Neuroprotective Properties of Dimethyl Fumarate Measured by Optical Coherence Tomography in Non-inflammatory Animal Models.
While great advances have been made in the immunomodulatory treatment of multiple sclerosis (MS), there is still an unmet need for drugs with neuroprotective potential. Dimethyl fumarate (DMF) has been suggested to exert both immunomodulatory and neuroprotective effects in MS. To investigate if DMF has neuroprotective effects independent of immunomodulation we evaluated its effects in the non-inflammatory animal models of light-induced photoreceptor loss and optic nerve crush. This might also reveal applications for DMF besides MS, such as age related macular degeneration. Retinal neurodegeneration was longitudinally assessed by in vivo retinal imaging using optical coherence tomography (OCT), and glutathione (GSH) measurements as well as histological investigations were performed to clarify the mode of action. For light-induced photoreceptor loss, one eye of C57BL/6J mice was irradiated with a LED cold light lamp while for optic nerve crush the optic nerve was clamped behind the eye bulb. The other eye served as control. GSH was measured in the optic nerve, choroid and retina and immunohistological staining of retinal microglia (Iba1) was performed. Mice were treated with 15 or 30 mg DMF/kg bodyweight or vehicle. While no protective effects were observed in optic nerve crush, in the light-induced retinal degeneration model DMF treatment significantly reduced retinal degeneration. In these mice, GSH levels in the retina and surrounding choroid were increased and histological investigations revealed less microglial activation in the outer retinal layers, suggesting both antioxidant and anti-inflammatory effects.


Serum Amyloid A1 Induces Classically Activated Macrophages: A Role for Enhanced Fibril Formation.
AA amyloidosis belongs to the group of amyloid diseases which can follow chronic inflammatory conditions of various origin. The disease is characterized by the deposition of insoluble amyloid fibrils formed by serum amyloid A1 (SAA1) leading eventually to organ failure. Macrophages are intimately involved in the fibrillogenesis as well as in the clearance of amyloid fibrils. In vivo, macrophages may occur as classically (M1) or alternatively activated (M2) macrophages. We investigate here how SAA1 might affect the macrophage phenotype and function. Gene microarray analysis revealed upregulation of 64 M1-associated genes by SAA1. M1-like polarization was further confirmed by the expression of the M1-marker MARCO, activation of the NF-κB transcription factor, and secretion of the M1-cytokines TNF-α, IL-6, and MCP-1. Additionally, we demonstrate here that M1-polarized macrophages exhibit enhanced fibrillogenic activity towards SAA1. Based on our data, we propose reconsideration of the currently used cellular amyloidosis models towards an in vitro model employing M1-polarized macrophages. Furthermore, the data suggest macrophage repolarization as potential intervention strategy in AA amyloidosis.


Macrovascular and microvascular outcomes after beginning of insulin versus additional oral glucose-lowering therapy in people with type 2 diabetes: an observational study.
In type 2 diabetes, the optimal stage to introduce insulin can be unclear. We compared the incidence of subsequent vascular disease between treatment regimens, that is, adding another oral glucose-lowering drug (OGLD) versus starting insulin treatment. People with poor control on OGLDs who intensified treatment (2000-2007) were grouped by number of baseline OGLDs. Two composite endpoints, of macrovascular disease (all-cause mortality, myocardial infarction, acute coronary syndrome and stroke) and of microvascular disease (peripheral neuropathy, nephropathy or retinopathy), together with HbA(1c) and weight change over a year, were compared in those beginning insulin versus an additional OGLD. All data came from The Health Information Network UK primary care database. After exclusions, 14,904 people intensified treatment from one OGLD, 7231 from two and 978 from three, 9, 41 and 90%, respectively, started insulin. Average follow-up was 3.5 years. The adjusted hazard ratios for macrovascular events, OGLD versus insulin, were 0.53 (95%CI 0.42, 0.69) from one baseline treatment, 0.85 (0.70 1.04) from two and 1.07 (0.50, 2.30) from three, with no difference in risk of microvascular disease in any comparison. Mean body weight increased, and mean HbA(1c) fell across groups; the only significant adjusted comparison was greater weight increase when commencing insulin from one OGLD. Starting insulin rather than adding another OGLD to double or triple oral therapy did not significantly increase the incidence of vascular events. Beginning insulin from one OGLD was uncommon. More incident macrovascular disease in this group may be caused by residual confounding.


Pathogenic cysteine mutations affect progranulin function and production of mature granulins.
Frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) can be caused by mutations in the progranulin gene (GRN). Progranulin (PGRN) is a cysteine-rich growth factor, which is proteolytically cleaved by elastase to produce several granulins (GRNs). All FTLD-U mutations in GRN characterized to date result in reduced secreted PGRN protein. We recently reported a Spanish family with progressive non-fluent aphasia and dementia in which a novel C521Y mutation segregates with disease. A second cysteine mutation (C139R) has also been reported to be disease specific. Allele-specific mRNA expression assays in brain reveal that the C521Y mutant allele is expressed at similar levels to the wild-type allele. Furthermore, plasma PGRN levels in C521Y carriers are comparable with non-carrier family relatives, suggesting that the mutation does not affect PGRN protein expression and secretion in vivo. Despite normal PGRN levels C521Y and C139R mutant GRNs show reduced neurite growth-stimulating activity in vitro. Further study revealed that these mutations also cause impaired cleavage of PGRN by elastase. Our data suggest that these mutations affect the function of full-length PGRN as well as elastase cleavage of PGRN into GRNs, leading to neurodegeneration.


Moving beyond guidelines: are report cards the answer to high rates of uncontrolled hypertension?
Hypertension control rates remain alarmingly low worldwide despite the extensive evidence for decreased rates of cardiovascular, cerebrovascular, and renal events in response to blood pressure (BP) lowering to recommended targets. Several classes of antihypertensive drugs are available, which in combination can produce major decreases in BP, with minimal side effects. Moreover, most patients only have mild hypertension and, in general, can be controlled to < 140/90 mm Hg by proper combinations of two antihypertensive drugs. Although patient-related factors clearly contribute to poor control of hypertension, physician-related factors, particularly "passive" therapeutic inertia, are as responsible if not more so. Recent studies clearly indicate that monitoring performance of individual physicians and providing feedback on the care delivered by them can move treatment of hypertension to BP control rates in the 60% to 70% range. If health care organizations would implement this approach, enormous benefits could be expected for the prevention of cardiovascular and cerebrovascular disease.


Solketal Removal from Aqueous Solutions Using Activated Carbon and a Metal-Organic Framework as Adsorbents.
The worldwide rise in biodiesel production has generated an excess of glycerol, a byproduct of the process. One of the most interesting alternative uses of glycerol is the production of solketal, a bioadditive that can improve the properties of both diesel and gasoline fuels. Even with its promising future, not much research has been performed on its toxicity in aqueous environments. In this work, solketal adsorption has been tested with two different commercial adsorbents: an activated carbon (Hydrodarco 3000) and a metal-organic framework (MIL-53). Diclofenac and caffeine were also chosen as emerging contaminants for comparison purposes. The effect of various parameters, such as the adsorbent mass or initial concentration of pollutants, has been studied. Adsorption kinetics with a better fit to a pseudo-second-order model, intraparticle diffusion, and effective diffusion coefficient were studied as well. Various isotherm equation models were employed to study the equilibrium process. The results obtained indicate that activated carbon is more effective in removing solketal from aqueous solutions than the metal-organic framework.


QM/QM' Direct Molecular Dynamics of Water-Accelerated Diels-Alder Reaction.
A QM/QM' direct molecular dynamics study of a water-accelerated Diels-Alder reaction in aqueous solution is reported. Cyclopentadiene and methyl vinyl ketone are known to react faster in water than in nonpolar solvents. We have explored how polarization of water molecules afforded by PM3 influences the nature of the transition state, and the reaction dynamics. We compare the results with previous studies on QM/MM and QM/MM+3QM water simulations from our laboratory. Transition state sampling in vacuum PM3 water boxes indicates that the asynchronicity is 0.54 Å in QM/QM', as compared to 0.48 Å in QM/MM, and 0.54 Å in QM/MM+3QM water. The mean time gap between the formation of two C-C bonds is 19 fs for QM/QM', compared to 20 fs for QM/MM, and 25 fs for QM/MM+3QM water. The samplings and time gaps are qualitatively consistent, indicating that water polarization is not significant in sampling and dynamics of bonding changes. The dynamics of hydrogen bonding between reacting molecules and water molecules was also analyzed. From reactants to transition states, H-bond shortening is 0.4 Å by QM/QM', while only 0.15 Å for QM/MM and QM/MM+3QM water. From reactants to transition states, the mean value of the H-bond angle increases by 19° in QM/QM', but only 4° in QM/MM, and 10° in QM/MM+3QM water. These suggest that water polarization is essential for the correct representation of dynamical formation of hydrogen bonds in the transition state by water reorientation. QM/QM' overestimates the hydrogen bonding enhancement because of its underestimation of neutral hydrogen bonding within the reactants, a general deficiency of PM3.


Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988-1994.
Studies suggest that homocysteine may elevate blood pressure and increase the risk of hypertension. The association of homocysteine with blood pressure and with the risk of hypertension was investigated using cross-sectional data from the Third National Health and Nutrition Examination Survey (1998-1994). Homocysteine had an independent positive association with blood pressure after adjusting for cardiovascular risk factors. A 1 standard deviation ( approximately 5 micro mol/liter) increase in homocysteine was associated with increases in diastolic and systolic blood pressure of 0.5 and 0.7 mmHg, respectively, in men and of 0.7 and 1.2 mmHg in women. Similarly, higher levels of homocysteine were associated with an increased risk of hypertension. In a comparison of the highest and lowest quintiles of homocysteine, women had a threefold increase in the risk of hypertension (95% confidence interval (CI): 1.7, 5.4), and men had a twofold increase (95% CI: 0.7, 5.1). In light of the homocysteine-blood pressure association, the association of homocysteine with prevalent cardiovascular disease was examined with and without adjusting for blood pressure. The results support a mediating role for blood pressure in women and suggest that the full effect of homocysteine on cardiovascular risk may be underestimated when blood pressure is adjusted.


