes and zinc in plasma exhibited decreased concentrations after amalgam removal in the Negative and Positive groups (p < 0.05). Silver in plasma and gold in erythrocytes decreased in the Zero and Positive groups after amalgam removal (p < 0.05). Copper in erythrocytes and silver and gold in plasma showed higher concentrations after amalgam removal in the Negative compared to the Positive group (p < 0.05), suggesting that patients in the Negative group excrete metals slowly. Moreover, the cobalt levels in plasma were lowest in the Negative group and only this group showed a significant increase in vitamin B12 levels in blood after amalgam removal.


Complete mitogenomes of two Puntius in Taiwan: P. semifasciolatus and P. snyderi (Cypriniformes: Cyprinidae).
We sequenced the complete mitochondrial genome of two spotted barbs native to Taiwan: Puntius semifasciolatus and Puntius snyderi. The complete mitochondrial genomes are 16,594 and 16,578 bp in size, respectively. Both of them contain 37 genes coding for 13 proteins, 2 rRNAs, 22 tRNAs, and 1 control region. They share the same gene arrangement pattern that was identical with most vertebrates. Nucleotide sequence divergence (K2P distance) between the two whole mitochondrial genomes was 7.63%. These two spotted barbs show very close relationship based on the comparison of the characters of their mitochondrial genomes.


Skin Perfusion Changes within 12 h after Axillary Plexus Block.
An improvement of the blood flow would be beneficial in microvascular upper-extremity reconstruction and in digit replantation. In the present work, skin perfusion changes and their duration due to axillary plexus block were quantified. The peripheral blood flow of the upper extremities in 20 patients undergoing trapeziectomy under axillary plexus block was analyzed. Laser Doppler spectrophotometry was used to measure perfusion factors over a 12-h period, with the contralateral hand acting as the control. Axillary plexus block produced a significant increase of peripheral oxygen saturation (117 ± 35% vs. control 93 ± 22%, p = 0.019), peripheral blood flow (220 ± 166% vs. 130 ± 77%, p = 0.037), and velocity (164 ± 58% vs. 117 ± 45%, p = 0.011). Axillary plexus block produces an improvement of peripheral tissue oxygen saturation of the upper extremities over the first 6 h after the inception of anesthesia. This suggests a potential benefit especially for critically perfused tissues.


[Liver regeneration after partial hepatectomy. Role of lipid mediators].
The paper contains current data on the different ways of the liver regeneration. There is still not enough data about control of the regeneration processes in the liver. However nuclear phosphatidylinositols and sphingomyelins have been shown to play a potent role of messengers signaling. The lipid messengers may be potent factors affecting process of liver regeneration after partial hepatectomy.


Trp86 --> Phe replacement in bacteriorhodopsin affects a water molecule near Asp85 and light adaptation.
Illumination of the Trp86 --> Phe mutant of bacteriorhodopsin causes anomalous light adaptation, i.e., isomerization of the retinal from all-trans to 13-cis, 15-syn. FTIR spectral analysis shows that illumination at 250 K yields two 13-cis photoproducts, the conventional 13-cis, 15-syn state, BR(C), and another termed BR(X). BR(X) is different from BR(C) because it has a lower N-H in-plane bending frequency and a higher C14-C15 stretching frequency, as well as an absence of coupling between these modes. BR(X), which is stable at 275 K, is more abundant in the photosteady state produced by longer wavelength light and detected as the only photoproduct at 170 K. Its different structural features result from distortion of the C14-C15 bond of the chromophore. In the W86F mutant protein, the small structural changes of a water molecule in the conversion between the all-trans and 13-cis, 15-syn forms and in the formation of the K photointermediate are absent, but the larger changes of water molecule(s) that normally occur in the L and M intermediates are present. We propose that Trp86, together with Asp85, is involved in binding the water molecule and in preventing the formation of the 13-cis, 15-syn photoproducts, BR(C) and BR(X), when the wild type protein is illuminated.


[Bone and muscular lesions in sarcoidosis].
Bone lesions are observed in 10 to 15 p. 100 of cases of sarcoidosis. They occur in women in 2 out of 3 cases; the age of onset is slightly later than that of the sarcoidosis; the lesions involve mainly the fingers and toes but any part of the skeleton may be affected. The lesions are nearly always lytic, sometimes associated with chronic cutaneous, ocular or nasal sarcoid lesions; progression is slow and improvement is usually observed with steroid therapy: mortality is higher in patients with sarcoidosis and bone lesions than when there are none. Muscle involvement is present in about 50 p. 100 of cases of sarcoidosis but is usually clinically latent. Symptoms are sometimes observed related either to intramuscular nodules or to pseudomyopathy . These clinical presentations may be the only clinical sign of sarcoidosis for some time. It is important to recognise the true underlying cause with the aid of histology as steroid treatment is effective.


A structured approach to the interpretation and reporting of ventilation/perfusion scans.
The aim of this study was to develop a structured approach to the reporting and in particular the clinical interpretation of ventilation/perfusion (V/Q) scan results. An initial audit indicated that there were significant variations in the clinical management of patients particularly after a non-diagnostic V/Q scan report. There were also differences in the approaches used to interpret the scan itself. In an attempt to improve this, a set of interpretation guidelines was produced based on the revised PIOPED data. To combat the problems with clinical interpretation, a standard method for assessing the pre-test clinical probability of pulmonary embolism was established. This clinical risk was then combined with the V/Q scan result to give an overall probability for the presence of pulmonary embolism. The more precise risk stratification which resulted allowed explicit clinical advice on patient management to be incorporated into the final report. A second audit was performed with the revised methodology in place. The level of inter-observer variability for scan reporting decreased from 30% to 12%. The prior assessment of clinical risk and the standardized method of combining this with the scan result led to an improvement in patient management. This was particularly true for the non-diagnostic group, in whom additional investigations were more appropriately used. A structured approach which allows the pre-test probability of pulmonary embolism to be combined in an explicit fashion with the V/Q scan result can provide a more precise risk stratification allowing appropriate recommendations to be made. Such an approach can result in improved patient management.


Hyperactivation of mTOR critically regulates abnormal osteoclastogenesis in neurofibromatosis Type 1.
Individuals with nerofibromatosis Type 1 (NF1) frequently suffer a spectrum of bone pathologies, such as abnormal skeletal development (scoliosis, congenital bowing, and congenital pseudoarthroses, etc), lower bone mineral density with increased fracture risk. These skeletal problems may result, in part, from abnormal osteoclastogenesis. Enhanced RAS/PI3K activity has been reported to contribute to abnormal osteoclastogenesis in Nf1 heterozygous (Nf1+/-) mice. However, the specific downstream pathways linked to NF1 abnormal osteoclastogenesis have not been defined. Our aim was to determine whether mammalian target of rapamycin (mTOR) was a key effector responsible for abnormal osteoclastogenesis in NF1. Primary osteoclast-like cells (OCLs) were cultured from Nf1 wild-type (Nf1+/+) and Nf1+/- mice. Compared to Nf1+/+ controls, there were 20% more OCLs induced from Nf1+/- mice. Nf1+/- OCLs were larger and contained more nuclei. Hyperactive mTOR signaling was detected in Nf1+/- OCLs. Inhibition of mTOR signaling by rapamycin in Nf1+/- OCLs abrogated abnormalities in cellular size and number. Moreover, we found that hyperactive mTOR signaling induced abnormal osteoclastogenesis major through hyper-proliferation. Our research suggests that neurofibromin directly regulates osteoclastogenesis through mTOR signaling pathway. Inhibiting mTOR may represent a viable strategy to treat NF1 bone diseases.


The horizontal computerized rotational impulse test.
Whole-body impulsive rotations were used to overcome several limitations associated with manual head impulse testing. A computer-controlled rotational chair delivered brief, whole-body, earth-vertical axis yaw impulsive rotations while eye movements were measured using video-oculography. Results from an unselected group of 20 patients with dizziness and a group of 22 control subjects indicated that the horizontal computerized rotational head impulse test (crHIT) is well-tolerated and provides an estimate of unidirectional vestibulo-ocular reflex gain comparable to results from caloric testing. This study demonstrates that the horizontal crHIT is a new assessment tool that overcomes many of the limitations of manual head impulse testing and provides a reliable laboratory-based measure of unilateral horizontal semicircular canal function.


A ratiometric fluorescent probe for hydrophobic proteins in aqueous solution based on aggregation-induced emission.
A novel fluorescent probe 1 is reported here with ratiometric response to hydrophobic proteins (casein) or proteins with hydrophobic pockets (BSA, HSA) through hydrophobic interaction. Probe 1 underwent deprotonation in aqueous solution at pH 7.4 and emitted blue fluorescence at 436 nm. Upon the addition of BSA, HSA or casein, the aggregation-induced emission fluorescence of 1 at 518 nm was turned on. The fluorescence intensity ratio, I518/I436 was linearly related to the concentrations of these proteins. The detection limits for BSA, HSA and casein based on IUPAC (CDL = 3Sb m(-1)) were 16.2 μg mL(-1), 10.5 μg mL(-1) and 5.7 μg mL(-1), respectively.


Effects of vanadate on organic ion accumulation in rat renal cortical slices.
Sodium vanadate is a potent inhibitor of Na-K-adenosine triphosphatase. p-Aminohippurate (PAH) and tetraethylammonium accumulation in rat renal cortical slices was inhibited by vanadate in a dose-dependent manner at medium vanadate concentrations from 10(-6) to 10(-3) M. Inhibition was reversible at vanadate concentrations less than 1.5 x 10(-5) M. The slice content of vanadium (7.5-325 micrometer V/g wt. of tissue) was linearly related to medium vanadate concentrations ranging from 10(-5) to 10(-3) M. The ability of slices to generate glucose and ammonia was not impaired by medium vanadate concentrations up to 5 x 10(-4) M, a concentration that maximally inhibited organic ion accumulation. Increasing medium K+ concentrations potentiated vanadate inhibition of PAH accumulation which correlated with inhibition of sodium pump activity, as determined by 42K+ uptake. Intraperitoneal administration of vanadate (1 or 5 mg V/kg) to rats produced a profound diuresis and natriuresis during the 1st hr. Inhibition of PAH accumulation of renal slices from these rats was related to tissue vanadium concentrations. These data suggest that vanadate exerts its action on proximal tubule transport of PAH via inhibition of Na-K-adenosine triphosphatase.


