[Spasmex treatment of patients with hyperactive urinary bladder].
Overactive urinary bladder (HAUB) is encountered in 16-20% patients with various voiding disorders. Etiologically, detrusor hyperactivity can be neurogenic and idiopathic. We studied efficacy of the antimuscarine drug spasmex in patients with imperative voiding disorders and compared its efficacy and tolerance with those of driptan and detrusitol. 193 female patients with imperative voiding disorders were examined. Spasmex given in a dose of 5 mg 3 times a day for 12 weeks produced a good effect in 56 patients: increased the effective capacity of the urinary bladder, reduced the number of voidings and episodes of incontinence for a day. A 3-month course of spasmex proved highly effective as shown by the patients' subjective response and positive changes in objective evidence. Being equally effective with detrusitol and driptan, spasmex is much superior to oxibutynin in safety.


Ultrasound-guided Intravenous Line Placement Course for Certified Registered Nurse Anesthetists: A Necessary Next Step.
Ultrasonography (US) proficiency has become a desirable skill for anesthesia providers. It is commonly used in the perioperative arena for establishing peripheral and central vascular access. Establishing intravenous access is one of the most common procedures performed by Certified Registered Nurse Anesthetists (CRNAs) as frontline anesthesia providers. However, there is no structured US training program for CRNAs for vascular access at our institution. We designed and implemented a multimodality US training program specifically for the use of surface US for central and peripheral vascular access for CRNAs. The course was conducted over 2 days and consisted of an online self-paced didactic component, integrated proctored hands-on workshops, and a posttraining examina-tion to quantify knowledge gain. Twenty-five CRNAs attended the course, with significant improvement in knowledge (pretest mean (SD) score = 59.13% (15.74%) vs posttest mean score = 70.0% (9.43%), P = .03). Two weeks after the course, each participant reported that they attempted 1.46 (1.56) ultrasound-guided vascular access procedures on average. Therefore, it is feasible to design short, focused, multimodality training programs for proficiency in the use of surface US for obtaining venous access. The CRNA's proficiency in US is likely to improve efficiency, patient experience, and safety.


Topiramate and word-finding difficulties in patients with epilepsy.
To evaluate the prevalence of word-finding difficulties as a treatment-emergent adverse event in patients with epilepsy taking topiramate and to identify a clinical phenotype at risk. The authors investigated the relationship of word-finding difficulties to topiramate titration schedule, seizure frequency and pattern, and EEG and neuroradiologic findings in 431 consecutively and prospectively collected patients taking topiramate. Thirty-one patients (7.2%) developed word-finding difficulties. Presence of simple partial seizures (OR = 6.7 p = 0.007) and a left temporal EEG epileptic focus (OR = 5.2 p = 0.021) were significantly associated with word-finding difficulties. The presence of word-finding difficulties seems to be a titration schedule independent phenomenon that occurs in a subgroup of patients with a specific biologic vulnerability.


Maternal HIV infection is associated with distinct systemic cytokine profiles throughout pregnancy in South African women.
Maternal HIV infection is associated with adverse pregnancy outcomes, but the mechanisms remain unknown. The course of pregnancy is regulated by immunological processes and HIV infection and antiretroviral therapy (ART) impact key immune mechanisms, which may disrupt the immune programme of pregnancy. We evaluated a broad range of systemic cytokines at each trimester of pregnancy in 56 women living with HIV (WLHIV) and 68 HIV-negative women, who were enrolled in a prospective pregnancy cohort study in Soweto, South Africa. The pro-inflammatory cytokine IP-10 was detected in each trimester in all WLHIV, which was significantly more than in HIV-negative women. The anti-viral cytokine IFNλ1 was detected more frequently in WLHIV, whereas IFNβ and IFNλ2/3 were detected more frequently in HIV-negative women. Th1 cytokines IL-12 and IL-12p70, Th2 cytokine IL-5, and Th17 cytokine IL-17A were detected more frequently in WLHIV throughout pregnancy. Il-6, IL-9, and IL-10 were more commonly detected in WLHIV in the first trimester. Trends of increased detection of Th1 (IL-2, IL-12p70), Th2 (IL-4, Il-5, Il-13) and Th17 (IL-17A, Il-17F, IL-21, IL-22) cytokines were associated with small-for-gestational-age babies. Our findings indicate that maternal HIV/ART is associated with distinct systemic cytokine profiles throughout pregnancy.


Localized bullous pemphigoid. A mimic of acute contact dermatitis.
A case of localized bullous pemphigoid that mimicked an acute contact dermatitis around a stoma site is presented. The diagnosis was confirmed by direct immunofluorescence and by indirect immunofluorescence on 1.0 mol/L of sodium chloride split skin. A review of the literature demonstrates 30 previous well-documented cases of localized bullous pemphigoid. As in our case, local factors such as trauma, ultraviolet light, or topical therapy seem to be frequently implicated in the production of lesions. The possibility that these patients might otherwise have subclinical bullous pemphigoid was considered. The disease has a benign course and generally responds to cessation of exacerbating factors and initiation of topical steroid therapy.


Seasonal and vertical distribution of Phyllophaga cuyabana (Moser)(Coleoptera: Melolonthidae) in the soil profile.
Phyllophaga cuyabana (Moser) temporal and vertical distribution patterns were evaluated in the soil profile, in order to subsidize methodology for population sampling, aiming at its management. In insect surveys carried out during three years, in Boa Esperança County, State of Parana, Brazil, Phyllophaga cuyabana was univoltine, with little overlap of the larval stages. Population peaked during December-February, but declined during the colder months, when larvae were in diapause. Different developmental stages exploited distinct soil depths. Eggs and early first instars tended to concentrate between 5 cm and 10 cm deep, but they spread more uniformly through the soil profile, reaching depths up to 30 cm, as they developed. Adults and eggs occurred in the spring (October to December) when active larvae also started to be observed; feeding larvae occurred up to late-April between 0 to 15 cm deep. Diapausing larvae and pupae were observed from early fall to early spring, mostly from 15 cm to 30 cm deep. Throughout the year, the number of insects in the soil (up to 40 cm deep) showed a positive functional relationship with air temperature and evapotranspiration. The relationship of percent distribution of larvae in the soil profile and soil temperature, however, was positive only above 10 cm. To estimate the insect population from November to April, samples can be collected until 20 cm deep; from May to October, however, samplings should be deeper, up to 30 cm.