Risperidone for psychosis of Alzheimer's disease and mixed dementia: results of a double-blind, placebo-controlled trial.
To evaluate the efficacy and safety of low-dose risperidone in treating psychosis of Alzheimer's disease (AD) and mixed dementia (MD) in a subset of nursing-home residents who had dementia and aggression and who were participating in a randomized placebo-controlled trial of risperidone for aggression. This post-hoc analysis included only patients diagnosed with AD or MD with psychosis, defined by a score of >or= 2 on any item of the Behavioral Pathology of Alzheimer's Disease (BEHAVE-AD) psychosis subscale at both screening and baseline. Co-primary efficacy endpoints were changes in scores on BEHAVE-AD psychosis subscale and Clinical Global Impression of Change (CGI-C). Overall, 93 patients (46 risperidone and 47 placebo) fulfilled the psychosis of AD criteria. Mean change at endpoint in BEHAVE-AD psychosis subscale with risperidone was superior to placebo (-5.2 vs -3.3; p = 0.039). Distribution of CGI-C at endpoint also favoured risperidone (p < 0.001). The superior improvement with risperidone compared with placebo occurred as early as the first two weeks and persisted to the end of the treatment period. At endpoint, 59% of risperidone-treated patients were responders (i.e. were 'very much' or 'much' improved) compared with 26% of patients receiving placebo. The mean risperidone dose was 1.03 +/- 0.61 mg/day. Twelve weeks of treatment were completed by 37 patients treated with risperidone (80%) and 35 with placebo (74%). A total of 46 (98%) placebo- and 44 (96%) risperidone-treated patients experienced at least one adverse event, with only somnolence occurring more frequently in the risperidone group. Risperidone effectively reduces psychosis and improves global functioning in elderly patients with moderate-to-severe psychosis of AD and MD.


Spinal cord injury and neural repair: focus on neuroregenerative approaches for spinal cord injury.
This review discusses the urgent need for improved therapeutic approaches aimed at restoring function following traumatic spinal cord injury (SCI). The focus of this paper is neuroregenerative approaches for SCI, with a highlighted comparison of recent advances in the field and comparisons to that made by Cethrin (Alseres Pharmaceuticals, Inc.), the leading nerve repair product. This review first provides the reader with an understanding of SCI. The market for promising therapeutics that can either intervene in secondary etiological mechanisms or ameliorate symptoms associated with SCI are then discussed. The reader will also learn about Cethrin and its current status in clinical evaluation. Review of the preclinical literature and clinical SCI trials relevant to the discovery and current development of Cethrin. In a recently concluded Phase I/IIa clinical trial involving 37 patients with either cervical or thoracic SCIs, the evidence for Cethrin indicates that topical administration of either 0.3, 1, 3 or 6 mg of the recombinant rho inhibitor following surgical decompression is safe. Alseres has announced that planning is underway for a Phase IIB trial of Cethrin to include a placebo arm to assess better the drugs' clinical efficacy.


Cyclodextrin-based bioactive supramolecular assemblies.
Cyclodextrins (CDs) are a class of cyclic oligosaccharides with six to eight D-glucose units linked by alpha-1,4-glucose bonds, and their capability of forming stable complexes with various organic/inorganic/biological molecules and ions makes them attractive as building blocks for the construction of nano-scale supramolecular systems. This tutorial review deals with representative contributions in the construction and the structural characteristics of CD-based supramolecular assemblies as well as their interactions with biologically important substrates. This review is addressed to students and researchers interested in supramolecular chemistry, biochemistry and nanotechnology.


Laboratory Test Predictors for Major Bleeding in Elderly (≥80 Years) Patients With Nonvalvular Atrial Fibrillation Treated With Edoxaban 15 mg: Sub-Analysis of the ELDERCARE-AF Trial.
Background We investigated the predictors related to major bleeding events during treatment with edoxaban 15 mg in patients aged ≥80 years with nonvalvular atrial fibrillation and high bleeding risk, for whom standard oral anticoagulants are inappropriate, focusing on standard laboratory tests related to bleeding. Methods and Results This was a prespecified subanalysis of the on-treatment analysis set of the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial. Major bleeding was the primary safety end point. The event rates were calculated according to prespecified characteristics at baseline. A total of 984 Japanese patients were randomly assigned to edoxaban 15 mg or placebo (n=492, each). During the study period, 20 and 11 major bleeding events occurred in the edoxaban and placebo groups, respectively. The adjusted analysis revealed that hemoglobin <12.3 g/dL (adjusted hazard ratio [aHR], 3.57 [95% CI, 1.10-11.55]) and prothrombin time ≥12.7 seconds; (aHR, 2.89 [95% CI, 1.05-8.02]) independently predicted major bleeding, while creatinine clearance <30 mL/min showed a tendency towards an increase in major bleeding (aHR, 2.68; 95% CI, 0.96-7.46). In patients treated with edoxaban lacking these 3 risk factors, no major bleeding occurred; major bleeding event rates increased with each risk factor. Patients with 3 risk factors were significantly more likely to have a major bleeding event at 11.05%/year (HR, 7.15 [95% CI, 1.92-26.71]). Conclusions In elderly patients with nonvalvular atrial fibrillation with high bleeding risk, baseline hemoglobin <12.3 g/dL, prothrombin time ≥12.7 seconds, and creatinine clearance <30 mL/min may predict major bleeding during treatment with edoxaban 15 mg. Registration URL: ELDERCARE-AF https://www.clinicaltrials.gov; Unique number: NCT02801669.


Thoracic Ultrasound: Technique, Applications, and Interpretation.
Thoracic ultrasound is used at the bedside in emergency and critical care settings. Advantages of ultrasound include rapid real-time, low-cost, diagnostic information that can direct patient care without the use of ionizing radiation. We describe methods on how to perform lung ultrasound, with the intent to educate the radiologist who might otherwise be relatively unfamiliar with thoracic sonography. We describe and depict the normal sonographic appearance of lung anatomy. We also show the sonographic appearance of a wide range of lung and pleural pathologies such as pneumonia, pneumothorax, as well as lung and pleural masses. We review various lines and signs described in the literature, such as A-lines, B-lines, the stratosphere sign, and the bat-wing sign. Finally, we correlate our findings with chest x-ray and computerized tomography to emphasize the anatomy.


L-dopa: effect on concentrations of dopamine, norepinephrine, and serotonin in brains of mice.
Large doses of L-dopa given to mice produced marked increases in brain dopamine, no change in norepinephrine, and a remarkable decrease in brain serotonin. This reduction apparently results from a release or displacement, or both, of serotonin from its storage sites.


Coordinated multidisciplinary rehabilitation after hip fracture.
To review the topic of coordinated multidisciplinary rehabilitation after hip fracture from a research perspective and to provide information to guide the provision of rehabilitation services for patients with hip fracture. Literature review including searches of Medline, Embase, Cochrane Collaboration and evidence based clinical guidelines, checking of references of publications and consultation with researchers. The research evidence is heterogeneous and remains inclusive. Programs that assist patients with hip fracture to regain function and return home as soon as feasible are likely to be effective as they appear to increase the percentage of patients who return home and remain there after hip fracture. Rehabilitation programs that achieve this are likely to be cost effective. These programs involve health professionals from multiple disciplines (nurses, allied health professionals and medical practitioners) who work collaboratively, may operate in several settings, and routinely provide specific treatments that are supported by strong evidence of effectiveness. Patients with hip fracture should be offered a coordinated a multidisciplinary rehabilitation program with the specific aim of regaining sufficient function to return to their pre-fracture living arrangements.


Is glaucoma an autoimmune disease?
There is increasing evidence from animal and human studies that glaucoma is an autoimmune disease. Evidence for this hypothesis includes the fact that antibodies as well as T-cell responses to heat-shock proteins (HSPs) are detectable in some patients with glaucoma and in an animal model of the disease. As in the human disease, experimental animal models of glaucoma have been found to demonstrate neurodegenerative changes in the optic nerve associated with immunoglobulin and T-cell infiltration. Although there is still insufficient evidence in humans to classify all cases of glaucoma as autoimmune diseases, the implications of this hypothesis have major impact on the diagnosis and treatment of glaucoma.


[Sex in Sweden--population based survey. Changed sexual pattern mirrors trends in the society].
In a survey commissioned by the National Institute of Public Health, and carried out by specially trained staff at SIFO Research and Consulting, a representative population sample (n = 2,810, or 59 per cent of the actual sample) were interviewed regarding sexual mores. The items included 800 variables reflecting social background, lifestyle, and health, as well as knowledge, attitudes and sexual behaviour. The results showed, for instance, that Swedes have more sexual partners than 30 years ago, that anal sex is a currently fashionable trend, that oral sex is common, that relatively few are coerced to participate in sexual practices, and that the abortion rate is disturbingly high.


Polysaccharide from Ganoderma lucidum alleviates cognitive impairment in a mouse model of chronic cerebral hypoperfusion by regulating CD4+CD25+Foxp3+ regulatory T cells.
Ganoderma lucidum (G. lucidum) is a kind of edible and medicinal mushroom. G. lucidum polysaccharide-1 (GLP-1) is one of the polysaccharides purified from crude GLP. Chronic cerebral hypoperfusion (CCH) as the common pathological basis of various forms of dementia is an important cause of cognitive impairment. In this study, a step-down test was used to evaluate the cognitive ability of CCH mice. Flow cytometry was used to detect the proportion of CD4+CD25+Foxp3+ regulatory T (Foxp3+Treg) cells. ELISA analysis and western blot analysis were used to detect the transforming growth factor-β1 (TGF-β1) and Interleukin-10 (IL-10) levels that Foxp3+Treg cells secreted. Metabolomic analysis based on gas chromatography-mass spectrometry (GC-MS) was used to evaluate the effect of GLP-1 on dysfunctional metabolism caused by inflammation. Results indicate that GLP-1 exhibited an alleviating cognitive impairment effect on CCH mice. The mechanism was related to GLP-1 by increasing Foxp3+Treg cell levels to increase levels of IL-10 and TGF-β1 and regulate abnormal energy metabolism. These findings could provide preliminary results to exploit G. lucidum as a health care product or functional food for the adjuvant therapy of cognitive impairment of CCH.


Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity.
Thousands of genetic variants have been identified, which contribute to the development of complex diseases, but determining how to elucidate their biological consequences for translation into clinical benefit is challenging. Conflicting evidence regarding the functional impact of genetic variants in the tyrosine kinase 2 (TYK2) gene, which is differentially associated with common autoimmune diseases, currently obscures the potential of TYK2 as a therapeutic target. We aimed to resolve this conflict by performing genetic meta-analysis across disorders; subsequent molecular, cellular, in vivo, and structural functional follow-up; and epidemiological studies. Our data revealed a protective homozygous effect that defined a signaling optimum between autoimmunity and immunodeficiency and identified TYK2 as a potential drug target for certain common autoimmune disorders.