Effect of Titanium Dioxide Nanoparticles on Surfactants and Their Impact on the Interfacial Properties of the Oil-Water-Rock System.
The application of nanoparticles (NPs) in the oil and gas industry has received wide attention in recent years because it is increasingly being considered a promising approach to recovering trapped oil in conventional hydrocarbon reservoirs. Numerous studies have demonstrated that combining nanoparticles with a surfactant can enhance surfactant performance by changing the interfacial properties of the solution when it comes in contact with crude oil and rock surfaces. However, more information and additional experimental data are required concerning the application of titanium dioxide nanoparticles in alkyl ethoxy carboxylic surfactants. In this study, we measure the changes in interfacial tension and wettability due to the addition of titanium dioxide nanoparticles (0, 100, 250, and 500 ppm) in alkyl ethoxy carboxylic surfactant using a spinning drop tensiometer and contact angle measurements. The interfacial tension of the crude oil-water (surfactant) system decreases by approximately two orders of magnitude with an increasing titanium dioxide concentration, exhibiting a minimum value of 5.85 × 10-5 mN/m. Similarly, the contact angle decreases on the surface of the Berea sandstone by combining the surfactant with titanium dioxide, reaching a minimum contact angle of 8.8°. These results demonstrate the potential of this new approach to maximize the recovery of trapped oil and significantly improve oil production.


Numerical simulations of bijel morphology in thin films with complete surface wetting.
Bijels are a relatively new class of soft materials that have many potential energy and environmental applications. In this work, simulation results of bijel evolution confined within thin films with preferential surface wetting are presented. The computational approach used is a hybrid Cahn-Hilliard/Brownian dynamics method. In the absence of suspended particles, we demonstrate that the model accurately captures the rich kinetics associated with diffusion-based surface-directed spinodal decomposition, as evidenced by comparison with previous theoretical and simulation-based studies. When chemically neutral particles are included in the films, the simulations capture surface-modified bijel formation, with stabilized domain structures comparable with the experimental observations of Composto and coworkers. Namely, two basic morphologies - bicontinuous or discrete - are seen to emerge, with direct dependence on the film thickness, particle volume fraction, and particle radius.


Deep-vein thrombosis in the elderly.
Venous thromboembolism, including deep-vein thrombosis and pulmonary embolism, is a major source of morbidity and mortality among elderly patients. To improve our understanding of elderly patients with deep-vein thrombosis, we compared 1932 patients with deep-vein thrombosis aged 70 years or older with 2554 nonelderly patients in a prospective registry of consecutive ultrasound-confirmed deep-vein thrombosis patients. The mean age of elderly patients was 78.9 +/- 6.1 years compared with 51.8 +/- 12.9 years in nonelderly (P < .0001). Elderly patients were more likely to have prior recent hospitalization (49.2% vs 44.7%, P = .03), congestive heart failure (20.5% vs 9.9%, P < .0001), chronic obstructive pulmonary disease (18.2% vs 11.7%, P < .0001), and recent immobilization (50.5% vs 39.6%, P < .0001) than the nonelderly patients. Elderly patients were less likely to present with typical deep-vein thrombosis symptoms of extremity discomfort (44.4% vs 60.6%, P < .0001) and difficulty ambulating (8.4% vs 11.2%, P = .002). Only 41% of elderly patients subsequently diagnosed with deep-vein thrombosis had received any venous thromboembolism prophylaxis. In conclusion, elderly patients with deep-vein thrombosis represent a particularly vulnerable population with numerous comorbid conditions. Diagnosis can present a challenge because typical deep-vein thrombosis symptoms may be absent. Fewer than 50% of elderly patients with deep-vein thrombosis had received any venous thromboembolism prophylaxis.


Defining the structure of undergraduate medical leadership and management teaching and assessment in the UK.
Medical leadership and management (MLM) skills are essential in preventing failings of healthcare; it is unknown how these attitudes can be developed during undergraduate medical education. This paper aims to quantify interest in MLM and recommends preferred methods of teaching and assessment at UK medical schools. Two questionnaires were developed, one sent to all UK medical school faculties, to assess executed and planned curriculum changes, and the other sent to medical students nationally to assess their preferences for teaching and assessment. Forty-eight percent of UK medical schools and 260 individual student responses were recorded. Student responses represented 60% of UK medical schools. 65% of schools valued or highly valued the importance of teaching MLM topics, compared with 93.2% of students. Students' favoured teaching methods were seminars or lectures (89.4%) and audit and quality improvement (QI) projects (77.8%). Medical schools preferred portfolio entries (55%) and presentations (35%) as assessment methods, whilst simulation exercises (76%) and audit reports (61%) were preferred by students. Preferred methods encompass experiential learning or simulation and a greater emphasis should be placed on encouraging student audit and QI projects. The curriculum changes necessary could be achieved via further integration into future editions of Tomorrow's Doctors.


Sex differences in the human brain's response to hunger and satiation.
Sex differences in eating behavior are well documented, but it is not known whether these differences have neuroanatomical correlates. Recent neuroimaging studies have provided functional maps of the human cerebral areas activated in response to hunger and satiation. The objective of this study was to assess whether the brain's response to a meal is sex-specific. Using positron emission tomography, we measured regional cerebral blood flow, a marker of neuronal activity, to investigate the functional neuroanatomy of hunger (36-h fast) and satiation (in response to a liquid meal) in 22 women and 22 men. We observed extensive similarities, as well as some differences, between the sexes. In response to hunger, the men tended to have greater activation in the frontotemporal and paralimbic areas than did the women (P < 0.005). In response to satiation, the women tended to have greater activation in the occipital and parietal sensory association areas and in the dorsolateral prefrontal cortex than did the men (P < 0.005); in contrast, the men tended to have greater activation in the ventromedial prefrontal cortex than did the women (P < 0.005). Despite extensive similarities in the brain responses to hunger and satiation between the men and women, our study showed sex-specific brain responses to a meal that indicate possible differences between men and women in the cognitive and emotional processing of hunger and satiation. This study provides a foundation for investigating the brain regions and cognitive processes that distinguish normal and abnormal eating behavior in men and women.


ADP-heptose: a bacterial PAMP detected by the host sensor ALPK1.
The innate immune response constitutes the first line of defense against pathogens. It involves the recognition of pathogen-associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs), the production of inflammatory cytokines and the recruitment of immune cells to infection sites. Recently, ADP-heptose, a soluble intermediate of the lipopolysaccharide biosynthetic pathway in Gram-negative bacteria, has been identified by several research groups as a PAMP. Here, we recapitulate the evidence that led to this identification and discuss the controversy over the immunogenic properties of heptose 1,7-bisphosphate (HBP), another bacterial heptose previously defined as an activator of innate immunity. Then, we describe the mechanism of ADP-heptose sensing by alpha-protein kinase 1 (ALPK1) and its downstream signaling pathway that involves the proteins TIFA and TRAF6 and induces the activation of NF-κB and the secretion of inflammatory cytokines. Finally, we discuss possible delivery mechanisms of ADP-heptose in cells during infection, and propose new lines of thinking to further explore the roles of the ADP-heptose/ALPK1/TIFA axis in infections and its potential implication in the control of intestinal homeostasis.


Primary hyperaldosteronism.
To characterize the syndrome of primary aldosteronism and summarize diagnostic and therapeutic strategies. We review the mechanisms of action of aldosterone and outline features that distinguish the major subtypes of aldosteronism. The state of aldosterone excess should be suspected in every patient manifesting hypertension and hypokalemia. The documentation of low renin activity and high plasma aldosterone concentration in such patients suggests the presence of primary aldosteronism. Lack of appropriate suppression of plasma aldosterone after saline infusion is thought to be the best maneuver for confirming primary aldosteronism. Nonetheless, a similar lack of aldosterone suppressibility after either oral salt loading for 3 days or oral administration of a single 25-mg dose of captopril may help achieve the same purpose. Once primary aldosteronism has been diagnosed, the distinction between two major subtypes--unilateral adrenal adenoma or Conn's syndrome and bilateral idiopathic adrenal hyperplasia--is important because of the difference in management. Certain physiologic maneuvers, such as change of posture from supine to upright, oral administration of cyproheptadine, and radiologic localization with several techniques including iodocholesterol scanning and adrenal venous sampling, will almost always help distinguish unilateral adenoma from bilateral hyperplasia. The distinction between adrenal adenoma and adrenal hyperplasia is critical because of the varied approach to treatment. Most patients with bilateral adrenal hyperplasia are managed medically with an aldosterone antagonist such as spironolactone, whereas most unilateral adenomas are resected after correction of hypertension and hypokalemia with appropriate medical therapy.