Humic substances: fulvic acid-dialkyl phthalate complexes and their role in pollution.
Fulvic acid is a water-soluble humic material with relatively low molecular weight that occurs widely in soils and waters. It can combine with lyophobic organic compounds such as alkanes, fatty acids, and dialkyl phthalates to form stable "complexes" that are soluble in water. Fulvic acid in an aquatic environment may act as a vehicle for the mobilization, transport, and immobilization of organic compounds, some of which may be toxic pollutants.


The Incidence of Irritable Bowel Syndrome in Children Using the Rome III Criteria and the Effect of Trimebutine Treatment.
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders and when compared to the vast knowledge pertaining to adults with IBS, very little is known about IBS in children and adolescents. We aimed to explore the prevalence of IBS, identify symptoms and contributing factors and also to examine the efficacy of trimebutine maleate in children and adolescents. The study involved 345 children and adolescents (4-18 years) and parents were requested to fill in a questionnaire, Rome III criteria was used to diagnose IBS. To exclude organic disease, all patients underwent medical investigations. Half of the randomly selected IBS patients were treated with trimebutine maleate while the rest of IBS patients were not. The IBS patients were reevaluated at the end of 3 weeks. The prevalence of IBS according to Rome III criteria in children and adolescents was 22.6% and IBS with constipation was the predominant subtype. Back pain (OR, 6.68), headache (OR, 4.72) and chronic fatigue (OR, 3.74) were significantly higher in IBS group. The prevalence of IBS in both parents and depression in mothers was greater for the patient group than the healthy controls (P < 0.0001). The prevalence of functional dyspepsia in IBS group was 80.8% and was significantly higher than control group. Clinical recovery was seen in 94.9% of the trimebutine maleate group versus spontaneous recovery in 20.5% of the non-medicated group. The difference was significant (P < 0.0001). IBS is a common disorder in children and adolescents. IBS is closely associated with somatic and familial factors. Trimebutine maleate is effective for pediatric IBS patients.


Effects of temporal and spatiotemporal cues on detection of dynamic road hazards.
While driving, dangerous situations can occur quickly, and giving drivers extra time to respond may make the road safer for everyone. Extensive research on attentional cueing in cognitive psychology has shown that targets are detected faster when preceded by a spatially valid cue, and slower when preceded by an invalid cue. However, it is unknown how these standard laboratory-based cueing effects may translate to dynamic, real-world situations like driving, where potential targets (i.e., hazardous events) are inherently more complex and variable. Observers in our study were required to correctly localize hazards in dynamic road scenes across three cue conditions (temporal, spatiotemporal valid and spatiotemporal invalid), and a no-cue baseline. All cues were presented at the first moment the hazardous situation began. Both types of valid cues reduced reaction time (by 58 and 60 ms, respectively, with no significant difference between them, a larger effect than in many classic studies). In addition, observers' ability to accurately localize hazards dropped 11% in the spatiotemporal invalid condition, a result with dangerous implications on the road. This work demonstrates that, in spite of this added complexity, classic cueing effects persist-and may even be enhanced-for the detection of real-world hazards, and that valid cues have the potential to benefit drivers on the road.


Demographic methods to assess food insecurity: a North Korean case study.
In complex emergencies, especially those involving famine and/or widespread food insecurity, assessments of malnutrition are critical to understanding the population's health status and to assessing the effectiveness of relief interventions. Although the Democratic People's Republic of Korea (DPRK) has benefited from some of the largest, most sustained appeals in the history of the World Food Program (WFP), the government in Pyongyang has placed restrictions on international efforts to gather data on the health and nutritional status of the affected population. Lacking direct means to assess the nutritional status of the North Korean populace, what other methodologies could be employed to measure the public health impacts of chronic food shortage? The paper begins with a review of methods for assessing nutritional status, particularly in emergencies; a brief history of the North Korean food crisis (1995-2001), and a review of the available nutritional and health data on the DPRK. The main focus of the paper is on the results of a survey of 2,692 North Korean adult migrants in China. Recognizing certain biases and limitations, the study suggests that sample households have experienced an overall decline in food security, as evidenced by both the decline in government rations from an average of 120 grams per person per day to less than 60 grams per day, and by the increase in the percentage of households relying on foraging or bartering of assets as their principal source of food. It also is apparent that the period 1995-1998 has been marked by elevated household mortality, declining fertility, and steadily rising out-migration. Taken together, the signs point toward famine, whether that is defined as a discrete event--that is, as a regional failure in food production or distribution leading to elevated mortality from starvation and associated disease--or as a more complex social process whose sub-states include not only elevated mortality, but declining fertility, eating of alternative 'famine foods', transfer of assets, and the uprooting and separation of families.


Human Bite-induced Cellulitis Due to Streptococcus pyogenes.
The rate of infection after a human bite is 10%-30%. Streptococcus spp. are the most common pathogens that may cause serious infections, such as necrotizing fasciitis. The authors describe a 5-year-old girl admitted to the emergency room with cellulitis due to S. pyogenes after human bites. She presented with fever and pain in her left arm, and her medical history revealed a human bite by her cousin on the arm 3 days prior. The wound culture yielded S. pyogenes. She was successfully treated with intravenous ampicillin-sulbactam regimen. S. pyogenes may cause serious wound infections following human bites. In such cases, the patient should be closely followed. Chemoprophylaxis should be initiated in an appropriate clinical setting to prevent secondary bacterial infections. This case was first reported as cellulitis due to S. pyogenes after a human bite.