An Efficient ECG Classification System Using Resource-Saving Architecture and Random Forest.
This paper presents a resource-saving system to extract a few important features of electrocardiogram (ECG) signals. In addition, real-time classifiers are proposed as well to classify different types of arrhythmias via these features. The proposed feature extraction system is based on two delta-sigma modulators adopting 250 Hz sampling rate and three wave detection algorithms to analyze outputs of the modulators. It extracts essential details of each heartbeat, and the details are encoded into 68 bits data that is only 1.48% of the other comparable methods. To evaluate our classification, we use a novel patient-specific training protocol in conjunction with the MIT-BIH database and the recommendation of the AAMI to train the classifiers. The classifiers are random forests that are designed to recognize two major types of arrhythmias. They are supraventricular ectopic beats (SVEB) and ventricular ectopic beats (VEB). The performance of the arrhythmia classification reaches to the F1 scores of 81.05% for SVEB and 97.07% for VEB, which are also comparable to the state-of-the-art methods. The method provides a reliable and accurate approach to analyze ECG signals. Additionally, it also possesses time-efficient, low-complexity, and low-memory-usage advantages. Benefiting from these advantages, the method can be applied to practical ECG applications, especially wearable healthcare devices and implanted medical devices, for wave detection and arrhythmia classification.


A new C-C linked benzophenathridine-2-quinoline dimer, and the antiplasmodial activity of alkaloids from Zanthoxylum holstzianum.
The CH2Cl2/MeOH (1:1) extract of Zanthoxylum holstzianum stem bark showed good antiplasmodial activity (IC50 2.5 ± 0.3 and 2.6 ± 0.3 µg/mL against the W2 and D6 strains of Plasmodium falciparum, respectively). From the extract five benzophenanthridine alkaloids [8-acetonyldihydrochelerythrine (1), nitidine (2), dihydrochelerythine (3), norchelerythrine (5), arnottianamide (8)]; a 2-quinolone alkaloid [N-methylflindersine (4)]; a lignan [4,4'-dihydroxy-3,3'-dimethoxylignan-9,9'-diyl diacetate (7)] and a dimer of a benzophenanthridine and 2-quinoline [holstzianoquinoline (6)] were isolated. The CH2Cl2/MeOH (1:1) extract of the root bark afforded 1, 3-6, 8, chelerythridimerine (9) and 9-demethyloxychelerythrine (10). Holstzianoquinoline (6) is new, and is the second dimer linked by a C-C bond of a benzophenanthridine and a 2-quinoline reported thus far. The compounds were identified based on spectroscopic evidence. Amongst five compounds (1-5) tested against two strains of P. falciparum, nitidine (IC50 0.11 ± 0.01 µg/mL against W2 and D6 strains) and norchelerythrine (IC50 value of 0.15 ± 0.01 µg/mL against D6 strain) were the most active.


Factors influencing home care nurse intention to remain employed.
To identify factors affecting Canadian home care nurse intention to remain employed (ITR). In developed nations, healthcare continues to shift into community settings. Although considerable research exists on examining nurse ITR in hospitals, similar research related to nurses employed in home care is limited. In the face of a global nursing shortage, it is important to understand the factors influencing nurse ITR across healthcare sectors. A qualitative exploratory descriptive design was used. Focus groups were conducted with home care nurses. Data were analysed using qualitative content analysis. Six categories of influencing factors were identified by home care nurses as affecting ITR: job characteristics; work structures; relationships/communication; work environment; nurse responses to work; and employment conditions. Findings suggest the following factors influence home care nurse ITR: having autonomy; flexible scheduling; reasonable and varied workloads; supportive work relationships; and receiving adequate pay and benefits. Home care nurses did not identify job satisfaction as a single concept influencing ITR. Home care nursing management should support nurse autonomy, allow flexible scheduling, promote reasonable workloads and create opportunities for team building that strengthen supportive relationships among home care nurses and other health team members.


Effect of IgG for intravenous use on Fc receptor-mediated phagocytosis by human monocytes.
Polyspecific IgG given intravenously at high doses (IVIG) is used for immunomodulatory therapy in autoimmune diseases such as idiopathic thrombocytopenic purpura and myasthenia gravis. It is assumed that the clinical effect is brought about in part by a modulation of mononuclear phagocyte function, in particular by an inhibition of Fc receptor (FcR) mediated phagocytosis. In the present study, the effect of IVIG on FcR-mediated phagocytosis by monocytes was analysed in vitro. Since monocytes exposed to minute amounts of surface-bound IgG displayed impaired phagocytosis of IgG-coated erythrocytes (EA), the effect of IVIG was studied with mononuclear cells suspended in teflon bags in medium containing 10% autologous serum and IVIG (2-10 mg/ml). Monocytes pre-exposed to IVIG and then washed, displayed impaired ingestion of EA when compared with control cells cultured in 10% autologous serum only. The decrease in phagocytosis was observed with sheep erythrocytes treated with either rabbit IgG or bovine IgG1 and with anti-D-treated human erythrocytes. This suggests that phagocytosis via both FcR type I (FcRI) and type II (FcRII) was decreased. The impairment of phagocytosis was dependent on the presence of intact IgG and was mediated by IVIG from nulliparous donors and from multigravidae to the same extent, suggesting that alloantibodies contained in IVIG have a minor role in modulating FcR-mediated phagocytosis by monocytes. A flow cytometric analysis using anti-FcRI, FcRII and FcRII monoclonal antibodies showed that IVIG treatment upregulated FcRI expression but did not significantly alter the expression of FcRII and FcRIII.


Too good to be true: when overwhelming evidence fails to convince.
Is it possible for a large sequence of measurements or observations, which support a hypothesis, to counterintuitively decrease our confidence? Can unanimous support be too good to be true? The assumption of independence is often made in good faith; however, rarely is consideration given to whether a systemic failure has occurred. Taking this into account can cause certainty in a hypothesis to decrease as the evidence for it becomes apparently stronger. We perform a probabilistic Bayesian analysis of this effect with examples based on (i) archaeological evidence, (ii) weighing of legal evidence and (iii) cryptographic primality testing. In this paper, we investigate the effects of small error rates in a set of measurements or observations. We find that even with very low systemic failure rates, high confidence is surprisingly difficult to achieve; in particular, we find that certain analyses of cryptographically important numerical tests are highly optimistic, underestimating their false-negative rate by as much as a factor of 280.


The economic impact of smoking in Canada.
A cost-benefit analysis of smoking, using an attributable risk approach, has been carried out for Canada and for three regions within Canada. The total cost of the consequences of tobacco use--in terms of extra deaths, disability, hospitalization, physician services, and fire losses due to tobacco use--in all cases exceeded the total consumer expenditure for tobacco products. The excess was estimated to have a range from $14 to $127 (1983 Canadian dollars) per person per year. This represents the amount that an individual in society would gain, on average, if tobacco use was eliminated from the society for one year. Tobacco use was also found to be responsible for 12 to 17 per cent of all adult deaths, 4 to 5 per cent of all adult disability days, 12 to 14 per cent of all days of hospitalization, and 2 to 3 per cent of all physician visits.


[Substantiation of the drug «Cytoflavin» application and cognitive-behavioral therapy in complex treatment of deforming coxarthrosis in elderly patients.]
The article presents the results of a study of the effectiveness of the addition of a standard course of conservative therapy to 104 patients of the older age group with coxarthrosis deforming the drug «Cytoflavin» and cognitive-behavioral therapy courses. It was found that such scheme increases the effectiveness of therapeutic interventions, which manifests itself as the improvement of the mental and physical components of quality of life by reducing pain and increasing the functionality of some of the affected hip. At the heart of positive clinical effect is a decrease in processes of inflammation and reduction of tension of regulatory processes in the organism.


Developing nurse leaders for today and tomorrow, Part 1, foundations of leadership in practice.
Primary care, with a community-based orientation, is the driving force of healthcare reform. To prepare nurses to provide leadership in this changing healthcare environment, the Manager as Developer Model, useful in the acute care setting, is discussed as a useful model for primary care. Part 1 describes the Manager as Developer Model of Leadership Preparation with its seven major concepts as the basis for development of professionals. Its application to nurse managers in acute care settings is supported by research studies undertaken in those settings. Also discussed is how the model is used as a process framework in a nursing administration curriculum and the research to date, with its application. In part 2 (October 1996), the authors predict how the model's use can guide the development of leadership and education for the future of community-based practice.


[Sonography of blunt abdominal trauma (author's transl)].
Sonographic examination of the abdomen after blunt abdominal trauma represents a rapid and effective diagnostic method without bothering the patient. It has proved its value not only in the confirmation or exclusion of free fluid in the abdomen caused by liver of spleen rupture, but also in such cases actually it replaces peritoneal lavage or exploratory laparotomy. It is also qualified for diagnosis of intraparenchymal or subcapsular hemorrhages, intraperitoneal as well as retroperitoneal and for follow up. In particular delayed bleedings including the risk of a retarded organ rupture can be detected early. A failure rate of 1.4% in 282 sonographically examined cases of blunt abdominal trauma further confirms the reliability of this method.


Aerosol-Assisted Assembly of Mesoporous Carbon Spheres With Fast and Stable K-ion Storage.
Cost effective anode material with rational design is of significance for rechargeable potassium ion batteries (KIBs). Graphite anode currently still suffers unfavorable rate capability and moderate cycling stability. In this work, we report a mesoporous carbon sphere with rich porous structure as an anode material for KIBs with the assistance of an aerosol spray technology. The as-developed carbon spheres exhibit a well-defined spherical structure with favorable surface area of 1106.32 m2 g-1. Furthermore, the effect of different electrolytes on the electrochemical performance of the carbon anode has been investigated systematically. As expected, the carbon material shows excellent potassium storage performance in terms of improved specific capacity of 188.2 mAh g-1, rate capability and prolonged cyclability with a high capacity of 105.3 mAh g-1 after 500 cycles at a rate of 100 mA g-1 toward potassium storage in KFSI based carbonate electrolyte.