[Effect of perocin (zineb) on the quality of ovine seminal fluid].
The fungicide perocin , an analogue of the preparation Zineb ( ditiocarbamate ) was applied orally with the feed to 11 rams divided into two test groups of three animals each and one control group of five rams. The preparation was administered at the rate of 1/50 and 1/100 of DL50 per kg body mass to the first and second test group, respectively, in the course of 4 months. During both the preparatory and the experimental period semen was sampled twice a week with the use of an artificial vagina, and investigations were carried out to evaluate the qualitative properties of the semen, the level of Na ions, the redoxi -potential and the activity of the alkaline phosphatase (APh). Apparently, the preparation triggered a trend toward increasing the number of pathologic spermatozoa (20-30 per cent) and decreasing to a lower extent the concentration of the sodium ions and the values of the redoxi -potential. The motility of spermatozoa was lowered by 4.3 per cent for the animals that were treated with 1/50 DL50 per kg body mass, and by 2.1 per cent for those that were offered 1/100 DL50 per kg body mass. There were certain differences between the values obtained although these were statistically insignificant so far as the alkaline phosphatase was concerned. They pointed to the fact that perocin contributed to the increase in the value relationships of some of the forms of this enzyme. The same applied also to the APh1 which is believed to have certain bearing upon preserving the activity of spermatozoa.


Immunomodulatory Device Promotes a Shift of Circulating Monocytes to a Less Inflammatory Phenotype in Chronic Hemodialysis Patients.
Patients with end-stage renal disease (ESRD) on chronic hemodialysis (HD) suffer accelerated morbidity and mortality rates caused by cardiovascular disease and infections. Chronic inflammation plays a critical role in these poor outcomes. The activated monocyte (MO) has become a prime therapeutic target to modulate this inflammatory process. A selective cytopheretic device (SCD) was evaluated to assess its effects on the circulating MO pool. A pilot trial was undertaken in 15 ESRD patients on HD with C-reactive protein (CRP) levels greater than 5 mg/dl. An excellent safety profile was observed with no decline in leukocyte (LE) or platelet counts. The effect of SCD therapy on MO phenotypes in these patients was determined on peripheral blood MO utilizing flow cytometry. SCD therapy promoted a shift in MO phenotype from predominantly CD14 expressing MO at baseline/pre-SCD therapy to CD14 expressing MO post-SCD therapy. A significant shift in MO population phenotype afforded by a single SCD therapy session was observed (p < 0.013). In a subset of patients (n = 7) presenting with type 2 diabetes mellitus (T2D), this persistent decline in MO CD14 expression was sustained as long as 2 weeks posttherapy. These results demonstrate that the SCD therapy has the potential to modulate the chronic proinflammatory state in ESRD patients.


Mycobacterium avium subsp. paratuberculosis inhibits gamma interferon-induced signaling in bovine monocytes: insights into the cellular mechanisms of Johne's disease.
Mycobacterium avium subsp. paratuberculosis is the causative agent of Johne's disease in cattle and may have implications for human health. Establishment of chronic infection by M. avium subsp. paratuberculosis depends on its subversion of host immune responses. This includes blocking the ability of infected macrophages to be activated by gamma interferon (IFN-γ) for clearance of this intracellular pathogen. To define the mechanism by which M. avium subsp. paratuberculosis subverts this critical host cell function, patterns of signal transduction to IFN-γ stimulation of uninfected and M. avium subsp. paratuberculosis-infected bovine monocytes were determined through bovine-specific peptide arrays for kinome analysis. Pathway analysis of the kinome data indicated activation of the JAK-STAT pathway, a hallmark of IFN-γ signaling, in uninfected monocytes. In contrast, IFN-γ stimulation of M. avium subsp. paratuberculosis-infected monocytes failed to induce patterns of peptide phosphorylation consistent with JAK-STAT activation. The inability of IFN-γ to induce differential phosphorylation of peptides corresponding to early JAK-STAT intermediates in infected monocytes indicates that M. avium subsp. paratuberculosis blocks responsiveness at, or near, the IFN-γ receptor. Consistent with this hypothesis, increased expression of negative regulators of the IFN-γ receptors SOCS1 and SOCS3 as well as decreased expression of IFN-γ receptor chains 1 and 2 is observed in M. avium subsp. paratuberculosis-infected monocytes. These patterns of expression are functionally consistent with the kinome data and offer a mechanistic explanation for this critical M. avium subsp. paratuberculosis behavior. Understanding this mechanism may contribute to the rational design of more effective vaccines and/or therapeutics for Johne's disease.


Peritoneal carcinosis of ovarian origin.
Epithelial ovarian cancer (EOC) is the second most common genital malignancy in women and is the most lethal gynecological malignancy, with an estimated five-year survival rate of 39%. Despite efforts to develop an effective ovarian cancer screening method, 60% of patients still present with advanced disease. Comprehensive management using surgical cytoreduction to decrease the tumor load to a minimum, and intraperitoneal chemotherapy to eliminate microscopic disease on peritoneal surface, has the potential to greatly improve quality of life and to have an impact on survival in ovarian cancer patients. Despite achieving clinical remission after completion of initial treatment, most patients (60%) with advanced EOC will ultimately develop recurrent disease or show drug resistance; the eventual rate of curability is less than 30%. Given the poor outcome of women with advanced EOC, it is imperative to continue to explore novel therapies.


Electroencephalographic order pattern analysis for the separation of consciousness and unconsciousness: an analysis of approximate entropy, permutation entropy, recurrence rate, and phase coupling of order recurrence plots.
Nonlinear electroencephalographic parameters, e.g., approximate entropy, have been suggested as measures of the hypnotic component of anesthesia. Compared with linear methods, they may detect additional information and quantify the irregularity of a dynamical system. High dimensionality of a signal and disturbances may affect these parameters and change their ability to distinguish consciousness from unconsciousness. Methods of order pattern analysis, in this investigation represented by permutation entropy, recurrence rate, and phase coupling of order recurrence plots, are suitable for any type of time series, whether deterministic or noisy. They may provide a better estimation of the hypnotic component of anesthesia than other nonlinear parameters. The current analysis is based on electroencephalographic data from two similar clinical studies in adult patients undergoing general anesthesia with sevoflurane or propofol. The study period was from induction until patients followed command after surgery, including a reduction of the hypnotic agent after tracheal intubation until patients followed command. Prediction probability was calculated to assess the parameter's ability to separate consciousness from unconsciousness at the transition between both states. Parameters of order pattern analysis provide a prediction probability of maximal 0.85 (training study) and 0.78 (evaluation study) with frequencies from 0 to 30 Hz, and maximal 0.87 (training study) and 0.83 (evaluation study) including frequencies up to 70 Hz, both higher than 0.77 (approximate entropy). Parameters of the nonlinear method order pattern analysis separate consciousness from unconsciousness and are grossly independent of high-frequency components of the electroencephalogram.


Beyond Geography: Social Quality Environments and Health.
The concept of social quality has garnered increasing attention as a composite indicator of the well-being of societies as well as individuals embedded within them. Prior research suggests four domains of social quality: socio-economic security, social cohesion, social inclusion, and social empowerment, based on the assumption that these domains influence health and well-being. In this paper, we investigate whether and to what extent social quality environments defined with reference to the cross-cutting social quality domains reliably predict various types of health, using data collected in a municipality in Switzerland as part of a participatory action research project. We found that social inclusion had the highest predictive power for mental health and functional health, while economic security had the highest predictive power for physical capacity and overall self-rated health. Results indicate interaction among various domains of social quality for a subset of health measures. Findings suggest that environments defined as combinations of social quality domains effectively distinguish between population segments with varying levels of health. Social quality represents a promising avenue for policy and intervention development, particularly from the social determinants of health perspective, as it jointly captures the multiple domains of social well-being relevant to population health. The online version contains supplementary material available at 10.1007/s11205-023-03073-1.


Immunomodulation of polyamine biosynthesis in tobacco plants has a significant impact on polyamine levels and generates a dwarf phenotype.
Ornithine decarboxylase (ODC) is a cytosolic enzyme that catalyses the direct decarboxylation of l-ornithine to putrescine, one of the rate-limiting steps of polyamine biosynthesis in plants. In the present study, an ODC-specific murine single-chain antibody fragment (scFvODC1) was generated by phage display technology. To evaluate the effect of the recombinant antibody fragment on ODC activity and polyamine levels, we produced transgenic tobacco plants that accumulated scFvODC1 in the cytosol. Expression levels of up to 4% total soluble protein (TSP) were achieved, resulting in the inhibition of up to 90% of endogenous ODC activity. A significant reduction in putrescine, spermidine and spermine levels was observed in transgenic lines producing high levels of scFvODC1. Furthermore, these lines showed developmental abnormalities and a dwarf phenotype. We show that the immunomodulation of enzyme activity is a powerful approach that can be used to alter complex and tightly controlled metabolic pathways, allowing specific steps in the pathway to be blocked and the resulting physiological effects to be investigated.


Improving the reversibility of thermal denaturation and catalytic efficiency of Bacillus licheniformis α-amylase through stabilizing a long loop in domain B.
The reversibility of thermal denaturation and catalytic efficiency of Bacillus licheniformis α-amylase were improved through site-directed mutagenesis. By using multiple sequence alignment and PoPMuSiC algorithm, Ser187 and Asn188, which located within a long loop in Domain B of Bacillus licheniformis α-amylase, were selected for mutation. In addition, Ala269, which is adjacent to Ser187 and Asn188, was also investigated. Seven mutants carrying the mutations S187D, N188T, N188S, A269K, A269K/S187D, S187D/N188T, and A269K/S187D/N188T were generated and characterized. The most thermostable mutant, A269K/S187D/N188T, exhibited a 9-fold improvement in half-life at 95°C and pH 5.5, compared with that of the wild-type enzyme. Mutant A269K/S187D/N188T also exhibited improved catalytic efficiency. The catalytic efficiency of mutant A269K/S187D/N188T reached 5.87×103±0.17 g·L-1·s-1 at pH 5.5, which is 1.84-fold larger than the corresponding value determined for the wild-type enzyme. Furthermore, the structure analysis showed that immobilization of the loop containing Ser187 and Asn188 plays a significant role in developing the properties of Bacillus licheniformis α-amylase.