Basic science review on circadian rhythm biology and circadian sleep disorders.
The sleep-wake cycle displays a characteristic 24-hour periodicity, providing an opportunity to dissect the endogenous circadian clock through the study of aberrant behaviour. This article surveys the properties of circadian clocks, with emphasis on mammals. Information was obtained from searches of peer-reviewed literature in the PUBMED database. Features that are highlighted include the known molecular components of clocks, their entrainment by external time cues and the output pathways used by clocks to regulate metabolism and behaviour. A review of human circadian rhythm sleep disorders follows, including recent discoveries of their genetic basis. The article concludes with a discussion of future approaches to the study of human circadian biology and sleep-wake behaviour.


Decreased in vitro humoral immune responses in aged humans.
Induction of antigen-specific and non-specific (polyclonal) humoral immune responses in vitro was investigated in peripheral blood mononuclear cells of aged (65-85 yr) and young (20-30 yr) volunteers. In vitro immunization of lymphocytes with antigen (sheep erythrocytes) was performed in a recently described microculture system, and anti-sheep erythrocyte plaque forming cells were quantitated in a direct hemolytic plaque assay. Immunoglobulin secreting cells, induced polyclonally with pokeweed mitogen, were quantitated in a reverse hemolytic plaque assay. Significant depressions of antigen-specific as well as polyclonal responses were noted in relation to advancing age. Antigen-specific responses were more frequently depressed than polyclonal responses. T cell mitogen concanavalin A (Con A) was used to amplify functions of autologous immunoregulatory T cells. Addition of 10 microgram/ml Con A to lymphocytes of young donors at culture initiation resulted in activation of suppressor cells and abrogated antigen-specific responses. Delayed addition of Con A, on the other hand, enhanced responses, presumably because of activation of helper T cells. Similar manipulations of lymphocyte cultures from aged donors showed failure of Con A to suppress antigen-specific responses in approximately half of the responders. In many nonresponders, responses within normal range were elicited by the delayed addition of Con A to their lymphocyte cultures. Deviations beyond the range of expected responses were noted in 32.5% of the co-cultures between pokeweed mitogen stimulated young and aged cells. Our findings suggest that age-related deficiencies of B cell function are frequently associated with dysfunction of immunoregulatory T cells and are only occasionally due to intrinsic defects of B cells.


Discovery and structural characterization of a new inhibitor series of HIV-1 nucleocapsid function: NMR solution structure determination of a ternary complex involving a 2:1 inhibitor/NC stoichiometry.
The nucleocapsid (NC) protein is an essential factor with multiple functions within the human immunodeficiency virus type 1 (HIV-1) replication cycle. In this study, we describe the discovery of a novel series of inhibitors that targets HIV-1 NC protein by blocking its interaction with nucleic acids. This series was identified using a previously described capsid (CA) assembly assay, employing a recombinant HIV-1 CA-NC protein and immobilized TG-rich deoxyoligonucleotides. Using visible absorption spectroscopy, we were able to demonstrate that this new inhibitor series binds specifically and reversibly to the NC with a peculiar 2:1 stoichiometry. A fluorescence-polarization-based binding assay was also developed in order to monitor the inhibitory activities of this series of inhibitors. To better characterize the structural aspect of inhibitor binding onto NC, we performed NMR studies using unlabeled and (13)C,(15)N-double-labeled NC(1-55) protein constructs. This allowed the determination of the solution structure of a ternary complex characterized by two inhibitor molecules binding to the two zinc knuckles of the NC protein. To the best of our knowledge, this represents the first report of a high-resolution structure of a small-molecule inhibitor bound to NC, demonstrating sub-micromolar potency and moderate antiviral potency with one analogue of the series. This structure was compared with available NC/oligonucleotide complex structures and further underlined the high flexibility of the NC protein, allowing it to adopt many conformations in order to bind its different oligonucleotide/nucleomimetic targets. In addition, analysis of the interaction details between the inhibitor molecules and NC demonstrated how this novel inhibitor series is mimicking the guanosine nucleobases found in many reported complex structures.


[Physico-chemical bases of the mechanism of thermal inactivation of the foot-and-mouth disease virus].
Experiments demonstrated that the effect of water activity on the solvate complex of virions underlies the mechanism of thermal inactivation of the foot and mouth disease virus in suspension; changes in the structure of the complex impair the electrophysical balance of the RNA-protein relations and hence, destroy the virus. Heating of virus-containing suspensions at moderate positive temperatures leads to destruction of the noninfectious part of virus population of 146S particles, thus decreasing the infectious activity of the virus.


[Social factors in the epidemiology of intestinal infections].
Epidemiological regularities of individual intestinal infections--morbidity dynamics, the spread along the territory among the urban and rural population, seasonality--were conditioned not only by biological peculairities of the causative agents, but also but the influence of the social factors on the formation of the epidemic process.


New development of atomic layer deposition: processes, methods and applications.
Atomic layer deposition (ALD) is an ultra-thin film deposition technique that has found many applications owing to its distinct abilities. They include uniform deposition of conformal films with controllable thickness, even on complex three-dimensional surfaces, and can improve the efficiency of electronic devices. This technology has attracted significant interest both for fundamental understanding how the new functional materials can be synthesized by ALD and for numerous practical applications, particularly in advanced nanopatterning for microelectronics, energy storage systems, desalinations, catalysis and medical fields. This review introduces the progress made in ALD, both for computational and experimental methodologies, and provides an outlook of this emerging technology in comparison with other film deposition methods. It discusses experimental approaches and factors that affect the deposition and presents simulation methods, such as molecular dynamics and computational fluid dynamics, which help determine and predict effective ways to optimize ALD processes, hence enabling the reduction in cost, energy waste and adverse environmental impacts. Specific examples are chosen to illustrate the progress in ALD processes and applications that showed a considerable impact on other technologies.