Evaluation of chitosan gel with 1% silver sulfadiazine as an alternative for burn wound treatment in rats.
Evaluation of the rheological, biological and therapeutic properties of a new topical formulation consisting of chitosan gel containing 1% silver sulfadiazine, as an alternative for the treatment of burn wounds. An experimental study was done with 21 Wistar rats divided into three groups. Group I was treated with chitosan gel without the antimicrobial, group II was treated with chitosan gel with 1% silver sulfadiazine and group III was treated with commercially available 1% silver sulfadiazine cream. Due to its pseudoplastic characteristic and good bioadhesiveness, the chitosan gels showed a satisfactory retention time over the wounds. No statistical difference was found in the amount of drug released from the chitosan gel and commercially available cream, as well as in the healing time among the groups. Wounds treated with chitosan gel with silver sulfadiazine showed a higher fibroblast production and a better angiogenesis than in the other groups, which are important parameters on the evolution of the healing process. The topical use of chitosan gel in association with silver sulfadiazine ameliorated the neovascularization and inflammatory reaction in burn wounds. This new formulation showed advantageous rheological properties and efficient release of the drug.


The impact of Ethiopian community-based health extension program on diarrheal diseases among under-five children and factors associated with diarrheal diseases in the rural community of Kalu district, Northeast Ethiopia: a cross-sectional study.
The health extension program is a community-based health care delivery program with eighteen defined packages. The main aim of the health extension program is to help to reduce child mortality. So, the aim of this study is to assess the impact of a health extension program on diarrheal disease under-five children in the rural community of Kalu district, Northeast Ethiopia, 2021. A community-based cross-sectional study design was conducted from March to April/2021. A Multi-stage sampling technique was used to get a total sample size of 556 (182 model households and 374 non-model households) with a response rate of 92.22%. Binary logistic regression analysis was done, and P-value < 0.05 was considered statistically significant. Propensity score matching analysis was used to determine the contribution of health extension program "model households" on diarrhea diseases among under-five children. The average treatment effect on the treated was calculated to compare the means of outcomes across model and non-model households. Health extension program (HEP) model household contributed a 17.7% (t = -5.02) decrease in children's diarrheal diseases among under-five children compared with HEP non-model households. Mothers from non-model households were 2.19 times more likely to develop under-five children diarrheal diseases AOR (Adjusted Odds Ratio): 2.19, 95% CI: 1.34-3.57 than mothers from model households. Households who got no frequent home visits were 3.28 times more likely to develop under-five diarrheal diseases AOR (Adjusted Odds Ratio): 3.28, 95% CI: 1.40-7.68. When the health extension program is implemented fully (model household), the prevalence of under-five diarrheal disease in the rural community could decrease. The need to develop supportive strategies for the sustainability of model households and encouraging households to be model households is very important.


Lactose-Induced Chronic Diarrhea Results From Abnormal Luminal Microbial Fermentation and Disorder of Ion Transport in the Colon.
Diarrhea is one of the major abdominal symptoms in lactose-intolerant subjects. The changes in the large intestinal luminal environment and disorder of the epithelial ion transport in lactose-induced diarrhea remain unclear. The present study aimed to investigate the effect of an incremental high-lactose diet (IHLD, 30%/40%/50%) on luminal microbiota, microbiota-derived metabolite concentrations and colonic ion transport. Gut microbiota were analyzed by 16S rRNA amplicon sequencing and the concentration of SCFAs by gas chromatography, galactose, lactose and lactic acid through assay kit; Ussing chamber was performed to detect basal and stimulated ion transport; The expression and location of SCFA transporters, the Na-H exchanger 3(NHE3), cystic fibrosis transporter regulater (CFTR) and NKCC1 in the colon mucosa were analyzed by western and immunostaining. The concentrations of lactose, galactose and lactic acid of the cecal content were markedly increased (P < 0.01) and SCFA concentration was significantly decreased (P < 0.01). This was associated with depletion of the Lachnospiraceae NK4A136 group and Ruminococcaceae UCG-005 and increased relative abundance of Lactobacillus, escherichia-shigella and megamonas in the cecal microbiota. The expression of monocarboxylate transporter 1 was decreased in the colonic mucosa of the IHLD group. Low NHE3 expression and phosphorylation levels, and decreases in delta basal short circuit current after apical Na+ removal in the colonic mucosa of the IHLD group contributed to Na+ accumulation in the lumen and decrease stimulated Cl- secretion with low CFTR and NKCC1 expression would compensate for water and electrolyte loss during the diarrhea process. These results indicated that the persistence of the diarrhea state was maintained by abnormal colonic microbiota fermentation leading to high concentrations of lactose, galactose and lactic acid and low SCFAs in the lumen, and decreased Na+ absorption with the low NHE3 expression and phosphorylation levels.


Three-dimensional computed tomographic analysis of airway anatomy in patients with obstructive sleep apnea.
To identify abnormalities in airway size and shape that correlate with the presence and severity of obstructive sleep apnea (OSA). This was a retrospective case series of patients undergoing treatment of OSA who had preoperative computed tomographic (CT) scans of the upper airway available. Patients who had undergone CT scanning for nonairway pathologic features during the same period served as the controls. Digital 3D-CT reconstructions were made and 12 parameters of airway size and 4 of shape were analyzed. The posterior airway space, middle airway space, and hyoid to mandibular plane distance were measured on the lateral cephalograms of the patients with OSA. Bivariate analysis was used to identify the factors associated with the presence and severity of OSA as measured by the respiratory disturbance index (RDI). Multiple regression analysis identified the factors that correlated with the RDI. Of the 44 patients with OSA, 15 (10 men and 5 women) had pre- and postoperative CT scans available. In addition, 17 patients (11 men and 6 women) were used as controls. The airway length was significantly increased in the patients with OSA (P < .01). On bivariate analysis, the length, lateral/retroglossal anteroposterior dimension ratio and genial tubercle to hyoid bone distance were associated with the RDI (P < .03). On multiple regression analysis, length (P < .01) had a positive correlation and the lateral/retroglossal anteroposterior dimension ratio (P = .04) an inverse correlation with the RDI. The results of this study indicate that the presence of OSA is associated with an increase in airway length. Airways that were more elliptical in shape and mediolaterally oriented (greater lateral/retroglossal anteroposterior dimension ratio) had a decreased tendency toward obstruction.


Microbiological quality and characteristics of probiotic products in China.
Probiotics are widely used in the food industry and medicine fields in China, but few studies have been conducted to evaluate the actual microbial amounts and species in probiotic products, which may conflict with the labels and mislead consumers to choose inappropriate foods or medicines. Twenty commercial dairy products and eight commercial 'healthcare' samples were collected from markets in China and tested using culture-dependent and culture-independent methods. The results suggested that the total bacterial counts of most commercial products met the minimum quantitative requirement of the Chinese national standard (6.00 log colony-forming units g(-1) ). However, the bacterial counts of specific species were inconsistent with the labelling. In parallel, denaturing gradient gel electrophoresis analysis indicated that some probiotic-containing products were wrongly labelled; no Bifidobacterium species were detected in the products claiming to contain bifidobacteria, and the probiotic characteristics (antimicrobial activity, acid resistance and bile resistance) of some isolates had degraded. Moreover, some contaminating bacteria, e.g. Enterobacter sp., Klebsiella sp. and Serratia sp., were also detected in these products. The combination of culture-dependent and culture-independent methods was proven to quickly and conveniently detect the microbial diversity in probiotic products, and more effort is required to regulate the probiotic market in China.


Deep abiotic weathering of pyrite.
Pyrite is a ubiquitous iron sulfide mineral that is oxidized by trace oxygen. The mineral has been largely absent from global sediments since the rise in oxygen concentration in Earth's early atmosphere. We analyzed weathering in shale, the most common rock exposed at Earth's surface, with chemical and microscopic analysis. By looking across scales from 10-9 to 102 meters, we determined the factors that control pyrite oxidation. Under the atmosphere today, pyrite oxidation is rate-limited by diffusion of oxygen to the grain surface and regulated by large-scale erosion and clast-scale fracturing. We determined that neither iron- nor sulfur-oxidizing microorganisms control global pyrite weathering fluxes despite their ability to catalyze the reaction. This multiscale picture emphasizes that fracturing and erosion are as important as atmospheric oxygen in limiting pyrite reactivity over Earth's history.


Mixed Adenoneuroendocrine Tumor of the Rectum in an Ulcerative Colitis Patient.
Patients with inflammatory bowel disease present a higher risk of colorectal cancer, especially patients with a high degree of disease activity. Although rare, carcinoid tumors can also be associated with inflammatory bowel disease. Mixed adenoneuroendocrine tumor is defined as a neoplasm with dual differentiation (neuroendocrine and adenoma) with each component accounting for at least 30% of the tumor. We present a case of a mixed adenoneuroendocrine tumor in a patient with inflammatory bowel disease.


A novel structure-based multimode QSAR method affords predictive models for phosphodiesterase inhibitors.
Quantitative structure-activity relationship (QSAR) methods aim to build quantitatively predictive models for the discovery of new molecules. It has been widely used in medicinal chemistry for drug discovery. Many QSAR techniques have been developed since Hansch's seminal work, and more are still being developed. Motivated by Hopfinger's receptor-dependent QSAR (RD-QSAR) formalism and the Lukacova-Balaz scheme to treat multimode issues, we have initiated studies that focus on a structure-based multimode QSAR (SBMM QSAR) method, where the structure of the target protein is used in characterizing the ligand, and the multimode issue of ligand binding is systematically treated with a modified Lukacova-Balaz scheme. All ligand molecules are first docked to the target binding pocket to obtain a set of aligned ligand poses. A structure-based pharmacophore concept is adopted to characterize the binding pocket. Specifically, we represent the binding pocket as a geometric grid labeled by pharmacophoric features. Each pose of the ligand is also represented as a labeled grid, where each grid point is labeled according to the atom types of nearby ligand atoms. These labeled grids or three-dimensional (3D) maps (both the receptor map (R-map) and the ligand map (L-map)) are compared to each other to derive descriptors for each pose of the ligand, resulting in a multimode structure-activity relationship (SAR) table. Iterative partial least-squares (PLS) is employed to build the QSAR models. When we applied this method to analyze PDE-4 inhibitors, predictive models have been developed, obtaining models with excellent training correlation (r(2) = 0.65-0.66), as well as test correlation (R(2) = 0.64-0.65). A comparative analysis with 4 other QSAR techniques demonstrates that this new method affords better models, in terms of the prediction power for the test set.