Evidence-based medicine in managed care: a survey of current and emerging strategies.
Evidence-based medicine is the "conscientious application of scientific best practice by clinicians in concert with patient understanding and values." Recent studies by the Institute of Medicine, RAND, and others have called attention to the gap between scientifically supported approaches to care and day-to-day practice by clinicians. Compounding the problem of non-adherence by providers, researchers have observed that patient compliance also falls short. As a result, avoidable costs from inappropriate variability in practice patterns coupled with patient noncompliance are a significant focus of managed care. Managed care plans play a key role in the selection of providers by consumers and in the design of benefits programs by employers. Avoidable costs from misuse, overuse, and under-use of care from clinicians is a strategic focus for health plans. The evidence upon which a plan makes coverage decisions and the incorporation of evidence in programs targeting providers, employers, and consumers was a focus of this study. A Delphi survey and 2-day interactive sessions with 128 clinical program directors and medical officers from 89 health plans were the primary methods used in this descriptive analysis. To test participant applications of evidence-based medicine in health plan medical management strategy, 3 conditions were used for illustrative purpose: managing rheumatoid arthritis, increasing remission in depression, and reducing heart disease among diabetics. Each provided a unique challenge to plans in terms of condition prevalence, strength of evidence, and cost. Health plans incorporate evidence-based medicine in 5 areas overseen by medical management: (1) coverage decisions wherein improvements in pharmaceutical and therapeutic review processes are sought, (2) disease management efforts wherein increased attention to secondary prevention is desirable, (3) provider profiling wherein increased use of adherence measures comparing practices is a focus, (4) pay-for-performance programs linking physician adherence to financial incentives, and (5) consumer-directed care programs wherein patient compliance to evidence-based treatment directives is the focus. Factors that influence a plan's approach to a patient population include prevalence of the condition, the strength of evidence about a particular diagnostic or prognostic strategy, costs associated with the condition, and the influence of employers in coverage decisions. Evidence-based medicine is the foundation for significant activity among plans to increase physician and patient adherence. There remain significant challenges in the implementation of evidence-based care management by plans, including the willingness of plans to agree on evidence-based guidelines, the willingness of employers to pay for evidence-based interventions, the balance of short- and long-term benefits for evidence-based interventions where secondary prevention is a consideration, and substantial distrust among providers.


Endoluminal intragastric treatment of gastric carcinoma.
Early gastric cancer accounts for more than 50% of resected gastric cancer cases in Japan. Because of the increased incidence of early gastric cancer, endoluminal minimally invasive intragastric treatments have been developed. The rate of lymph node metastasis is very low in early gastric cancer, especially in mucosal cancer. There are two popular strategies in Japan for the management of patients with mucosal cancer: endoscopic mucosal resection (EMR) and intragastric mucosal resection (IGMR). EMR is more popular: from 1993 to 1997, over 35,000 cases of early gastric cancer have been treated by EMR in Japan. IGMR was developed in 1993, and 256 cases of early gastric cancer, which were not appropriate for EMR because of size and location, have been treated successfully by IGMR. These data suggest that in Japan 20%-30% of patients with early gastric cancer are treated by endoluminal intragastric procedures. In this paper we review the indications for, techniques pertaining to, and outcomes of EMR and IGMR in Japan.


Trypanosoma brucei: the dynamics of calcium movement between the cytosol, nucleus, and mitochondrion of intact cells.
Targeted aequorins (CYT-AEQ, NUC-AEQ, and MT-AEQ) were used to measure Ca2+ concentrations within organelles of live trypanosomes. We determined that the nuclear envelope is a slight barrier to the free diffusion of Ca2+. This situation was especially evident when Ca2+ influx across the plasma membrane was stimulated with 200 nM melittin ([Ca2+]cyt = 1.2 +/- 0.4 microM and [Ca2+]nuc = 0.85 +/- 0.15 microM). By contrast, the ionophores nigericin (2.7 microM) or monensin (2 microg/ml) were used to induce Ca2+ efflux from the acidic storage compartment. Small transient elevations in [Ca2+]cyt were observed (peaking at 660 +/- 200 and 580 +/- 120 nM, respectively). Parallel and equivalent changes in [Ca2+1]nuc were recorded. Active accumulation of Ca2+ into the nucleus was not observed. Nigericin or monensin did not disrupt mitochondrial Ca2+ transport in vivo. Instead, the mitochondrion actively sequestered large quantities of Ca2+ in the presence of these ionophores, with peak values of 2.7 +/- 1.4 and 4.4 +/- 1.1 microM, respectively. Overall, these data demonstrate that significant quantities of Ca2+ enter the nucleus following influx across the plasma membrane or following efflux from an intracellular acidic storage compartment. However, the magnitude of change for [Ca2+]cyt and [Ca2+]nuc is small compared to the total amount of exchangeable Ca2+ since the majority of released Ca2+ is actively sequestered by the mitochondrion.


Effects of Parental Attitudes Toward Spousal Violence on Early Childhood Development and Learning Support Among Ghanaian Children.
The prevalence of condoning attitudes toward spousal violence (SV) is high in Ghana, yet much is not known about how the development of children is compromised in households where attitudes toward SV are tolerated. This study is premised on two objectives: (a) examination of the effect of parents condoning attitudes toward SV on early childhood development; and (b) investigation of the effect of parents condoning attitudes toward SV on the amount of learning support children receive from household members. Data on 2,740 children aged between 36 and 59 months were drawn from the 2011 Ghana Multiple Indicator Cluster Survey for the first objective and 1,595 households with children aged between 4 and 15 years were sourced from the 2014 Ghana Demographic and Health Survey for the second. Analytical methods employed are descriptive statistics, instrumental variable (IV), and ordinary least squares (OLS) micro-econometric estimation techniques. The findings suggest that parents who condone attitudes toward SV reduce early childhood development by 3.269 units. Compared with the physical and socioemotional domains, parents tolerating attitudes toward SV have the highest adverse effect on the literacy, numeracy, and learning development domain of early childhood development (2.916 units). In addition, households that accept attitudes toward SV reduce the amount of learning support offered to children by 0.261 units, and every additional attitude toward SV acceptance reduces child learning support by 0.079 units. Attitudes of parents toward condoning SV retard the early development of children, impair children's cognitive development, and compromise the amount of learning support children receive from household members. This study reinforces the evidence that parental attitudes are related to child outcomes in Ghana. The evidence calls for strengthening healthy family environments and child protection systems through behavioral change communication interventions and awareness creation among parents.


Nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure for preterm infants with respiratory distress syndrome: a meta-analysis and up-date.
To evaluate whether nasal intermittent positive pressure ventilation (NIPPV) would decrease the requirement for endotracheal ventilation compared with nasal continuous positive airway pressure(NCPAP) for preterm infants with respiratory distress syndrome (RDS) and compare the related complications between these two noninvasive variations of respiratory support A search of major electronic databases, including Medline (1980-2013) and the Cochrane Central Register of Controlled Trials, for randomized controlled trials that compared NIPPV versus NCPAP for preterm infants with RDS was performed. Six randomized controlled trials met selection criteria (n = 1,527). The meta-analyses demonstrated significant decrease in the need for invasive ventilation in the NIPPV group (RR:0.53; 95% CI, 0.33-0.85). In the subgroup of infants who received surfactant also demonstrated a significant rate of failure of nasal support in the NIPPV group (RR:0.57; 95% CI 0.42-0.78). However, the subgroup of infants whose gestational age (GA) ≤ 30 weeks or birth weight (BW) < 1,500 g showed no difference between the two groups (RR:0.59; 95% CI 0.27-1.26); and the subgroup of infants whose GA > 30 weeks or BW > 1,500 g also showed no difference between the two groups (RR:0.63; 95% CI 0.29-1.39). No differences in other outcome variables were observed between the two groups. Among preterm infants with RDS, there was a significant decrease in the need for invasive ventilation in the NIPPV group as compared with NCPAP group, especially for the infants who received surfactant. However, NIPPV could not decrease the need for invasive ventilation both in the subgroup of infants whose GA ≤ 30 weeks or BW < 1,500 g and the subgroup of infants with BW of >30 weeks or BW > 1,500 g. It is limited to analysis the primary outcome generally. Larger trials of this intervention are needed to assess the difference in this primary outcome and the related complications between both forms of noninvasive respiratory support.


Systematic versus on-demand early palliative care: results from a multicentre, randomised clinical trial.
Early palliative care (EPC) in oncology has been shown to have a positive impact on clinical outcome, quality-of-care outcomes, and costs. However, the optimal way for activating EPC has yet to be defined. This prospective, multicentre, randomised study was conducted on 207 outpatients with metastatic or locally advanced inoperable pancreatic cancer. Patients were randomised to receive 'standard cancer care plus on-demand EPC' (n = 100) or 'standard cancer care plus systematic EPC' (n = 107). Primary outcome was change in quality of life (QoL) evaluated through the Functional Assessment of Cancer Therapy - Hepatobiliary questionnaire between baseline (T0) and after 12 weeks (T1), in particular the integration of physical, functional, and Hepatic Cancer Subscale (HCS) combined in the Trial Outcome Index (TOI). Patient mood, survival, relatives' satisfaction with care, and indicators of aggressiveness of care were also evaluated. The mean changes in TOI score and HCS score between T0 and T1 were -4.47 and -0.63, with a difference between groups of 3.83 (95% confidence interval [CI] 0.10-7.57) (p = 0.041), and -2.23 and 0.28 (difference between groups of 2.51, 95% CI 0.40-4.61, p = 0.013), in favour of interventional group. QoL scores at T1 of TOI scale and HCS were 84.4 versus 78.1 (p = 0.022) and 52.0 versus 48.2 (p = 0.008), respectively, for interventional and standard arm. Until February 2016, 143 (76.9%) of the 186 evaluable patients had died. There was no difference in overall survival between treatment arms. Systematic EPC in advanced pancreatic cancer patients significantly improved QoL with respect to on-demand EPC.