Thermochemical properties of the ammonia-water ionized dimer probed by ion-molecule reactions.
The thermochemical properties of some small clusters such as the (H2O)2*+ dimer have already been investigated by both experimental and theoretical methods. The recent method to selectively prepare the ammonia-water ionized dimer [NH3, H2O]*+ (and not its proton transfer isomer [NH4+, OH*]) allowed us to study its chemical reactivity. This study focuses on the charge and proton transfer pathways: Ion-molecule reactions in the cell of an FT-ICR mass spectrometer were carried out with a range of organic compounds. Examination of the reactivity of the [NH3, H2O]*+ ionized dimer versus ionization energy and proton affinity of the neutral reagents shows a threshold in the reactivity in both instances. This leads to a bracketing of thermochemical properties related to the dimer. From these experiments and in agreement with ab initio calculations, the adiabatic recombination energy of the [NH3, H2O]*+ dimer was evaluated at -9.38 +/- 0.04 eV. The proton affinity bracketing required the reevaluation of two reference gas-phase basicity values. The results, in good agreement with the calculation, lead to an evaluation of the proton affinity of the [NH2*, H2O] dimer at 204.4 +/- 0.9 kcal mol(-1). These two experimental values are respectively related to the ionization energy of NH3*+ and to the proton affinity of NH2* by the difference in single water molecule solvation energies of ionized ammonia, of neutral ammonia, and of the NH2* radical.


Mass spectrometry MALDI imaging of colon cancer biomarkers: a new diagnostic paradigm.
Colorectal cancer (CRC), is the second-leading cause of cancer-related deaths in the USA, affecting both men and women. Current projections show little or no change since the publication of a morbidity and mortality study in 2005. The projected number of new cases for 2008 is 154,000, and the projected number of CRC cancer deaths for 2008 is 53,000. The standard diagnostic paradigm is based on histopathology of either biopsy or surgical specimens. This article suggests a new paradigm for colon cancer diagnosis and staging using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS or IMS). IMS may identify potential tumors in normal tissue of cancer patients and predict those cancer patients who are at risk for recurrent cancer.


Differential effects of lipopolysaccharide and tumor necrosis factor on monocytic IkappaB kinase signalsome activation and IkappaB proteolysis.
The inflammatory mediators lipopolysaccharide (LPS) and tumor necrosis factor (TNF) are potent activators of NF-kappaB. This study compared the effect of these stimuli on endogenous IkappaB kinase (IKK) signalsome activation and IkappaB phosphorylation/proteolysis in human monocytic cells and investigated the role of the signalsome proteins IKK-alpha, IKK-beta, NF-kappaB-inducing kinase (NIK), IKK-gamma (NF-kappaB essential modulator), and IKK complex-associated protein. Kinase assays showed that TNF elicited a rapid but short-lived induction of IKK activity with a 3-fold greater effect on IKK-alpha than on IKK-beta, peaking at 5 min. In contrast, LPS predominantly stimulated IKK-beta activity, which slowly increased, peaking at 30 min. A second peak was observed at a later time point following LPS stimulation, which consisted of both IKK-alpha and -beta activity. The endogenous levels of the signalsome components were unaffected by stimulation. Furthermore, our studies showed association of the IKK-alpha/beta heterodimer with NIK, IkappaB-alpha and -epsilon in unstimulated cells. Exposure to LPS or TNF led to differential patterns of IkappaB-alpha and IkappaB-epsilon disappearance from and reassembly with the signalsome, whereas IKK-alpha, IKK-beta, and NIK remained complex-associated. NIK cannot phosphorylate IkappaB-alpha directly, but it appears to be a functionally important subunit, because mutated NIK inhibited stimulus-induced kappaB-dependent transcription more effectively than mutated IKK-alpha or -beta. Overexpression of IKK complex-associated protein inhibited stimulus-mediated transcription, whereas NF-kappaB essential modulator enhanced it. The understanding of LPS- and TNF-induced signaling may allow the development of specific strategies to treat sepsis-associated disease.


Analytical solution for the covariance and for the decorrelation time of the angle of arrival of a wave front corrugated by atmospheric turbulence.
The two-dimensional (2D) spatial covariance of the angle-of-arrival (AA) fluctuations is often used to investigate the properties of wave fronts corrugated by the atmosphere for high-angular-resolution techniques. Theoretical series expansions of this covariance are presented. The fast convergence of these series reduces the calculation time of the covariance done by numerical integration. The 2D covariance is a nonradial function. A physical interpretation of this anisotropy is proposed. The spatiotemporal correlation of the AA is deduced from the covariance assuming the "frozen-flow" hypothesis. The impact of the anisotropy on the evaluation of the number of predominant turbulent layers and on the corresponding winds is investigated, and an analysis of temporal correlations is performed. A simple theoretical approximation of the decorrelation time of the AA is given, which is found to be in agreement with experimental results.