Activation of interleukin-1 receptor-associated kinase by gram-negative flagellin.
Flagellin from various species of gram-negative bacteria activates monocytes to produce proinflammatory cytokines. We have analyzed the pathway by which Salmonella enteritidis flagellin (FliC) activates murine and human monocyte/macrophage-like cell lines. Since lipopolysaccharide (LPS), the principal immune stimulatory component of gram-negative bacteria, is known to signal through Toll-like receptor 4 (TLR4), we tested the possibility that FliC also signals via TLR4. When murine HeNC2 cells were stimulated with LPS in the presence of a neutralizing anti-TLR4 monoclonal antibody, tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) production were markedly reduced. In contrast, FliC-mediated TNF-alpha and NO production were minimally affected by the anti-TLR4 antibody. Furthermore, FliC, unlike LPS, stimulated TNF-alpha production in the TLR4 mutant cell line, GG2EE, indicating that TLR4 is not essential for FliC-mediated signaling. To test the possibility that FliC signals via another TLR, we measured FliC-mediated activation of interleukin-1 (IL-1) receptor-associated kinase (IRAK), a central component in IL-1R/TLR signaling. FliC induced IRAK activation in HeNC2 and GG2EE cells as well as in the human promonocytic cell line THP-1. IRAK activation was rapid in HeNC2 cells, with maximal activity observed after 5 min of treatment with FliC. In addition, FliC-mediated IRAK activation exhibited the same concentration dependence as was demonstrated for the induction of TNF-alpha. These results represent the first demonstration of IRAK activation by a purified bacterial protein and strongly suggest that a TLR distinct from TLR4 is involved in the macrophage inflammatory response to FliC.


Synthesis and antimicrobial activity of hydroxyalkyl- and hydroxyacyl-phenols and their benzyl ethers.
New phenolic compounds with hydrophilic side chains were prepared from 4-benzyloxybenzaldehyde and alkenyl magnesium bromides, followed by Sharpless dihydroxylation and hydrogenolytic removal of the benzyl group. The resulting compounds were tested in an agar diffusion assay against gram positive bacteria, gram negative bacteria, and against the fungi Candida glabrata and Aspergillus niger.


Central action of narcotic analgesics. IX. Participation of serotonin in the development of tolerance to cataleptogenic effects of morphine in rats.
Subcutaneous implantation of morphine-base (75 mg) pellets over a period of 72 h caused the development of tolerance ot cataleptogenic action of morphine in rats. The development of morphine tolerance was inhibited by p-chlorophenylalanine (pCPA) or reserpine, drugs which decrease the content of brain serotonin (5-HT). Administration of 5-hydroxytryptophan (5-HTP(, which protected 5-HT stores against depleting action of reserpine, prevented the above of reserpine on the development of morphine tolerance in rats. Blockade of 5-HT neurotransmission by pizotifen or cyproheptadine inhibited the development of morphine tolerance, while the increase of it by imipramine did not alter the development of this tolerance . The Obtained results have shown that serotonergic system plays an important role in the development of tolerance to cataleptogenic effects of morphine.


Adaptive and Maladaptive Coping Strategies in Adult Pathological Gamblers and Their Mediating Role with Anxious-Depressive Symptomatology.
Coping plays a central role in the appearance and persistence of pathological gambling. Anxious and depressive symptomatology also influence pathological gambling and are related to coping. This study aimed to analyze pathological gamblers' coping strategies and styles, as well as associated anxious and depressive symptomatology. The study sample included 167 male pathological gamblers (mean age = 39.29 years) and 107 non-gamblers (mean age = 33.43 years). Measures of gambling, coping, and anxious and depressive symptomatology were used. Results showed that pathological gamblers' scored higher in all the maladaptive coping strategies, problem- and emotion-focused disengagement, and disengagement subscales. These subscales also correlated with pathological gambling, and anxious and depressive symptomatology. Pathological gamblers also scored higher in emotional expression and emotion-focused engagement, with no differences in the rest of the adaptive coping strategies. Coping was also found to predict pathological gambling and anxious and depressive symptomatology. It was found that coping mediated the relationship between pathological gambling and anxious symptomatology when controlling for the effect of age. Specifically, social withdrawal and disengagement stood out as mediators. These results provide practical information for use in clinical settings with people diagnosed with pathological gambling.


Characterization and quantitation of concanavalin a binding by plasma membrane enriched fractions from soybean root.
The binding of concanavalin A (Con A) to soybean root membranes in plasma membrane enriched fractions (recovered from the 34/45% interface of simplified discontinuous sucrose density gradients) was studied using a radiochemical assay employing tritiated ((3)H)-Con A. The effect of lectin concentration, time, and membrane protein concentration on the specific binding of (3)H-Con A by the membranes was evaluated. Kinetic analyses showed that Con A will react with membranes in that fraction in a characteristic and predictable manner. The parameters for an optimal and standard binding assay were established. Maximal binding occurred with Con A concentrations in the range of 8 to 16% of the total membrane protein with incubation times greater than 40 min at 22 C. Approximately 10(15) molecules of (3)H-Con A were bound per microgram of membrane protein at saturation. Binding was reversible. Greater than 92% of the total Con A bound at saturation was released by addition of alpha-methyl mannoside.A major peak of (3)H-Con A binding was also observed in fractions recovered from the 25/30% interface of a complex discontinuous sucrose density gradient when membranes were isolated in the absence of Mg(2+). When high Mg(2+) was present in the isolation and gradient media, the peak was shifted to a fraction recovered from the 34/38% sucrose interface. These results suggest that Con A binding sites are also present on membranes of the endoplasmic reticulum. The amount of Con A bound by endoplasmic reticulum membranes was at least twice the amount bound by membranes in plasma membrane enriched fractions when binding was compared on a per unit membrane protein basis. In contrast, mitochondrial inner membranes, which equilibrate at the same density as plasma membranes, had little ability to bind the lectin.


The Influence of PDCA Process Management on the Incidence of Stab Wound and Psychological Anxiety of Nursing Interns.
To research the influence of PDCA (Plan-Do-Check-Act) process management on the incidence of needle injury and psychological anxiety of nursing interns. This study belonged to the experimental study. A total of 180 nursing interns who practiced in the hospital from March 2020 to April 2022 were studied. A total of 135 interns from March 2020 to March 2021 were selected as the control group and 175 interns from April 2021 to April 2022 as the research group. PDCA process management was carried on in the research group. The control group did not make any intervention only following the routine teaching plan. The incidence of needle injury, theoretical knowledge, behavior score, self-rating anxiety scale (SAS), professional self-efficacy questionnaire score, and nursing practice satisfaction score were evaluated before and after 12 months of management. After management, the incidence of needle injury in the research group was lower compared to that in the control group, and there are statistically significant differences between groups (P < 0.05). The scores of theoretical knowledge, attitude, and behavior in the research group were higher compared to those in the control group, and there are statistically significant differences between groups (P < 0.05) after management. After 12 months of management, the SAS score of the research group was lower compared to that of the control group, and there are statistically significant differences between groups (P < 0.05). The score of occupational self-efficacy questionnaire in the research group was higher compared to that in the control group, and there are statistically significant differences between groups (P < 0.05) after PDCA process management. After 12 months of management, the satisfaction score of nursing practice in the research group was higher compared to that in the control group, and there are statistically significant differences between groups (P < 0.05). Through PDCA process management, we can keep abreast of the situation of needlestick injuries among nursing students in practice and analyze in more detail the root cause of each nursing student's occupational exposure and the outcome of treatment. The nursing students not only learn more practical knowledge in clinical practice but also feel that the hospital values and cares for them, which greatly increases their satisfaction.


Investigating the Metabolic Mesosulfuron-Methyl Resistance in Aegilops tauschii Coss. By Transcriptome Sequencing Combined with the Reference Genome.
Aegilops tauschii Coss. is a malignant weed in wheat fields in China, its herbicide resistance has been threatening crop production. This study identified one mesosulfuron-methyl-resistant(R) population, JJMHN2018-05 (R), without target resistance mutations. To fully understand the resistance mechanism, non-target site resistance was investigated by using transcriptome sequencing combined with a reference genome. Results showed that the cytochrome P450 monooxygenase (P450) inhibitor malathion significantly increased the mesosulfuron-methyl sensitivity in R plants, and greater herbicide-induced glutathione S-transferase (GST) activity was also confirmed. Liquid chromatography with tandem mass spectrometry analysis further supported the enhanced mesosulfuron-methyl metabolism in R plants. Gene expression data analysis and qRT-PCR validation indicated that eight P450s, six GSTs, two glycosyltransferases (GTs), four peroxidases, and one aldo-keto reductase (AKRs) stably upregulated in R plants. This research demonstrates that the P450s and GSTs involved in enhanced mesosulfuron-methyl metabolism contribute to mesosulfuron-methyl resistance in A. tauschii and identifies potential contributors from metabolic enzyme families.


Use of Botulinum Toxin A in the Treatment of Intermittent Exotropia: Factors Affecting Treatment Outcome.
To evaluate the efficiency of botulinum toxin A (BTA) injection in the treatment of intermittent exotropia (IXT) and determine factors affecting treatment outcome. A total of 74 patients diagnosed with any type of IXT were included in the study. BTA injection was administered into both lateral rectus muscles. Gender, refractive error, age, pre- and post-injection measurements of ocular deviation, age at the time of the first BTA injection, number of injections, duration of misalignment, age at the onset of misalignment, presence of amblyopia, presence of anisometropia, preterm birth history, type of delivery, presence of any neurological disorder, follow-up period, postoperative ptosis, and vertical deviation were recorded. The final angle of deviation was used in the statistical analysis. Successful motor alignment was defined as a deviation of ≤10 prism diopters (PD) at distance. The relationship of all factors with treatment success was analyzed using the binary logistic regression analysis. A total of 74 patients, 40 female and 34 male, were included in the study. All the patients were followed up for six to 53 months after the first BTA injection, and the mean follow-up was 16.1 ± 11.1 months. Before the first BTA injection of the patients, the mean amount of deviation was measured as 25.7 ± 14.2 (range, 0-60) PD at near and 37.1 ± 10.9 (range, 16-65) PD at distance. According to the most recent examination of the patients, the mean amount of deviation was 10.6 ± 9.8 (range, 0-45) PD at near and 16.4 ± 10.2 (range, 0-45) PD at distance. There was a statistically significant difference between the first and last examinations of the patients in relation to the amount of deviations measured at both near and distance (p < .001). Successful motor alignment (orthotropia within 10 PD for exodeviation) was achieved in 42 patients (56.7%). Thesuccess of treatment increased with the decreased amount of deviation at distance before the BTA injection. In patients with IXT, BTA injection into the lateral rectus muscles is an effective procedure, which is also less invasive and taking shorter time than surgery, and it can be considered as an alternative treatment option in those with small-medium angle IXT.