HpaR, the Repressor of Aromatic Compound Metabolism, Positively Regulates the Expression of T6SS4 to Resist Oxidative Stress in Yersinia pseudotuberculosis.
HpaR, a MarR family transcriptional regulator, was first identified in Escherichia coli W for its regulation of the hpa-meta operon. Little else is known regarding its functionality. Here, we report that in Yersinia pseudotuberculosis, HpaR negatively regulates the hpa-meta operon similar to in E. coli W. To investigate additional functions of HpaR, RNA sequencing was performed for both the wild-type and the ΔhpaR mutant, which revealed that the type VI secretion system (T6SS) was positively regulated by HpaR. T6SS4 is important for bacteria resisting environmental stress, especially oxidative stress. We demonstrate that HpaR facilitates bacteria resist oxidative stress by upregulating the expression of T6SS4 in Y. pseudotuberculosis. HpaR is also involved in biofilm formation, antibiotic resistance, adhesion to eukaryotic cells, and virulence in mice. These results greatly expand our knowledge of the functionality of HpaR and reveal a new pathway that regulates T6SS4.


Severe fatty change of the graft liver caused by a portosystemic shunt of mesenteric varices.
Portosystemic shunt is a common complication in patients with portal hypertension. Mesenteric varix is one of the collaterals that can cause post-transplant liver dysfunction. In this case report, a 45-year-old woman underwent living relative donor liver transplantation for alcoholic cirrhosis. Although the early postoperative course was uneventful, she was readmitted for treatment of liver hypofunction. Fatty change in the graft liver was confirmed by histopathology of the biopsy specimen. The venous phase of a superior mesenteric angiogram revealed large-caliber mesenteric varices comprising portosystemic venous shunts. Surgery was performed to ligate the shunts. The intraoperative color Doppler ultrasonography showed hepatofugal portal blood flow, which was corrected to hepatopetal blood flow by clamping the shunt vessels. The portal pressure was moderately elevated from 13.6 cm to 21.8 cm H(2)O. Two shunt vessels were ligated and divided. Her liver function returned to nearly normal thereafter. We recommend that descending collaterals be divided during liver transplantation.


Pretreatment sonographic evaluation of inguinal lymph nodes in patients with vulvar malignancy.
The state of the inguinal nodes is a major prognostic factor in vulvar carcinoma. Because of new surgical trends with selective inguinal lymphadenectomy, the preoperative evaluation of inguinal lymph nodes is essential for adequate treatment of vulvar carcinoma. To evaluate the adequacy of clinical examination and high-frequency transducer sonography in detecting metastatic inguinal lymph nodes, we studied 25 patients with vulvar malignancy who underwent operation. Histopathologically proved lymph node metastases were found in 11 (22%) of 50 inguinal areas studied. All of the suspected metastases were in patients with stage III-IV disease. The inguinal lymph node metastases were found by sonography in nine (82%), by preoperative palpation in one (9%), and by operative palpation in six (55%) of 11 areas. The difference between sonography and palpation was statistically significant (P < 0.01). The sensitivity and specificity were 82% and 87% for sonography, 9% and 100% for preoperative palpation, and 55% and 90% for operative palpation.


Use of social information in seabirds: compass rafts indicate the heading of food patches.
Ward and Zahavi suggested in 1973 that colonies could serve as information centres, through a transfer of information on the location of food resources between unrelated individuals (Information Centre Hypothesis). Using GPS tracking and observations on group movements, we studied the search strategy and information transfer in two of the most colonial seabirds, Guanay cormorants (Phalacrocorax bougainvillii) and Peruvian boobies (Sula variegata). Both species breed together and feed on the same prey. They do return to the same feeding zone from one trip to the next indicating high unpredictability in the location of food resources. We found that the Guanay cormorants use social information to select their bearing when departing the colony. They form a raft at the sea surface whose position is continuously adjusted to the bearing of the largest returning columns of cormorants. As such, the raft serves as a compass signal that gives an indication on the location of the food patches. Conversely, Peruvian boobies rely mainly on personal information based on memory to take heading at departure. They search for food patches solitarily or in small groups through network foraging by detecting the white plumage of congeners visible at long distance. Our results show that information transfer does occur and we propose a new mechanism of information transfer based on the use of rafts off colonies. The use of rafts for information transfer may be common in central place foraging colonial seabirds that exploit short lasting and/or unpredictably distributed food patches. Over the past decades Guanay cormorants have declined ten times whereas Peruvian boobies have remained relatively stable. We suggest that the decline of the cormorants could be related to reduced social information opportunities and that social behaviour and search strategies have the potential to play an important role in the population dynamics of colonial animals.


Feasibility of Submandibular Gland Preservation in cT1-2N0 Squamous Cell Carcinoma in the Floor of the Mouth.
Purpose: Our goal was to analyze the feasibility of submandibular gland (SMG) preservation in cT1-2N0 floor of the mouth (FOM) squamous cell carcinoma (SCC) patients. Methods: Patients with cT1-2N0 FOM SCC were retrospectively enrolled and divided into two groups according to the management of the SMG. Level 1b tissues were divided into six groups according to their location with respect to the SMG. The Kaplan-Meier method was used to calculate the locoregional control (LRC) and disease-specific survival (DSS) rates. A Cox model was used to determine the independent risk factors. Results: Twenty-nine patients underwent SMG-preserving neck dissection, and lymph node metastasis occurred in the superior group in 3 of the 37 dissections with a prevalence of 8.1% and in the anterior group in 2 of the 37 dissections with a prevalence of 5.4%. In patients without SMG preservation, lymph node metastasis occurred in the superior group in 7 of the 137 dissections with a prevalence of 5.1% and in the anterior group in 6 of the 137 dissections with a prevalence of 4.4%. The only pattern of SMG involvement was invasion by positive lymph nodes. The 5-year LRC rates for patients with SMG preservation and patients with SMG excision were 84 and 73%, respectively, and the difference was not significant (p = 0.239). The 5-year DSS rates for patients with SMG preservation and patients with SMG excision were 88 and 84%, respectively, and the difference was not significant (p = 0.524). Conclusions: In early-stage FOM SCC patients, SMG involvement is rare, the most common metastatic site in level 1b is the superior group, and SMG preservation does not decrease the LRC or DSS rates. Therefore, the findings suggest that there might be high feasibility of SMG-preserving neck dissection in cT1-2N0 FOM SCC.


Chemisorption of HCl to the MgO(001) surface: a DFT study.
We use plane wave and embedded cluster ab initio density functional calculations to study adsorption, dissociation and diffusion of the HCl molecule on the MgO(001) surface. The two methods yield comparable results for adsorption of an isolated HCl molecule and complement each other when considering charged species and coverage effects. We find dissociative chemisorption at a coverage smaller than 0.5 monolayer with a Cl(-) ion electrostatically coupled to the OH(-) ion at the surface oxygen site. The adsorption energy of the Cl(-)[dot dot dot](OH)(-) complex is 1.5 eV and the activation energy of Cl(-) diffusion away from OH(-) is 0.6 eV. There is no significant activation energy for rotation of Cl(-) around the adsorption site. At rising coverage, an increase in dipole-dipole repulsion between HCl molecules leads to a lowering of the adsorption energy per HCl and a change of binding towards hydrogen-bridge type as well as a lowering of the activation energy for Cl(-) diffusion. OH(-) formed in the surface due to HCl adsorption has a stretch frequency of 3,083 cm(-1) with Cl(-) associated and 3,648 cm(-1) with Cl(-) removed.


[Luteinizing hormone-releasing hormone (LRH) agonist in the treatment of breast cancer, osteosarcoma and prostate carcinoma--analysis of 12 patients].
This paper first reports the results of 12 patients with sex hormone-dependent neoplasms, including 9 women with breast cancer, 2 men with osteosarcoma and 1 man with prostate carcinoma, treated by LRH agonist, (D-Ala6, des-Gly-NH2(10))-LRH-ethylamide (LRH-A) 100-200 micrograms, IM, QD. After 15-30 days of administration, the concentrations of plasma mean estradiol, progesterone, testosterone, serum luteinizing hormone and follicle-stimulating hormone were lowered significantly in the peripheral blood of all patients, associating with improvement of the patients' general condition and reduction of the tumors and/or metastatic foci. No serious side effects were observed except vaginal irregular bleeding in isolated patients. Three patients died and the others were alive in follow-up of 4-30 months. The results suggest that LRH-A be useful in the treatment of the sex hormone-dependent tumors and worth further study.


[The Effect of Different Positions on Block Plane of Isobaric Bupivacaine for Caesarean Section with Combined Spinal-Eqidural Analgesia].
To evaluate the effect of horizontal and trendelenburg left lateral position on the onset time and the spread of intrathecal isobaric bupivacaine for elective cesarean delivery. 180 parturients were enrolled to undergo elective cesarean delivery with combined spinal-epidural anesthesia (CSE). They were randomly divided into 3 groups (n = 60) according to the different positions during anesthesia: Group I horizontal position, Group II trendelenburg position 5 degrees, Group III trendelenburg position 10 degrees. A combined spinal-eqidural (CSE) analgesia was performed at the L3-4 interspace in either horizontal or trendelenburg left lateral position, according to randomization. 2 mL of 0.5% isobaric bupivacaine was injected into subarachnoid space when cerebrospinal fluid outflew. Then the patient was placed in a supine position. The success criteria of anesthesia was: T6 sensory block, Bromage grade 2 or 3 (motor block), anesthesia effect ≥ grade III. The systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), sensory block, motor block and adverse reactions such as hypotension, bradycardia, chest distress were observed after the 3 groups parturients entered into operating room. The numbers and success rate of Group I, II and III which got T6 sensory block in ten minutes were observed. Among Group I, II and III, there were no significant differences in onset time of sensory block and motor block (P > 0.05). The cold and pinprick sensation level in 10 min of Group I1 and Group III were higher than that of Group I (P < 0.05). The success rate of Group II or III was higher than Group I (P < 0.05). The success rate of Group III was higher than that of Group II, but not with significant difference (P > 0.05). There were no significant differences in hemodynamics, adverse reactions such as hypotension, bradycardia, chest distress among three groups (P > 0.05). The trendelenburg 5 degrees position can meet the requirement of operation without high anesthesia level.