Climate Change and Simulation of Cardiovascular Disease Mortality: A Case Study of Mashhad, Iran.
Weather and climate play a significant role in human health. We are accustomed to affects the weather conditions. By increasing or decreasing the environment temperature or change of seasons, some diseases become prevalent or remove. This study investigated the role of temperature in cardiovascular disease mortality of city of Mashhad in the current decade and its simulation in the future decades under conditions of climate change. Cardiovascular disease mortality data and the daily temperatures data were used during (2004-2013) period. First, the correlation between cardiovascular disease mortality and maximum and minimum temperatures were calculated then by using General Circulation Model, Emissions Scenarios, and temperature data were extracted for the next five decades and finally, mortality was simulated. There is a strong positive association between maximum temperature and mortality (r= 0.83, P-value<0.01), also observed a negative and weak but significant association between minimum temperatures and mortality. The results obtained from simulation show increased temperature in the next decades in Mashhad and a 1 °C increase in maximum temperature is associated with a 4.27% (95%CI: 0.91, 7.00) increase in Cardiovascular disease mortality. By increasing temperature and the number of hot days the cardiovascular disease mortality increases and these increases will be intensified in the future decades. Therefore, necessary preventive measures are required to mitigate temperature effects with greater attention to vulnerable group.


Clinicopathological outcomes after radical cystectomy for clinical T2 urothelial carcinoma: further evidence to support the use of neoadjuvant chemotherapy.
To evaluate the clinicopathological outcomes for patients with clinical T2 (cT2) urothelial carcinoma treated with radical cystectomy (RC) without neoadjuvant chemotherapy (NC). We identified 212 patients with cT2 tumours who underwent RC at our institution without NC. Pathological assessment of RC specimens was correlated with clinical stage. The impact of various clinicopathological factors on the outcome of patients with cT2 disease was analysed. In total, 153/212 (73.2%) patients with cT2 bladder cancer had either pT3/T4 or pN+ tumours at RC. Moreover, only 58/153 (37.9%) of these patients received adjuvant chemotherapy. The median follow-up was 28 (months 0.6-107.5) (range). The 5-year recurrence-free survival and cancer-specific survival (CSS) was 56.5% and 59.5%, respectively. On multivariate analysis, increasing age (hazard ratio [HR] 1.04; P= 0.04), advanced pathological stage (HR 1.83; P= 0.02), and positive lymph nodes (HR 3.72; P= 0.001) were adversely associated with CSS, while receipt of adjuvant chemotherapy was protective of disease-specific mortality (HR 0.45; P= 0.04). Pathological upstaging is prevalent and survival remains modest in patients with cT2 tumours treated with RC without NC. Unfortunately, only 40% of patients that had locally advanced and/or regionally metastatic disease received adjuvant treatment. These data further support the value of NC for patients with muscle-invasive bladder cancer, even in those with apparent clinically organ-confined tumours.


Identification and management of comorbidity in psoriatic arthritis: evidence- and expert-based recommendations from a multidisciplinary panel from Spain.
The objective is to establish recommendations, based on evidence and expert opinion, for the identification and management of comorbidities in patients with psoriatic arthritis (PsA). The following techniques were applied: discussion group, systematic review, and Delphi survey for agreement. A panel of professionals from four specialties defined the users, the sections of the document, possible recommendations, and what systematic reviews should be performed. A second discussion was held with the results of the systematic reviews. Recommendations were formulated in the second meeting and voted online from 1 (total disagreement) to 10 (total agreement). Agreement was considered if at least 70% voted ≥7. The level of evidence and grade of recommendation were assigned using the Oxford Centre for Evidence-Based Medicine guidance. The full document was critically appraised by the experts, and the project was supervised at all times by a methodologist. In a final step, the document was reviewed and commented by a patient and a health management specialist. Fourteen recommendations were produced, together with a checklist to facilitate the implementation. The items with the largest support from evidence were those related to cardiovascular disease and risk factors. The panel recommends paying special attention to obesity, smoking, and alcohol consumption, as they are all modifiable factors with an impact on treatment response or complications of PsA. Psychological and organizational aspects were also deemed important. We herein suggest practical recommendations for the management of comorbidities in PsA based on evidence and expert opinion.


[Educational status and patterns of weight gain in adulthood in Brazil: Estudo Pró-Saúde].
The aim of the present study was to investigate the association between participant and parental educational status (considered as an indicator of socioeconomic status) and participant pattern of weight gain in adulthood. We analyzed data from 2 582 baseline participants (1999) of Estudo Pró-Saúde (Pro-Health Study), a longitudinal investigation of civil servants from a public university in Rio de Janeiro, Brazil. Self-administered questionnaires were used to identify patterns of weight gain in adulthood. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated for the association between parental and participant educational status and steady weight gain or weight cycling, with stable weight as a reference, using multinomial logistic regression models. For males, lower paternal educational level entailed a chance about 55% lower of weight cycling as compared to stable weight (OR = 0.45; IC95% = 0.26-0.78), whereas lower maternal schooling was related to increased risk of weight cycling, although without reaching statistical significance (OR = 1.68; IC95% = 0.94-3.00). The association between participant educational status and weight history was not statistically significant among men. In women, lower educational status entailed a chance 94% higher of self-reported weight cycling (OR = 1.94; 95% CI = 1.17-3.23), and there was no association between parental educational level and history of weight gain. In this study, changes in weight throughout life, both steady and cyclic, were associated with parental and participant educational status, with major differences between genders.


An overview of professional liability in occupational therapy.
Occupational therapists occasionally are sued for professional malpractice; thus, they need to be aware of the law of malpractice, those areas of practice that present the greatest legal challenges, and strategies to reduce client injury and liability risks. This article provides an overview of the law of professional malpractice, explains the impact of various employment relationships on liability risks, reviews specific malpractice actions against occupational therapists, and provides suggestions on how to reduce the risk of injuring a client in therapy. By increasing one's awareness of the legalities of professional malpractice and implementing certain strategies, therapists can improve quality of care and reduce their exposure to malpractice liability.