Factors affecting differences in Medicare reimbursements for physicians' services.
Under Medicare's Part B program, wide variations are found in average reimbursements for physicians' services by demographic and geographic characteristics of the beneficiaries. Average reimbursements per beneficiary enrolled in the program depend upon the percentage of enrolled persons who exceed the deductible and receive reimbursements, the average allowed charge per service, and the number of services used. This study analyzes differences in average reimbursements per beneficiary for physicians' services in 1975 and discusses allowed charges and use factors that affect average reimbursements. Differences in the level of allowed charges and their impact on meeting the annual deductible are also discussed. The study indicates that average reimbursements per beneficiary are likely to continue to vary significantly year after year under the present Part B cost-sharing and reimbursement mechanisms.


Enhancing functional electrical stimulation for emerging rehabilitation robotics in the framework of HYPER project.
This paper presents the development of a novel functional electrical stimulation (FES) system. New approaches in emerging rehabilitation robotics propose the use of residual muscular activity or limbs movements during the rehabilitation process of neuromotor. More ambitious projects propose the use of FES systems to restore or compensate motor capabilities by controlling existing muscles or subject limbs. These emerging approaches require more sophisticated FES devices in terms of channels, signals controls and portability. In the framework of HYPER project, such devices are being developed to support the main objective of the project: the development of neurorobots and neuroprosthetics to restore functional motor capabilities in patients who suffered cerebrovascular accidents or spinal cord injury. The presented portable FES system includes novel elec-trostimulator circuits and improved channel switching capacities to enable emerging approaches in rehabilitation robotics.


Prolonged administration of a dithiol antioxidant protects against ventricular remodeling due to ischemia-reperfusion in mice.
The prolonged production of reactive oxygen species due to ischemia-reperfusion (I/R) is a potential cause of the pathological remodeling that frequently precedes heart failure. We tested the ability of a potent dithiol antioxidant, bucillamine, to protect against the long-term consequences of I/R injury in a murine model of myocardial infarction. After transiently occluding the left anterior descending coronary artery for 30 min, saline or bucillamine (10 microg/g body wt) was injected intravenously as a bolus within the first 5 min of reperfusion. The antioxidant treatment continued with daily subcutaneous injections for 4 wk. There were no differences in infarct sizes between bucillamine- and saline-treated animals. After 4 wk of reperfusion, cardiac hypertrophy was decreased by bucillamine treatment (ventricular weight-to-body weight ratios: I/R + saline, 4.5 +/- 0.2 mg/g vs. I/R + bucillamine, 4.2 +/- 0.1 mg/g; means +/- SE; P < 0.05). Additionally, the hearts of bucillamine-treated mice had improved contractile function (echocardiographic measurement of fractional shortening) relative to saline controls: I/R + saline, 32 +/- 3%, versus I/R + bucillamine, 41 +/- 4% (P < 0.05). Finally, I/R-induced injury in the saline-treated mice was accompanied by a fetal pattern of gene expression determined by ribonuclease protection assay that was consistent with pathological cardiac hypertrophy and remodeling [increased atrial natriuretic peptide, beta-myosin heavy chain (MHC), skeletal alpha-actin; decreased sarco(endo)plasmic reticulum Ca2+ ATPase 2a, and alpha-MHC-to-beta-MHC ratio]. These changes in gene expression were significantly attenuated by bucillamine. Therefore, treatment with a dithiol antioxidant for 4 wk after I/R preserved ventricular function and prevented the abnormal pattern of gene expression associated with pathological cardiac remodeling.


The effect of MTHFR ala222val polymorphism on open-angle glaucoma: a meta-analysis.
Glaucoma is the second leading cause of irreversible blindness worldwide, among which primary open-angle glaucoma (POAG) is the most common form of glaucoma in some populations. To date, published data on the association between MTHFR (Ala222Val) polymorphism and POAG risk are still inconclusive. In this work, we performed a meta-analysis of available case-control study in order to assess the association between MTHFR (Ala222Val) polymorphism and POAG susceptibility. In total we compiled 13 studies (1970 POAG patients and 1712 control subjects) into the meta-analysis. Overall, no obvious associations between MTHFR (Ala222Val) polymorphism and POAG susceptibility was found under all four genetic models (Val/Val versus Ala/Ala: OR = 1.05, 95% CI = 0.77-1.43; Ala/Val versus Ala/Ala: OR = 1.05, 95% CI = 0.86-1.26; Ala/Val + Val/Val versus Ala/Ala: OR = 1.08, 95% CI = 0.87-1.34; Val/Val versus Ala/Val + Ala/Ala: OR = 1.14, 95% CI = 0.67-1.92). In the stratified analysis by ethnicity, significant associations were still not observed in all genetic models. In conclusion, based on 13 eligible studies, the result provided strong evidences that MTHFR Ala222Val polymorphism is not associated with POAG.


Self-Reported Reasons for Abstinence from Illicit Drugs.
To provide a more balanced understanding of the initiation and restraint of substance use, educators, clinicians, and researchers would benefit from a review of research assessing the reasons nonusers report for having abstained from drugs. Based on searches of computerized databases and the reference sections of relevant articles, we identified 15 relevant studies that assessed and quantified participants' expressed reasons for having abstained from (a) one or more named substances or (b) drugs (or alcohol and drugs) with little or no further specification. We defined as more salient those 25% of reasons in each study that were endorsed most frequently, ranked highest, or rated most influential. Five reasons - concerns about physical health, lack of interest, harmful psychological consequences, personal beliefs/morals, and peer/family disapproval - were most frequently identified as salient across studies and substances. These salient reasons are consistent with outcome expectancy and social learning models that have been proposed to explain drug initiation. To enhance the value of future research, we recommend testing whether importance ratings differ across contexts; repeatedly assessing within-subject variability of reasons across time; evaluating the association of psychological characteristics with reasons for abstaining; and continuing to evaluate which reasons for abstaining vary by type of drug, gender, ethnicity, and religiosity. We also recommend additional research comparing which reasons predict continued abstinence and which predict initiation of use during follow-up.


[Simultaneous determination of eleven components in Ginkgo biloba leaves by high performance liquid chromatography method].
To study Ginkgo biloba leaves in different producing area, we establish an HPLC method for the simultaneously determination of seven flavonoids glycosides and four biflavonoids in G. biloba leaves. The analysis was performed on an Agilent ZORBAX SB-C₁₈ column(4.6 mm×250 mm, 5 μm) wich acetonitrile, and 0.4% phosphoric acid as mobile phase at flow rate of 1 mL•min⁻¹ in a gradient edution, and the detection was carried out at 254 nm.The calibration curves of the seven flavonoids glycosides and four biflavonoids had a good linearitiy with good recoveries. The established HPLC method is simple, rapid, accurate, reliable, and sensitive, and can be applied to the identification and quality control of G. biloba leaves.


Computational Analysis and Predictive Cheminformatics Modeling of Small Molecule Inhibitors of Epigenetic Modifiers.
The dynamic and differential regulation and expression of genes is majorly governed by the complex interactions of a subset of biomolecules in the cell operating at multiple levels starting from genome organisation to protein post-translational regulation. The regulatory layer contributed by the epigenetic layer has been one of the favourite areas of interest recently. This layer of regulation as we know today largely comprises of DNA modifications, histone modifications and noncoding RNA regulation and the interplay between each of these major components. Epigenetic regulation has been recently shown to be central to development of a number of disease processes. The availability of datasets of high-throughput screens for molecules for biological properties offer a new opportunity to develop computational methodologies which would enable in-silico screening of large molecular libraries. In the present study, we have used data from high throughput screens for the inhibitors of epigenetic modifiers. Computational predictive models were constructed based on the molecular descriptors. Machine learning algorithms for supervised training, Naive Bayes and Random Forest, were used to generate predictive models for the small molecule inhibitors of histone methyl-transferases and demethylases. Random forest, with the accuracy of 80%, was identified as the most accurate classifier. Further we complemented the study with substructure search approach filtering out the probable pharmacophores from the active molecules leading to drug molecules. We show that effective use of appropriate computational algorithms could be used to learn molecular and structural correlates of biological activities of small molecules. The computational models developed could be potentially used to screen and identify potential new biological activities of molecules from large molecular libraries and prioritise them for in-depth biological assays. To the best of our knowledge, this is the first and most comprehensive computational analysis towards understanding activities of small molecules inhibitors of epigenetic modifiers.


Examining clinical decision support integrity: is clinician self-reported data entry accurate?
The aim of this study was to assess the accuracy of clinician-entered data in imaging clinical decision support (CDS). We used CDS-guided CT angiography (CTA) for pulmonary embolus (PE) in the emergency department as a case example because it required clinician entry of d-dimer results which could be unambiguously compared with actual laboratory values. Of 1296 patients with CTA orders for suspected PE during 2011, 1175 (90.7%) had accurate d-dimer values entered. In 55 orders (4.2%), incorrectly entered data shielded clinicians from intrusive computer alerts, resulting in potential CTA overuse. Remaining data entry errors did not affect user workflow. We found no missed PEs in our cohort. The majority of data entered by clinicians into imaging CDS are accurate. A small proportion may be intentionally erroneous to avoid intrusive computer alerts. Quality improvement methods, including academic detailing and improved integration between electronic medical record and CDS to minimize redundant data entry, may be necessary to optimize adoption of evidence presented through CDS.


[Hyperprolactinemia in children with celiac disease].
The serum prolactin level was determined serially in patients with coeliac disease during gluten uptake and on gluten free diet, and in one to 14 years old healthy children serving as controls. The prolactin levels in healthy controls and in coeliac patients on diet were within normal limits whereas in children with coeliac disease taking gluten in their meals significant hyperprolactinaema was found.


International Classification of Diseases coding changes lead to profound declines in reported idiopathic pulmonary arterial hypertension mortality and hospitalizations: implications for database studies.
Database studies have reported several associations between the diagnosis of idiopathic pulmonary arterial hypertension (IPAH) and mortality attributable to IPAH, including older age, black race, and diabetes. We investigated reported deaths and hospital discharges coded as IPAH and compared these with other forms of pulmonary hypertension. Three databases were used: the US National Center for Health Statistics database (1979-2006), queried for mortality data; the Nationwide Inpatient Sample database (1993-2007), queried for hospital discharge data; and the University of Texas Southwestern Hospital-Zale Lipshy discharge database (1999, 2002). Marked increases in mortality attributable to IPAH and to pulmonary hypertension (all codes combined) generally were reported from 1979 until 2002 in the National Center for Health Statistics database. In 2003, reported IPAH mortality fell sharply while total pulmonary hypertension deaths increased. The Nationwide Inpatient Sample database showed a similar pattern of changes beginning approximately 2 years earlier. In both cases, the timing of these observations corresponded with changes made to the International Classification of Diseases (ICD) coding system in use for pulmonary hypertension in that particular database. Review of pulmonary hypertension discharge data from the University of Texas Southwestern Hospital-Zale Lipshy showed similar changes in diagnosis code use. Sudden shifts in reported IPAH mortality and hospital discharges were seen in all databases, likely related to coding changes. These findings raise questions about the accuracy of pulmonary hypertension diagnosis codes. Studies based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, 10th Revision codes may have inadvertently included patients with other forms of pulmonary hypertension and should be reevaluated in this context. Validation studies of the IPAH diagnosis code are needed, and changes to the ICD coding system should be considered.