Quantification of total mitochondrial DNA and mitochondrial common deletion in the frontal cortex of patients with schizophrenia and bipolar disorder.
Data published during the last decade are suggestive of a role for mitochondrial dysfunction in the pathogenesis of schizophrenia, bipolar disorder and other psychiatric diseases. In order to determine if the mitochondrial deficits reported in the literature are caused by abnormalities in the mitochondrial DNA of psychiatric patients, we quantified mitochondrial DNA (mtDNA) levels and the 5 kb common mitochondrial deletion (CD) in postmortem frontal cortex tissue. The mitochondrial CD and mtDNA levels were measured in tissue obtained from the frontal cortex (Brodmann Area 46) of 144 individuals (45 patients with schizophrenia, 40 patients with bipolar disorder, 44 controls, and 15 patients with major depression). These variables were measured using newly developed SYBR green and TaqMan real time PCR assays. Both the TaqMan and the SYBR green assays gave similar results. There was no statistically significant difference for the quantity of the common mitochondrial deletion between controls and patients. We also did not detect a difference in the mtDNA levels amongst the diagnosis groups. There were statistically significant differences for the evaluated parameters for smokers, schizophrenic patients on antipsychotic drugs at time of death, and bipolar patients with antidepressant use and alcohol abuse. Based on this study and other reports, we conclude that neither the common mitochondrial deletion nor changes in mitochondrial DNA levels are likely to account for the mitochondrial changes associated with bipolar disorder or schizophrenia. The effect of premortem agonal factors and medication on mitochondrial dysfunction still needs further elucidation.


Forum. A comparison between the midline and paramedian approaches to the extradural space.
A prospective, randomised study was devised to compare the midline and paramedian approaches to the extradural space in women during labour. The two approaches were equally successful with respect to catheter insertion and analgesia and had a similar incidence of complications, although the paramedian approach caused patients more discomfort. Since only 2 ml of 1% lignocaine with adrenaline were infiltrated prior to insertion of the Tuohy needle, a greater volume of the local anaesthetic may reduce the discomfort of using the paramedian approach.


Putative imprinted gene expression in uniparental bovine embryo models.
Altered patterns of gene expression and the imprinted status of genes have a profound effect on cell physiology and can markedly alter embryonic and fetal development. Failure to maintain correct imprinting patterns can lead to abnormal growth and behavioural problems, or to early pregnancy loss. Recently, it has been reported that the Igf2R and Grb10 genes are biallelically expressed in sheep blastocysts, but monoallelically expressed at Day 21 of development. The present study investigated the imprinting status of 17 genes in in vivo, parthenogenetic and androgenetic bovine blastocysts in order to determine the prevalence of this unique phenomenon. Specifically, the putatively imprinted genes Ata3, Impact, L3Mbtl, Magel2, Mkrn3, Peg3, Snrpn, Ube3a and Zac1 were investigated for the first time in bovine in vitro fertilised embryos. Ata3 was the only gene not detected. The results of the present study revealed that all genes, except Xist, failed to display monoallelic expression patterns in bovine embryos and support recent results reported for ovine embryos. Collectively, the data suggest that monoallelic expression may not be required for most imprinted genes during preimplantation development, especially in ruminants. The research also suggests that monoallelic expression of genes may develop in a gene- and time-dependent manner.


Molecular cloning, expression, and functional significance of a cytochrome P450 highly expressed in rat heart myocytes.
A cDNA encoding a P450 monooxygenase was amplified from reverse transcribed rat heart and liver total RNA by polymerase chain reaction using primers based on the 5'- and 3'-end sequences of two rat pseudogenes, CYP2J3P1 and CYP2J3P2. Sequence analysis revealed that this 1,778-base pair cDNA contained an open reading frame and encoded a new 502 amino acid protein designated CYP2J3. Based on the deduced amino acid sequence, CYP2J3 was approximately 70% homologous to both human CYP2J2 and rabbit CYP2J1. Recombinant CYP2J3 protein was co-expressed with NADPH-cytochrome P450 oxidoreductase in Sf9 insect cells using a baculovirus expression system. Microsomal fractions of CYP2J3/NADPH-cytochrome P450 oxidoreductase-transfected cells metabolized arachidonic acid to 14,15-, 11,12-, and 8, 9-epoxyeicosatrienoic acids and 19-hydroxyeicosatetraenoic acid as the principal reaction products (catalytic turnover, 0.2 nmol of product/nmol of cytochrome P450/min at 37 degrees C). Immunoblotting of microsomal fractions prepared from rat tissues using a polyclonal antibody raised against recombinant CYP2J2 that cross-reacted with CYP2J3 but not with other known rat P450s demonstrated abundant expression of CYP2J3 protein in heart and liver. Immunohistochemical staining of formalin-fixed paraffin-embedded rat heart tissue sections using the anti-CYP2J2 IgG and avidin-biotin-peroxidase detection localized expression of CYP2J3 primarily to atrial and ventricular myocytes. In an isolated-perfused rat heart model, 20 min of global ischemia followed by 40 min of reflow resulted in recovery of only 44 +/- 6% of base-line contractile function. The addition of 5 microM 11, 12-epoxyeicosatrienoic acid to the perfusate prior to global ischemia resulted in a significant 1.6-fold improvement in recovery of cardiac contractility (69 +/- 5% of base line, p = 0.01 versus vehicle alone). Importantly, neither 14,15-epoxyeicosatrienoic acid nor 19-hydroxyeicosatetraenoic acid significantly improved functional recovery following global ischemia, demonstrating the specificity of the biological effect for the 11, 12-epoxyeicosatrienoic acid regioisomer. Based on these data, we conclude that (a) CYP2J3 is one of the predominant enzymes responsible for the oxidation of endogenous arachidonic acid pools in rat heart myocytes and (b) 11,12-epoxyeicosatrienoic acid may play an important functional role in the response of the heart to ischemia.


WNT5A expression is regulated by the status of its promoter methylation in leukaemia and can inhibit leukemic cell malignant proliferation.
Although down-regulation of WNT5A expression has been reported in some types of leukaemias, the level of WNT5A expression has not been assessed in leukaemia complete remission (CR) cases, the relationship among WNT5A expression level, the status of its promoter methylation, and the curative effect of leukaemia has not been reported, and the effect of WNT5A on cell proliferation has not been assessed. In this study, we analyzed WNT5A expression in various kinds of leukaemia cases, leukaemia CR cases, non-malignant hematopoietic (NMH) cases, as well as in leukemic cell lines and CD34+ cells. The methylation status of the WNT5A promoter and the levels of the Wnt5a protein were also studied. We also investigated the effect of Wnt5a on leukemic cell proliferation. WNT5A expression level was higher in NMH but lower in leukaemia cases compared to that in CR-cases (P<0.01), and was expressed at low level in leukemic cell lines K562, U937 and Jurkat. Wnt5a protein was positive in NMH, CR cases and CD34+, but negative in leukaemia cases. WNT5A promoter was methylated in leukaemia cases and all leukemic cell lines, but not in NMH and CR cases. WNT5A expression was up-regulated after exposure to the demethylating agent 5-Aza-2'-deoxycytidine (Aza) in the K562, U937, Jurkat leukemic cell lines and in 83.3% (10/12) of CR patients after cure, respectively. The increased Wnt5a protein can inhibit K562 malignant proliferation and arrest cell cycle at the G2/M phase after exposure to Aza. These results indicate that WNT5A expression was restored in complete remission cases due to demethylation, and Wnt5a can inhibit leukaemic cell proliferation. We propose that WNT5A can act as a suppressor factor in leukemogenesis and can be used as a potential marker for curative effect assessment in leukaemia.


Ultrastructural modifications during the metabolism of metronidazole by Trypanosoma cruzi.
Trypanosoma cruzi epimastigotes incubated in the presence of [14C] metronidazole are capable of a rapid uptake of the drug as shown by timecourse experiments and by autoradiography of the cells. The drug is metabolized to a more polar compound which has the chromatographic behavior of 2-methyl-5-nitroimidazole-1-yl-acetic acid. Mass spectral analysis of the metabolite shows diagnostic mass values (185, 184, 126) which are compatible with the 2-methyl-5-nitroimidazole-1-yl-acetic acid derivative. Flavone dramatically increases the production of the metabolite both in control and cells pretreated with phenobarbital. The cells show the presence of vesicles whose number is not significantly increased by phenobarbital. Metronidazole, on the other hand, significantly increases the number of vesicles in both control and cells grown in phenobarbital. The vesicles do not contain acid phosphatase and/or polyphosphates. It is concluded that the vesicles may correspond to a marked proliferation of the endoplasmic reticulum. A secondary effect of flavone is the proliferation of the mitochondrial membranes.