Studies on bacteriemia. V. The effect of simultaneous leukopenia and reticuloendothelial blockade on the early blood stream clearance of staphylococci and Escherichia coli.
Observations are presented on the course of experimental bacteriemia in rabbits modified by thorotrast reticuloendothelial "blockade" and mechlorethamine induced leukopenia, given singly and together. The production of severe granulocytopenia did not impair the clearance of staphylococci from the blood stream and did not enhance the impairment of clearance produced by thorotrast reticuloendothelial "blockade." Neither severe granulocytopenia nor thorotrast blockade alone produced consistent impairment in the removal of circulating E. coli from the blood stream, whereas when these conditions were present together, the early phases of clearance in these animals were virtually prevented. These results indicate that the host mechanisms operative in the control of bacteriemia differ for staphylococci and E. coli. It is suggested that the fate of bacteria within polymorphonuclear leukocytes may in part determine the importance of these cells in the removal of bacteria from the blood stream.


Myocardial blood flow and its transit time, oxygen utilization, and efficiency of highly endurance-trained human heart.
Highly endurance-trained athlete's heart represents the most extreme form of cardiac adaptation to physical stress, but its circulatory alterations remain obscure. In the present study, myocardial blood flow (MBF), blood mean transit time (MTT), oxygen extraction fraction (OEF) and consumption (MVO2), and efficiency of cardiac work were quantified in highly trained male endurance athletes and control subjects at rest and during supine cycling exercise using [(15)O]-labeled radiotracers and positron emission tomography. Heart rate and MBF were lower in athletes both at rest and during exercise. OEF increased in response to exercise in both groups, but was higher in athletes (70 ± 21 vs. 63 ± 11 % at rest and 86 ± 13 vs. 73 ± 10 % during exercise). MTT was longer and vascular resistance higher in athletes both at rest and during exercise, but arterial content of 2,3-diphosphoglycerate (oxygen affinity) was unchanged. MVO2 per gram of myocardium trended (p = 0.08) lower in athletes both at rest and during exercise, while myocardial efficiency of work and MVO2 per beat were not different between groups. Arterial levels of free fatty acids were ~twofold higher in athletes likely leading to higher myocardial fatty acid oxidation and hence oxygen cost, which may have blunted the bradycardia-induced decrease in MVO2. Finally, the observed group differences in MBF, OEF, MTT and vascular resistance remained significant also after they were controlled for differences in MVO2. In conclusion, in highly endurance-trained human heart, increased myocardial blood transition time enables higher oxygen extraction levels with a lower myocardial blood flow and higher vascular resistance. These physiological adaptations to exercise training occur independently of the level of oxygen consumption and together with training-induced bradycardia may serve as mechanisms to increase functional reserve of the human heart.


Auditory steady state cortical responses indicate deviant phonemic-rate processing in adults with dyslexia.
Speech intelligibility is strongly influenced by the ability to process temporal modulations. It is hypothesized that in dyslexia, deficient processing of rapidly changing auditory information underlies a deficient development of phonological representations, causing reading and spelling problems. Low-frequency modulations between 4 and 20 Hz correspond to the processing rate of important phonological segments (syllables and phonemes, respectively) in speech and therefore provide a bridge between low-level auditory and phonological processing. In the present study, temporal modulation processing was investigated by auditory steady state responses (ASSRs) in normal-reading and dyslexic adults. Multichannel ASSRs were recorded in normal-reading and dyslexic adults in response to speech-weighted noise stimuli amplitude modulated at 80, 20, and 4 Hz. The 80 Hz modulation is known to be primarily generated by the brainstem, whereas the 20 and 4 Hz modulations are mainly generated in the cortex. Furthermore, the 20 and 4 Hz modulations provide an objective auditory performance measure related to phonemic- and syllabic-rate processing. In addition to neurophysiological measures, psychophysical tests of speech-in-noise perception and phonological awareness were assessed. On the basis of response strength and phase coherence measures, normal-reading and dyslexic participants showed similar processing at the brainstem level. At the cortical level of the auditory system, dyslexic subjects demonstrated deviant phonemic-rate responses compared with normal readers, whereas no group differences were found for the syllabic rate. Furthermore, a relationship between phonemic-rate ASSRs and psychophysical tests of speech-in-noise perception and phonological awareness was obtained. The results suggest reduced cortical processing for phonemic-rate modulations in dyslexic adults, presumably resulting in limited integration of temporal information in the dorsal phonological pathway.


[Basic arrhythmogenic mechanisms in both inherited and acquired long QT syndrome].
The heterologous expression system will provide clues for understanding the basic mechanism of arrhythmogenicity in both inherited and acquired long QT syndrome, which are reviewed here, with emphasis on the K+ channels. Endothelin is implicated in the morphological and electrical remodeling of cardiac muscles in heart failure. The effects of endothelin on the transient outward K+ currents (Ito) were compared between Kv1.4 (rich in endocardial muscle) and Kv4.3 (rich in epicardial muscle) channels in the Xenopus oocytes expression system. Both Itos were decreased by stimulation of endothelin receptor ETA coexpressed with the K+ channels. Ito of Kv1.4 was decreased by about 85% after 10(-8) M ET-1, whereas that of Kv4.3 was decreased by about 60%. By mutagenesis experiments, we identified two phosphorylation sites of PKC and CaMKII in Kv1.4 responsible for the decrease in Ito by ET-1. In Kv4.3 we identified a PKC phosphorylation site that is partly responsible for the decrease. Differences in the suppression of Ito could be due to the differences in intracellular signaling including the number of phosphorylation sites. These findings show some of the molecular mechanisms of ventricular arrhythmias in heart failure, resulting in dispersion and prolongation of action potential which elicit reentry and after depolarization.