Toward the Development of Rapid, Specific, and Sensitive Microfluidic Sensors: A Comprehensive Device Blueprint.
Recent advances in nano/microfluidics have led to the miniaturization of surface-based chemical and biochemical sensors, with applications ranging from environmental monitoring to disease diagnostics. These systems rely on the detection of analytes flowing in a liquid sample, by exploiting their innate nature to react with specific receptors immobilized on the microchannel walls. The efficiency of these systems is defined by the cumulative effect of analyte detection speed, sensitivity, and specificity. In this perspective, we provide a fresh outlook on the use of important parameters obtained from well-characterized analytical models, by connecting the mass transport and reaction limits with the experimentally attainable limits of analyte detection efficiency. Specifically, we breakdown when and how the operational (e.g., flow rates, channel geometries, mode of detection, etc.) and molecular (e.g., receptor affinity and functionality) variables can be tailored to enhance the analyte detection time, analytical specificity, and sensitivity of the system (i.e., limit of detection). Finally, we present a simple yet cohesive blueprint for the development of high-efficiency surface-based microfluidic sensors for rapid, sensitive, and specific detection of chemical and biochemical analytes, pertinent to a variety of applications.


The Influence of Visual Input on Electromyographic Patterns of Masticatory and Cervical Spine Muscles in Subjects with Myopia.
This study aimed to analyze the change of visual input on electromyographic patterns of masticatory and cervical spine muscles in subjects with myopia. After applying the inclusion criteria, 50 subjects (18 males and 32 females) with myopia ranging from -0.5 to -5.75 Diopters (D), were included in the study. Four muscle pairs were analyzed: the anterior part of the temporalis muscle (TA), the superficial part of the masseter muscle (MM), the anterior belly of the digastric muscle (DA), and the middle part of the sternocleidomastoid muscle belly (SCM) during resting and functional activity. Statistical analysis showed a significant decrease within functional indices (FCI) for the sternocleidomastoid muscle (FCI SCM R, FCI SCM L, FCI SCM total) during clenching in the intercuspal position with eyes closed compared to eyes open. During maximum mouth opening, a statistically significant increase of functional opening index for the left temporalis muscle (FOI TA L) was observed. Within the activity index (AcI), there was a statistically significant decrease during clenching on dental cotton rollers with eyes closed compared to eyes open.


Exact solution for mean first-passage time on a pseudofractal scale-free web.
The explicit determinations of the mean first-passage time (MFPT) for trapping problem are limited to some simple structure, e.g., regular lattices and regular geometrical fractals, and determining MFPT for random walks on other media, especially complex real networks, is a theoretical challenge. In this paper, we investigate a simple random walk on the the pseudofractal scale-free web (PSFW) with a perfect trap located at a node with the highest degree, which simultaneously exhibits the remarkable scale-free and small-world properties observed in real networks. We obtain the exact solution for the MFPT that is calculated through the recurrence relations derived from the structure of PSFW. The rigorous solution exhibits that the MFPT approximately increases as a power-law function of the number of nodes, with the exponent less than 1. We confirm the closed-form solution by direct numerical calculations. We show that the structure of PSFW can improve the efficiency of transport by diffusion, compared with some other structure, such as regular lattices, Sierpinski fractals, and T-graph. The analytical method can be applied to other deterministic networks, making the accurate computation of MFPT possible.


Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocrotaline-induced pulmonary hypertensive rats.
In monocrotaline (MCT)-induced pulmonary hypertension (PH), only the right ventricle (RV) endures overload, but both ventricles are exposed to enhanced neuroendocrine stimulation. To assess whether in long-standing PH the left ventricular (LV) myocardium molecular/contractile phenotype can be disturbed, we evaluated myocardial function, histology, and gene expression of autocrine/paracrine systems in rats with severe PH 6 wk after subcutaneous injection of 60 mg/kg MCT. The overloaded RV underwent myocardial hypertrophy (P < 0.001) and fibrosis (P = 0.014) as well as increased expression of angiotensin-converting enzyme (ACE) (8-fold; P < 0.001), endothelin-1 (ET-1) (6-fold; P < 0.001), and type B natriuretic peptide (BNP) (15-fold; P < 0.001). Despite the similar upregulation of ET-1 (8-fold; P < 0.001) and overexpression of ACE (4-fold; P < 0.001) without BNP elevation, the nonoverloaded LV myocardium was neither hypertrophic nor fibrotic. LV indexes of contractility (P < 0.001) and relaxation (P = 0.03) were abnormal, however, and LV muscle strips from MCT-treated compared with sham rats presented negative (P = 0.003) force-frequency relationships (FFR). Despite higher ET-1 production, BQ-123 (ET(A) antagonist) did not alter LV MCT-treated muscle strip contractility distinctly (P = 0.005) from the negative inotropic effect exerted on shams. Chronic daily therapy with 250 mg/kg bosentan (dual endothelin receptor antagonist) after MCT injection not only attenuated RV hypertrophy and local neuroendocrine activation but also completely reverted FFR of LV muscle strips to positive values. In conclusion, the LV myocardium is altered in advanced MCT-induced PH, undergoing neuroendocrine activation and contractile dysfunction in the absence of hypertrophy or fibrosis. Neuroendocrine mediators, particularly ET-1, may participate in this functional deterioration.


Exaggerated and prolonged thyrotrophin releasing hormone (TRH) test responses in tertiary hypothyroidism.
A 60 year old man with panhypopituitarism due to a large meningioma and prolonged and exaggerated thyroid stimulating hormone (TSH) responses is described. Initial investigations showed a subnormal urinary free cortisol concentration, a low serum cortisol taken at 0900 hours, and a low free T4 concentration. The TSH was towards the upper end of the normal range. Subsequently pituitary function tests showed subnormal production of luteinising hormone in response to luteinising hormone releasing hormone (LHRH) and a short synacthen test with a low 30 minute cortisol value. Long synacthen testing showed a normal response at four days, confirming that the abnormalities were due to a pituitary or hypothalamic cause. A computed tomogram showed a large meningioma compressing the hypothalamus, pituitary, and temporal lobe. TRH testing showed a prolonged and exaggerated response, consistent with tertiary hypothyroidism.


Effects of taphonomic deformation on geometric morphometric analysis of fossils: a study using the dicynodont Diictodon feliceps (Therapsida, Anomodontia).
Taphonomic deformation, the distortion of fossils as a result of geological processes, poses problems for the use of geometric morphometrics in addressing paleobiological questions. Signal from biological variation, such as ontogenetic trends and sexual dimorphism, may be lost if variation from deformation is too high. Here, we investigate the effects of taphonomic deformation on geometric morphometric analyses of the abundant, well known Permian therapsid Diictodon feliceps. Distorted Diictodon crania can be categorized into seven typical styles of deformation: lateral compression, dorsoventral compression, anteroposterior compression, "saddle-shape" deformation (localized collapse at cranial mid-length), anterodorsal shear, anteroventral shear, and right/left shear. In simulated morphometric datasets incorporating known "biological" signals and subjected to uniform shear, deformation was typically the main source of variance but accurate "biological" information could be recovered in most cases. However, in empirical datasets, not only was deformation the dominant source of variance, but little structure associated with allometry and sexual dimorphism was apparent, suggesting that the more varied deformation styles suffered by actual fossils overprint biological variation. In a principal component analysis of all anomodont therapsids, deformed Diictodon specimens exhibit significant dispersion around the "true" position of this taxon in morphospace based on undistorted specimens. The overall variance associated with deformation for Anomodontia as a whole is minor, and the major axes of variation in the study sample show a strong phylogenetic signal instead. Although extremely problematic for studying variation in fossil taxa at lower taxonomic levels, the cumulative effects of deformation in this study are shown to be random, and inclusion of deformed specimens in higher-level analyses of morphological disparity are warranted. Mean morphologies of distorted specimens are found to approximate the morphology of undistorted specimens, so we recommend use of species-level means in higher-level analyses when possible.


Bacille Calmette-Guérin (BCG)-associated inflammation and fibrosis: modulation by recombinant BCG expressing interferon-gamma (IFN-gamma).
Immunization with existing BCG vaccines has failed to confer consistent protection against tuberculosis. One of the ways to improve the efficacy of BCG is by enhancing its ability to induce a type-1 T cell response. However, this approach carries the risk that enhanced immunoreactivity may exacerbate tissue pathology associated with vaccination. The aim of the present study was to determine whether use of a recombinant BCG expressing IFN-gamma (BCG-IFN) would result in an alteration in the pattern of inflammation and local tissue fibrosis. A murine intravenous BCG infection model was used in which there was a time- and dose-dependent increase in the weight and number of granulomas in the liver. Infection was associated with increased inflammatory activity in the liver, as shown by the increase in expression of inducible nitric oxide synthase (iNOS) assessed by immunochemistry and by measurement of specific mRNA, and in fibrosis measured by hydroxyproline content of the liver and percentage of granuloma cells staining positively for type 1 procollagen. Infection with BCG-IFN resulted in a reduction in organ weight and bacterial load on day 21 compared with infection with control BCG transformed with vector alone (BCG-plasmid). By day 21, there was also a reduction in iNOS mRNA and iNOS+ cells in granulomas in mice infected with BCG-IFN compared with infection with BCG-plasmid, and a similar reduction in both total number of granulomas and liver hydroxyproline content. These results demonstrate that the granulomas in the areas of mycobacterial infection are active sites of both inflammation and fibrosis, and that the local expression of IFN-gamma by the recombinant BCG results in more efficient bacterial clearance which is accompanied by a reduction in tissue pathology.