Bioactive constituents from Chinese natural medicines. XX. Inhibitors of antigen-induced degranulation in RBL-2H3 cells from the seeds of Psoralea corylifolia.
The ethyl acetate-soluble fraction of the methanolic extract from the seeds of Psoralea corylifolia was found to inhibit the release of beta-hexosaminidase, as a marker of antigen-IgE-induced degranulation in RBL-2H3 cells. Sixteen constituents were isolated from the ethyl acetate-soluble fraction and several constituents, Delta(1),3-hydroxybakuchiol (IC(50) = 49 microM), Delta(3),2-hydroxybakuchiol (69 microM, bavachin (58 microM), and psoralidin (ca. 100 microM), showed inhibitory activities against the antigen-induced degranulation.


Risk stratification of elderly patients with acute pulmonary embolism.
Combining high-sensitivity cardiac Troponin T (hs-cTnT), NT-pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) may improve risk stratification of patients with pulmonary embolism (PE) beyond the PESI risk score. In the prospective multicentre SWITCO65+ study, we analysed 214 patients ≥ 65 years with a new submassive PE. Biomarkers and clinical information for the PESI risk score were ascertained within 1 day after diagnosis. Associations of hs-TnT, NT-proBNP, hs-CRP and the PESI risk score with the primary endpoint defined as 6-month mortality were assessed. The discriminative power of the PESI risk score and its combination with hs-cTnT, NT-proBNP and hs-CRP for 6-month mortality was compared using integrated discrimination improvement (IDI) index and net reclassification improvement (NRI). Compared with the lowest quartile, patients in the highest quartile had a higher risk of death during the first 6 months for hs-cTnT (adjusted HR 10.22; 95% CI 1.79-58.34; P = 0.009) and a trend for NT-proBNP (adjusted HR 4.3; 95% CI 0.9-20.41; P = 0.067) unlike hs-CRP (adjusted HR 1.97; 95% CI 0.48-8.05; P = 0.344). The PESI risk score (c-statistic 0.77 (95% CI 0.69-0.84) had the highest prognostic accuracy for 6-month mortality, outperforming hs-cTnT, NT-proBNP and hs-CRP (c-statistics of 0.72, 0.72, and 0.54), respectively. Combining all three biomarkers had no clinically relevant impact on risk stratification when added to the PESI risk score (IDI = 0.067; 95% CI 0.012-0.123; P = 0.018; NRI = 0.101 95% CI -0.099-0.302; P = 0.321). In elderly patients with PE, 6-month mortality can adequately be predicted by the PESI risk score alone.


Length of Stay and Inpatient Costs Under Medicaid Managed Care in Florida.
This study examines the patterns of length of stay (LOS) and inpatient costs for both Medicaid managed care and nonmanaged care patients using data from Medicaid patients aged 18 to 64 years who were discharged from hospitals in Florida between 2006 and 2012. This study used pooled cross-sectional multilevel modeling. The results show that the type of Medicaid program in which patients were enrolled was significantly related to the hospital LOS and inpatient costs. Medicaid managed care patients had 7% shorter LOSs and a 1.9% lower inpatient cost than did Medicaid fee-for-service (FFS) patients. Medicaid managed care patients had shorter LOSs in the Medicaid managed care market with high competition. High managed care penetration generates a cost-decreasing spillover to Medicaid FFS patients.


Use of rice straw biochar simultaneously as the sustained release carrier of herbicides and soil amendment for their reduced leaching.
The sustained release and reduced leaching of herbicides is expected for enhancing their efficacy and minimizing their pollution. For this purpose, the rice straw biochar made at a relatively low temperature (350 °C) (RS350) was used simultaneously as the carrier for incorporating herbicides besides as the soil amendment. In this way, the sustained release of herbicides acetochlor and 2,4-D was obtained in the release experiments, due to the high and reversible sorption by RS350 biochar. Besides, the RS350 biochar significantly reduced the leached amount of herbicides by 25.4%-40.7% for acetochlor, and by 30.2%-45.5% for 2,4-D, depending on the depth (50 or 100 mm) of biochar-amended soil horizon. The high retention of both herbicides in the biochar-amended topsoil makes it possible to extend their efficacy. The results suggest a potential way of using low temperature biochars to reduce the leaching of herbicides without impacting their efficacy.


[Stress and stress tolerance in chronic heart failure].
Exercise intolerance in patients with chronic heart failure (CHF) shows no correlation to the degree of left ventricular dysfunction. This surprising finding has directed attention to peripheral changes in CHF. During the last years several different peripheral factors as determinants of exercise intolerance have been defined, i.e. abnormalities in ventilation, reduced endothelium-dependent vasodilatation of peripheral conduit and resistance vessels, and altered skeletal muscle metabolism. Skeletal muscle alterations are characterized by a reduced oxidative capacity, a catabolic state with reduced local IGF-I expression and muscle atrophy, chronic inflammation with local expression of the inducible isoform of nitric oxide synthase (iNOS) and an accelerated rate of programmed cell death (apoptosis). Physical exercise training has evolved as an important therapeutic approach to influence these non-cardiac causes of exercise intolerance. After the first studies documenting the effect of aerobic training on the peripheral causes of exercise intolerance in CHF the question was asked: Should we treat the heart or the periphery to improve exercise intolerance in CHF? Today, we have come closer to the answer: It is now clear that these two systems are not mutually exclusive. Exercise training in CHF has been shown to improve skeletal muscle metabolism and function, to avert muscle catabolism, to reduce neurohumoral overactivation, to reverse endothelial dysfunction and to contribute to the prevention of pathologic left ventricular remodeling. After 6 months of regular exercise training oxidative capacity of the working skeletal muscle increases by approximately 40%. Regular exercise training leads to a significant improvement of endothelium-dependent vasodilatory capacity of peripheral resistance vessels, thereby reducting peripheral resistance in particular during exercise. These beneficial training effects result in a small, but significant improvement of stroke volume and reduction in cardiomegaly. Although several questions regarding patient selection, optimal training protocol and training intensity remain unanswered, exercise training can been seen as an established adjunct to pharmacotherapy in CHF. We may soon reach the conclusion that by treating the periphery with exercise programs we are in fact treating the heart, as well. All exercise-induced adaptations converge to increase peak oxygen uptake by up to 2 ml/kg.min. For patients in stable CHF on optimal cardiac medication a combination of in-hospital and home-based aerobic endurance training in combination with local muscle strength training seems most promising. Although exercise training offers no causal treatment of CHF, it has great potentials as an adjunct therapy directed at improving exercise tolerance and expanding the physical limits of CHF patients.


A poor metabolizer for cytochromes P450 2D6 and 2C19: a case report on antidepressant treatment.
Scientific literature has never described a poor metabolizer for both the cytochrome P450 (CYP) 2D6 and the CYP 2C19. They are expected to be rare (<1% in different ethnic groups) and prone to adverse drug reactions with many antidepressants. In an ongoing pharmacogenetic study, after genotyping 1,576 subjects in three Kentucky state hospitals we have found one poor metabolizer for both CYP 2D6 and CYP 2C19, which corresponds to a prevalence of 0.06% (95% CI 0.01 to 0.36). The naturalistic antidepressant treatment of this poor metabolizer for both enzymes is described in this article. As genotyping reaches clinical practice, it will be interesting to prospectively establish whether mirtazapine is a reasonable choice as an antidepressant for these patients, as the data and this case suggest.


Impact of prostate cancer testing: an evaluation of the emotional consequences of a negative biopsy result.
When testing for prostate cancer, as many as 75% of men with a raised prostate-specific antigen (PSA) have a benign biopsy result. Little is known about the psychological effect of this result for these men. In all, 330 men participating in the prostate testing for cancer and treatment (ProtecT) study were studied; aged 50-69 years with a PSA level of > or = 3 ng ml(-1) and a negative biopsy result. Distress and negative mood were measured at four time-points: two during diagnostic testing and two after a negative biopsy result. The majority of men were not greatly affected by testing or a negative biopsy result. The impact on psychological health was highest at the time of the biopsy, with around 20% reporting high distress (33 out of 171) and tense/anxious moods (35 out of 180). Longitudinal analysis on 195 men showed a significant increase in distress at the time of the biopsy compared with levels at the PSA test (difference in Impact of Events Scale (IES) score: 9.47; 95% confidence interval (CI) (6.97, 12.12); P<0.001). These levels remained elevated immediately after the negative biopsy result (difference in score: 7.32; 95% CI (5.51, 9.52); P<0.001) and 12 weeks later (difference in score: 2.42; 95% CI (0.50, 1.15); P=0.009). Psychological mood at the time of PSA testing predicted high levels of distress and anxiety at subsequent time-points. Most men coped well with the testing process, although a minority experienced elevated distress at the time of biopsy and after a negative result. Men should be informed of the risk of distress relating to diagnostic uncertainty before they consent to PSA testing.


Effect of agmatine on brain L-citrulline production during morphine withdrawal in rats: a microdialysis study in nucleus accumbens.
Agmatine, an endogenous nitric oxide (NO) synthase inhibitor and ligand for imidazoline receptors, has been previously shown to prevent morphine dependence in rats. The present study was designed to investigate NO formation in nucleus accumbens core region (NAcc) during naloxone (NL)-precipitated morphine withdrawal in rats treated with agmatine or l-NAME by using intracerebral microdialysis in freely moving rats, through measuring extracellular l-citrulline concentrations, an indirect sign of NO production since equal amounts of l-citrulline and NO are produced from l-arginine. l-Citrulline levels in the NAcc core did not change following administration of agmatine (40 mg/kg i.p.) or l-NAME (100 mg/kg i.p.) in control rats. Both agmatine and l-NAME attenuated withdrawal symptoms of morphine in NL (2 mg/kg i.p.)-precipitated withdrawal. l-Citrulline levels showing the release of NO increased in morphine-dependent rats during NL-precipitated withdrawal. Agmatine and l-NAME treatments significantly suppressed the increase in l-citrulline levels compared to physiological saline-treated rats in this setting. The results suggest that the release of l-citrulline in NAcc may be involved in the processes of morphine withdrawal and agmatine as an endogenous inhibitor of NO synthase may be one of the factors involved in the changes in the physiology and behavioral state during opioid withdrawal and may have pharmacological importance.