MAGI2 genetic variation and inflammatory bowel disease.
Despite recent advances the majority of inflammatory bowel disease (IBD) susceptibility 'genes' remain undiscovered. Recent data suggest that autoimmune conditions may 'share' susceptibility loci. Epidemiological evidence indicates an association between celiac disease and IBD and both conditions demonstrate increased gut permeability. MAGI2, recently implicated in ulcerative colitis (UC) and celiac disease, encodes a scaffolding protein involved in epithelial integrity. Our aim was to test MAGI2 variants for association with IBD and also their role in determining intermediate hereditary phenotypes defined by antibody production to microbial antigens. We genotyped 113 MAGI2 single nucleotide polymorphisms (SNPs) in 681 cases of Crohn's disease (CD), 259 UC cases, and 195 controls. The most significant IBD association was in intron 6 (rs2160322, P = 0.009) and both UC (P = 0.006) and CD (P = 0.03) contributed to this association. The most significant CD association was with an intron 2 haplotype (rs7785088/rs323149/rs13246026, P = 0.002). We observed highly significant associations with UC in intron 6 (rs7803276/rs7803705, P = 0.002) and also significant associations in introns 2, 6, and 20. Significant associations were seen with: immunoglobulin G (IgG) anti-Saccharomyces cerevisiae antibodies (ASCA)-positive CD in intron 3 (P = 0.003), intron 6 (P = 0.003), and intron 20 (P = 0.001); anti-CBir1-positive CD in intron 3 (P = 0.0001) and intron 6 (P = 0.008); and anti-outer membrane porin C (OmpC)-positive CD in intron 3 (P = 0.0009), and intron 9 (P = 0.007). Quantitative antibody levels were also associated with variants in intron 4 (anti-IgA ASCA, P = 0.0003 and anti-IgG ASCA, P = 0.0002). These findings support the significance of the epithelial barrier in IBD pathogenesis.


Simultaneous trabeculectomy and cataract extraction.
A combined trabeculectomy and cataract extraction was performed on 46 eyes of 39 patients. The average follow-up period was of 27 months. The intraocular pressure remained controlled without the need of postoperative medication in 33 eyes (71.74%); 12 eyes (26.09%) needed further medical treatment; and in one eye the pressure remained uncontrolled and further surgery was necessary. After surgery the visual acuity improved considerably and the complications were few. The combined procedure has many advantages. The patient is cured by one surgical procedure, his visual acuity improves, his intraocular pressure is reduced to normal, and he is relieved from the need for medication postoperatively. By a single stay in hospital and by reducing the number of postoperative medical routine controls the expenses are reduced considerably. Owing to these advantages the combined procedure deserves to be considered in cases of glaucoma and cataract.


Prenatal diagnosis of sickle cell anemia and beta-thalassemia by amniocentesis.
Prenatal diagnosis by amniocentesis alone is possible for about 90% of pregnancies at risk for sickle cell anemia and about 70-75% of pregnancies at risk for beta-thalassemia. It should be stressed that to obtain these percentages, a previous homozygous normal or affected child or, alternatively, the couple's parents are needed to confirm the linkage of variant genes to respective DNA markers (polymorphic restriction sites). Families at risk should be studied prior to or early in pregnancy to determine whether these methods will be applicable to their specific case. If appropriate markers are identified and their linkage to the genes being studied is verified, then prenatal diagnosis by amniocentesis can be done at 16-18 weeks; and for these couples, fetoscopy, with its increased risk of fetal loss, can be avoided. The change of errors in diagnosis due to crossing-over between the mutant gene and the linked marker is small. The probability of such a recombination between the beta-globin gene and the polymorphic G gamma Hind III or the 3' Hpa I site is 1/3,000 and 1/14,000 per generation, respectively (13). A more serious problem is non-paternity because of the errors caused in linkage analysis. Improved methods to enable direct detection of the beta S and/or beta thal mutations would remove both of these potential sources of error.


Engineering cuboctahedral N-doped C-coated p-CuO/n-TiO2 heterojunctions toward high-performance photocatalytic cross-dehydrogenative coupling.
The low separation efficiency of photogenerated electron-hole (e-h) pairs severely limits the activation of photocatalyts. One brilliant strategy is to construct a p-n type semiconductor heterojunction, which can establish an inner electric field to separate the e-h pairs with high efficiency. Here, for the first time, a cuboctahedral N-doped carbon-coated CuO/TiO2 p-n heterojunction (CuO-TiO2@N-C) was designed and fabricated successfully via direct calcination of a benzimidazole-modulated cuboctahedral HKUST-Cu with titanium-tetraisopropanolate absorbed inside concomitantly. Full structural characterizations incorporating DFT computations demonstrate that the CuO/TiO2 p-n heterostructure can greatly boost the transport and separation of photoinduced e-h pairs. The nitrogen-doped carbon coating, with its excellent conductivity, porosity, stability and surface reaction activity, plays a pivotal role in promoting the overall performance and effectiveness of the reaction. The CuO-TiO2@N-C displays significantly higher photocurrent density (0.042 μA cm-2) than the CuO@N-C (0.014 μA cm-2) and TiO2@N-C (0.03 μA cm-2) electrodes, proving that the p-n heterojunction can improve the e-h generation efficiency. This unique photocatalyst affords superior photocatalytic efficiency, cycle stability and substrate scope towards cross-dehydrogenative coupling reactions.