QT dispersion in renal transplant recipients.
An increased QT dispersion (QTd) is associated with a variety of cardiac diseases and predicts sudden death. Although chronic renal failure patients and patients on hemodialysis are shown to have an increased QTd, evidence of increased QTd in renal transplant patients is scarce. In this study, renal transplant patients were evaluated to find out if they had an increased QTd. Thirty-four renal transplant recipients aged 35 +/- 8 years and 34 healthy control subjects aged 34 +/- 8 years were included in the study. The mean time after transplantation was 51.8 +/- 40.4 (range 5-154) months. The QT interval was measured by 12-lead electrocardiogram, and the QTd was defined as the difference between the maximum and minimum QT interval. Bazett's formula was used to correct for the heart rate (QTc). Both QTd and QTc dispersion (QTcd) in renal transplant patients were compared with those of control subjects. All patients underwent transthoracic echocardiographic assessment and 24-hour ambulatory blood pressure monitoring. Renal transplant recipients had similar QTd (37 +/- 15 vs. 39 +/- 17 ms) and QTcd (50 +/- 18 vs. 55 +/- 20 ms) compared to control subjects. QTd and QTcd were similar in patients with and without left ventricular hypertrophy (QTd 37 +/- 14 vs. 36 +/- 17 ms and QTcd 50 +/- 14 vs. 49 +/- 21 ms, respectively). No association was found between QTd and left ventricular mass index or blood pressure measurements. The QTd was not found to be increased in renal transplant recipients as compared with that of healthy controls in this study. Normalization of the QTd after renal transplantation may be through the correction of several factors responsible for increased QTd in uremic patients.


Goodness-of-fit tests for correlated paired binary data.
We review a few popular statistical models for correlated binary outcomes, present maximum likelihood estimates for the model parameters, and discuss model selection issues using a variety of goodness-of-fit test statistics. We apply bootstrap strategies that are computationally efficient to evaluate the performance of goodness-of-fit statistics and observe that generally the power and the type I error rate of the goodness-of-fit statistics depend on the model under investigation. Our simulation results show that careful choice of goodness-of-fit statistics is an important issue especially when we have a small sample and the outcomes are highly correlated. Two biomedical applications are included.


Evaluation of Structural Neural Connectivity Between the Primary Auditory Cortex and Cognition-Related Brain Areas Using Diffusion Tensor Tractography in 43 Normal Adults.
BACKGROUND Little is known about the structural neural connectivity between the primary auditory cortex and cognition-related brain areas in the human brain. This study aimed to evaluate the structural neural connectivity between the primary auditory cortex and cognition-related brain areas in normal subjects, using diffusion tensor tractography (DTT). MATERIAL AND METHODS Forty-three healthy subjects with no prior history of audiological, neurological, physical, or psychiatric illnesses were recruited for this study. Diffusion tensor imaging data analysis was performed using the Oxford Centre for Functional Magnetic Resonance Imaging of Brain (FMRIB) Software Library. In each subject, a region of interest was set on the primary auditory cortex, including the subcortical white matter. We assessed the neural connectivity between the primary auditory cortex and cognition-related brain areas (the dorsolateral prefrontal cortex [DLPFC]; ventrolateral prefrontal cortex [VLPFC]; orbitofrontal cortex [OFC]; hippocampus; parahippocampal cortex; amygdala, anterior and posterior cingulate gyrus; and fornix). RESULTS According to the results of DTT, the primary auditory cortex showed neural connectivity (over 50%) with the following areas: the threshold of 1 streamline - the VLPFC (94.2%), OFC (84.9%), fornix (80.2%), hippocampus (76.7%), parahippocampal cortex(74.4%) and DLPFC (58.1%); the threshold of 5 streamlines - the VLPFC (88.4%), OFC (81.4%), fornix (66.3%), hippocampus (55.8%), and parahippocampal cortex (53.5%); and the threshold of 15 streamlines - the VLPFC (82.6%), OFC (74.4%), and fornix (53.5%). CONCLUSIONS In normal human subjects, DTT showed that the primary auditory cortex had a high degree of neural connectivity with the prefrontal cortex, fornix, hippocampus, and parahippocampal cortex, which are brain areas associated with cognition and memory.


Imprinting and expression of insulin-like growth factor-II and H19 in normal breast tissue and breast tumor.
Insulin-like growth factor (IGF)-II is a mitogenic peptide that has been reported to play an important role in the formation and growth of a variety of tumors. In most tissues, the IGF-II gene (IGF2) is parentally imprinted, with only the paternal allele being expressed. IGF2 messenger RNA (mRNA) and protein are overexpressed in some benign and malignant tumors. H19, a tumor suppressor gene located directly downstream from IGF2, is also genomically imprinted, but the paternal allele is silenced. It has been suggested that alterations in the imprinting of these two genes, which are located at chromosome 11p15.5, may lead to a malignant diathesis. We examined 18 fresh-frozen (FF) breast tumors with their adjacent normal breast tissue and 14 sets of paraffin-embedded formalin-fixed tissues for IGF2 and H19 gene expression and imprinting. IGF2 mRNA and H19 RNA could be quantitated in 15 of the 18 FF tumors. Although three of these tumors showed a > or = 2-fold increase in IGF2 expression when compared with the normal control tissues, the average abundance of IGF2 mRNA in 8 of 15 FF samples was < 50% that observed in the normal tissue. The expression of H19 RNA in these tumors was increased by > or = 2-fold in 5 tumors, but decreased by < or = 50% in 6 tumors when compared with normal adjacent tissue. By examining the ApaI and CA-repeat polymorphisms in the IGF2 gene, we found that the imprinting of IGF2 was maintained in all but 2 of the 17 informative subjects. H19 imprinting was maintained in all 18 informative fresh-frozen and paraffin-embedded formalin-fixed samples. Our data suggest that alterations in IGF2 and H19 gene expression and loss of imprinting do not occur reliably in breast cancer.


Peanut agglutinin appearance in the blood circulation after peanut ingestion mimics the action of endogenous galectin-3 to promote metastasis by interaction with cancer-associated MUC1.
Peanut agglutinin (PNA), which accounts for ~0.15% of the weight of the common peanut, is a carbohydrate-binding protein that binds the oncofoetal Thomsen-Friedenreich (TF) disaccharide (galactoseβ1,3N-acetylgalactosamineα-) that is overexpressed by ~90% of human cancers. Previous studies have shown that PNA is highly resistant to cooking and digestion and rapidly enters the human blood circulation after peanut ingestion. This study investigates the hypothesis that PNA appearance in the circulation after peanut ingestion may mimic the actions of endogenous TF-binding human galectin-3 in metastasis promotion. It shows that PNA at concentrations similar to those found in blood circulation after peanut ingestion increases cancer cell heterotypic adhesion to the blood vascular endothelium and enhances the formation of tumour cell homotypic aggregates, two important steps in the metastasis cascade, and enhances metastasis in a mouse metastasis model. These effects of PNA are shown to result from its interaction with the cancer-associated TF disaccharide on the transmembrane mucin protein MUC1, causing MUC1 cell surface polarization that reveals underlying cell surface adhesion molecules. Thus, PNA appearance in the blood circulation after peanut ingestion mimics the actions of endogenous galectin-3 and promotes cancer cell metastatic spread by interaction with cancer-associated TF/MUC1. As metastasis accounts for the majority of cancer-associated fatality, regular consumption of peanuts by cancer patients would therefore be expected to have an adverse effect on cancer survival.


Phospho-signaling couples polar asymmetry and proteolysis within a membraneless microdomain in C. crescentus.
Asymmetric cell division in bacteria is achieved through cell polarization, where regulatory proteins are directed to specific cell poles. Curiously, both poles contain a membraneless microdomain, established by the polar assembly hub PopZ, through most of the cell cycle, yet many PopZ clients are unipolar and transiently localized. We find that PopZ's interaction with the response regulator CpdR is controlled by phosphorylation, via the histidine kinase CckA. Phosphorylated CpdR does not interact with PopZ and is not localized to cell poles. At poles where CckA acts as a phosphatase, de-phosphorylated CpdR binds directly with PopZ and subsequently recruits ClpX, substrates, and other members of a protease complex to the cell pole. We also find that co-recruitment of protease components and substrates to polar microdomains enhances their coordinated activity. This study connects phosphosignaling with polar assembly and the activity of a protease that triggers cell cycle progression and cell differentiation.


Infrared multiphoton dissociation tandem charge detection-mass spectrometry of single megadalton electrosprayed ions.
This work presents the implementation of tandem mass spectrometry for experiments on single electrosprayed ions from compounds of megadalton (MDa) molecular weight, using two charge detection devices. The first mass spectrometry stage (first charge detection device) combined with an ion gate allows both mass-to-charge ratio and charge selections of the megadalton ion of interest. The second stage is based on an electrostatic ion trap and consists of an image charge detection tube mounted between two ion mirrors. Single MDa ions can be stored for several dozen milliseconds. During the trapping time, single ions can be irradiated by a continuous wavelength CO(2) laser. We observe stepwise changes in the charge of a single trapped ion owing to multiphoton activation. Illustration of infrared multiphoton dissociation tandem mass spectrometry are given for single megadalton ions of poly(ethylene oxide)s and DNAs.


Pyroptosis-related gene-based prognostic signature for predicting the overall survival of oral squamous cell carcinoma patients.
Oral squamous cell carcinoma (OSCC) is the most common oral cancer worldwide. Pyroptosis is a type of programmed cell death mediated by caspase, accompanied by an inflammatory response, and plays an important role in cancer progression. The purpose of this study was to explore and identify potential biomarkers and further elucidate the potential role of cell pyroptosis in OSCC. We regarded the samples from The Cancer Genome Atlas database as a training dataset, screened differentially expressed genes (DEGs), and further screened out OSCC phenotypic characteristic genes by using weighted gene co-expression network analysis. The analysis of 42 known pyroptosis-related genes showed that Psuch genes were widely expressed, mutated, and methylated in OSCC samples. Through correlation analysis, we identified our OSCC pyroptosis-related DEGs. To further evaluate the prognostic value of pyroptosis-related regulators, we constructed a seven gene-based prognostic signature using Cox univariate analysis and least absolute shrinkage and selection operator Cox regression analysis. Meanwhile, we found that patients in the low-risk group had higher immune infiltration. Moreover, our results also indicated significant differences in sensitivity to cisplatin and gefitinib between the high-risk and low-risk groups. Our study successfully constructed the pyroptosis-related prognostic signature, which might play a potential prediction role in OSCC prognosis. Our findings also suggested that pyroptosis-related regulators might be novel biomarkers for tumor diagnosis and treatment in OSCC.