A rice fungicide blasticidin S efficiently binds Cu(II) ions and prevents DNA from metal-induced damage.
Blasticidin S is a representative of the aminoacylnucleoside class of antibiotics and it possesses fungicidal properties against the virulent fungus which causes a serious rice blast disease in Asia. It is widely used to control rice blast by foliar application as a crop protection agent. Serious copper contamination is observed in some areas of China. Moreover, some paddy soils present a potential risk of copper accumulation in the human body through the food chain, leading to several disorders. This work presents the results of combined potentiometric and spectroscopic (UV-visible, EPR, CD, NMR) data which lead to the conclusion that the antibiotic is capable of binding copper, and the resulting complexes are likely to form in the soil. The process of complex formation has a potential influence on the population feeding on a rice-based diet. Moreover, the results of electrophoretic experiments revealed that complexes do not cleave DNA. On the contrary, the presence of blasticidin S may prevent DNA from a Cu(II)-induced damage.


Social support moderates outcome in a randomized controlled trial of exposure therapy and (or) cognitive restructuring for chronic posttraumatic stress disorder.
To understand what predicts good outcome in psychiatric treatments, thus creating a pathway to improving efficacy. Our study investigated relations between predictor variables and outcome (on the Clinician Administered Posttraumatic Stress Disorder [PTSD] Scale [CAPS]) at posttreatment for 77 treatment completers in a randomized controlled trial of exposure therapy and (or) cognitive restructuring, compared with relaxation, for chronic PTSD in adults. More social support on the Significant Others Scale significantly predicted better outcome on the CAPS, even after controlling for the effects of treatment group and of pretreatment severity. Importantly, social support was only a significant predictor of outcome for participants receiving cognitive restructuring and (or) exposure therapy and not for participants in the relaxation condition. Better social support is associated with significantly greater gain following cognitive restructuring and (or) exposure therapy for PTSD. Future interventions should consider augmenting social support as an adjunct to treatment.


Carbon monoxide protects against hepatic steatosis in mice by inducing sestrin-2 via the PERK-eIF2α-ATF4 pathway.
Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has emerged as one of the most common causes of chronic liver disease in developed countries over the last decade. NAFLD comprises a spectrum of pathological hepatic changes, including steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Autophagy, a homeostatic process for protein and organelle turnover, is decreased in the liver during the development of NAFLD. Previously, we have shown that carbon monoxide (CO), a reaction product of heme oxygenase (HO) activity, can confer protection in NAFLD, though the molecular mechanisms remain unclear. We therefore investigated the mechanisms underlying the protective effect of CO on methionine/choline-deficient (MCD) diet-induced hepatic steatosis. We found that CO induced sestrin-2 (SESN2) expression through enhanced mitochondrial ROS production and protected against MCD-induced NAFLD progression through activation of autophagy. SESN2 expression was increased by CO or CO-releasing molecule (CORM2), in a manner dependent on signaling through the protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor-2 alpha (eIF2α)/ activating transcription factor-4 (ATF4)-dependent pathway. CO-induced SESN2 upregulation in hepatocytes contributed to autophagy induction through activation of 5'-AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) complex I (mTORC1). Furthermore, we demonstrate that CO significantly induced the expression of SESN2 and enhanced autophagy in the livers of MCD-fed mice or in MCD-media treated hepatocytes. Conversely, knockdown of SESN2 abrogated autophagy activation and mTOR inhibition in response to CO. We conclude that CO ameliorates hepatic steatosis through the autophagy pathway induced by SESN2 upregulation.


Harnessing Facebook for Smoking Reduction and Cessation Interventions: Facebook User Engagement and Social Support Predict Smoking Reduction.
Social media technologies offer a novel opportunity for scalable health interventions that can facilitate user engagement and social support, which in turn may reinforce positive processes for behavior change. By using principles from health communication and social support literature, we implemented a Facebook group-based intervention that targeted smoking reduction and cessation. This study hypothesized that participants' engagement with and perceived social support from our Facebook group intervention would predict smoking reduction. We recruited 16 regular smokers who live in the United States and who were motivated in quitting smoking at screening. We promoted message exposure as well as engagement and social support systems throughout the intervention. For message exposure, we posted prevalidated, antismoking messages (such as national antismoking campaigns) on our smoking reduction and cessation Facebook group. For engagement and social support systems, we delivered a high degree of engagement and social support systems during the second and third week of the intervention and a low degree of engagement and social support systems during the first and fourth week. A total of six surveys were conducted via Amazon Mechanical Turk (MTurk) at baseline on a weekly basis and at a 2-week follow-up. Of the total 16 participants, most were female (n=13, 81%), white (n=15, 94%), and between 25 and 50 years of age (mean 34.75, SD 8.15). There was no study attrition throughout the 6-time-point baseline, weekly, and follow-up surveys. We generated Facebook engagement and social support composite scores (mean 19.19, SD 24.35) by combining the number of likes each participant received and the number of comments or wall posts each participant posted on our smoking reduction and cessation Facebook group during the intervention period. The primary outcome was smoking reduction in the past 7 days measured at baseline and at the two-week follow-up. Compared with the baseline, participants reported smoking an average of 60.56 fewer cigarettes per week (SD 38.83) at the follow-up, and 4 participants out of 16 (25%) reported 7-day point prevalence smoking abstinence at the follow-up. Adjusted linear regression models revealed that a one-unit increase in the Facebook engagement and social support composite scores predicted a 0.56-unit decrease in cigarettes smoked per week (standard error =.24, P=.04, 95% CI 0.024-1.09) when baseline readiness to quit, gender, and baseline smoking status were controlled (F4, 11=8.85, P=.002). This study is the first Facebook group-based intervention that systemically implemented health communication strategies and engagement and social support systems to promote smoking reduction and cessation. Our findings imply that receiving one like or posting on the Facebook-based intervention platform predicted smoking approximately one less cigarette in the past 7 days, and that interventions should facilitate user interactions to foster user engagement and social support.


The genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia.
It has recently been demonstrated that mutations in the gene for Bruton's tyrosine kinase (BTK) are responsible for X-linked agammaglobulinemia. Southern blot analysis and sequencing of cDNA were used to document deletions, insertions, and single base pair substitutions. To facilitate analysis of BTK regulation and to permit the development of assays that could be used to screen genomic DNA for mutations in BTK, we determined the genomic organization of this gene. Subcloning of a cosmid and a yeast artificial chromosome showed that BTK is divided into 19 exons spanning 37 kilobases of genomic DNA. Analysis of the region 5' to the first untranslated exon revealed no consensus TATAA or CAAT boxes; however, three retinoic acid binding sites were identified in this region. Comparison of the structure of BTK with that of other nonreceptor tyrosine kinases, including SRC, FES, and CSK, demonstrated a lack of conservation of exon borders. Information obtained in this study will contribute to our understanding of the evolution of nonreceptor tyrosine kinases. It will also be useful in diagnostic studies, including carrier detection, and in studies directed towards gene therapy or gene replacement.


Intermolecular cross-double-michael addition between nitro and carbonyl activated olefins as a new approach in C-C bond formation.
A novel intermolecular cross-double-Michael addition between nitro and carbonyl activated olefins has been developed through Lewis base catalysis. The reaction took place with a large group of beta-alkyl nitroalkenes and alpha,beta-unsaturated ketone/esters, producing an allylic nitro compound in good to excellent yields.


[Prophylactic effect of matrix metalloproteinase inhibitor on acute graft-versus-host disease in a murine model].
To explore the prophylactic effect of tissue inhibitor of matrix metalloproteinase (TIMP) on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a murine model. The murine model of aGVHD after allo-HSCT was established by using female C57BL/b (H-2b) mouse as the donor, and male BALB/c (H-2b) as the recipient. After allo-HSCT, recipient mice were divided into 3 groups. For aGVHD prophylaxis group A was given TIMP (2 mg/d) , group B CsA (5 mg x kg(-1) x d (-1)) was given, and group C nothing. Physical signs, mean survival time (MST), peripheral blood counts and aGVHD histopathology were observed. Mice in group C developed typical aGVHD and 100% of mortality, with a MST of 8 days, and those in group A and B had longer survival, the MST being (4.8 +/- 1.4) d and (4.3 +/- 0.9) d respectively, with no statistical difference in peripheral blood count between these two groups. Mice in group A showed less severe signs. TIMP markedly prolongs MST of allo-HSCT recipients, delays the onset of aGVHD signs, and has no adverse effect on hematopoiesis reconstitution.


Women are less likely to be admitted to substance abuse treatment within 30 days of assessment.
The information gathered in a centralized intake unit (CIU) allows payers and administrators to examine if there are access issues for their population. For this study, the authors examined whether there were gender differences in the rate at which people are admitted to treatment within 30 days of assessment. Of the 5,004 individuals seeking publicly-funded substance abuse treatment in Detroit for the years 1996-97, 50.3% of those assessed at the CIU actually entered treatment. Women (31% of the people assessed) had a lower rate of admission (45% for women versus 53% for men) a difference that was maintained even after controlling for known risk factors. Women who were given priority for admission (i.e., those who were pregnant, had children, or injected drugs) had a higher rate of admission than other women (73% versus 39%), but only 17% of the women presenting were included in the priority groups. Men who were injecting drugs (a priority group) also had a higher rate of admission than other men (83% versus 49%). In multivariate analysis controlling for priority groups and known risk factors, women were still less likely to be admitted to treatment within 30 days of admission than men. Establishing priorities improves the rate of admission within 30 days of assessment for those groups, but more needs to be done to improve the admission rate for women. These results demonstrate that a CIU allows administrators to monitor for access issues.