Envelope variants from women recently infected with clade A human immunodeficiency virus type 1 confer distinct phenotypes that are discerned by competition and neutralization experiments.
Women infected with clade A human immunodeficiency virus type 1 harbor a virus population that is genetically diverse in the envelope gene, a fact that contrasts with the homogeneous virus population identified in newly infected men. It is not known whether viral genetic diversity at this early stage of infection is manifested as phenotypic diversity. This is a significant question because phenotypic diversity in the viral population that establishes infection in women may have important implications for pathogenesis and therapeutic intervention. Thus, in this study we compared the biological properties of three pairs of chimeric viruses that contained envelope genes representative of variant groups in each of three infected women-Q23, Q45, and Q47. Envelope chimeras were evaluated for replication in stimulated and resting peripheral blood mononuclear cells alone and in competition, for coreceptor use, and for neutralization sensitivity. All viruses utilized CCR5 exclusively and had a non-syncytium-inducing phenotype on MT-2 cells and in primary culture. There were no significant differences in replication parameters between paired variants in individual cultures. However, in competition experiments, one chimera of each variant pair always dominated. The dominant virus from Q23 and Q47, but not from Q45, infected a significantly higher number of CCR5- and CD4-expressing GHOST cells than the weaker chimeras. Significantly, chimeric viruses from Q47 and Q45 showed markedly different neutralization sensitivity to antibodies to CCR5 and gp120, respectively. These data indicate that distinct envelope genotypes identified in clade A-infected women near seroconversion confer unique phenotypes that affect viral fitness and that may be due, in part, to different requirements for relative configuration of CD4 and CCR5 on infected cells.


RecQ helicase translocates along single-stranded DNA with a moderate processivity and tight mechanochemical coupling.
Maintenance of genome integrity is the major biological role of RecQ-family helicases via their participation in homologous recombination (HR)-mediated DNA repair processes. RecQ helicases exert their functions by using the free energy of ATP hydrolysis for mechanical movement along DNA tracks (translocation). In addition to the importance of translocation per se in recombination processes, knowledge of its mechanism is necessary for the understanding of more complex translocation-based activities, including nucleoprotein displacement, strand separation (unwinding), and branch migration. Here, we report the key properties of the ssDNA translocation mechanism of Escherichia coli RecQ helicase, the prototype of the RecQ family. We monitored the pre-steady-state kinetics of ATP hydrolysis by RecQ and the dissociation of the enzyme from ssDNA during single-round translocation. We also gained information on the translocation mechanism from the ssDNA length dependence of the steady-state ssDNA-activated ATPase activity. We show that RecQ occludes 18 ± 2 nt on ssDNA during translocation. The hydrolysis of ATP is noncooperative in the presence of ssDNA, indicating that RecQ active sites work independently during translocation. In the applied conditions, the enzyme hydrolyzes 35 ± 4 ATP molecules per second during ssDNA translocation. RecQ translocates at a moderate processivity, with a mean run length of 100-320 nt on ssDNA. The determined tight mechanochemical coupling of 1.1 ± 0.2 ATP consumed per nucleotide traveled indicates an inchworm-type mechanism.


Plasmon-induced transparency with detuned ultracompact Fabry-Perot resonators in integrated plasmonic devices.
We demonstrate the realization of on-chip plasmonic analogue of electromagnetically induced transparency (EIT) in integrated plasmonic devices using detuned Fabry-Perot resonators aperture-side-coupled to a metal-insulator-metal (MIM) waveguide, with the transmission peak occurring at the intermediate wavelength. Strong MIM mode confinement along with localized side-coupling allows one to realize subwavelength photonic components with EIT-like transmission. Numerical results show that MIM components exhibiting pronounced EIT-like spectra in near infrared with the footprint of < 0.15 μm2 and group index of ~26 can be designed.


Evaluation of ischemia-modified albumin and C-reactive protein in type 2 diabetics with and without ketosis.
To investigate whether serum ischemia-modified albumin or C-reactive protein is reliable for predicting type 2 diabetic patients with ketosis. One hundred and four diabetic patients, 48 with diabetic ketosis, and 33 controls were enrolled in the study. Serum ischemia-modified albumin and C-reactive protein were measured and evaluated for their ability to distinguish diabetic ketosis. Compared to the controls, the ischemia-modified albumin and C-reactive protein levels were higher in patients with diabetic ketosis and type 2 diabetes at the baseline. The levels of ischemia-modified albumin were higher in patients with type 2 diabetes than in the controls. C-reactive protein and ischemia-modified albumin levels were reduced after insulin treatment. The level of ischemia-modified albumin was an independent risk marker for diabetic ketosis (OR = 1.085, P = 0.008, 95% CI: 1.022-1.152). Receiver operating characteristic curves revealed that the areas under the curve were 0.917 for the modified albumin and 0.357 for C-reactive protein. This study indicates that ischemia-modified albumin was significantly associated with diabetic ketosis and was more sensitive than C-reactive protein in reflecting diabetic ketosis.


How safe is percutaneous ethanol injection for treatment of thyroid nodule? Report of a case of severe toxic necrosis of the larynx and adjacent skin.
Since 1990, percutaneous ethanol injection therapy (PEIT) has been clinically applied as a treatment for autonomous functioning nodules of the thyroid as well as for cystic lesions. Some additional indications are currently under consideration, e.g. inoperable advanced cancer of the thyroid. Since its inception, PEIT has generally been regarded as an effective, low-risk, inexpensive procedure which can be performed on an ambulatory basis. We report the first case of severe ethyl toxic necrosis of the larynx combined with necrotic dermatitis in a patient treated with PEIT by a radiologist. The patient was admitted to hospital, where the necrosis and dermatitis were treated conservatively. A cyst which developed in the right false vocal fold was removed by microsurgery 10 months later. Voice was restored almost to normal but a significant reduction in nodular volume was not seen, probably due to the inexperience of the operator. PEIT for functional thyroid gland autonomy is an inexpensive method of treating hyperthyroidism with focal autonomy on an ambulatory basis if surgical intervention and radioiodine therapy are not feasible either for medical reasons or because of refusal by the patient. Severe complications must be taken into consideration and discussed with the patient. To avoid complications, substantial experience and a precise ultrasound-guided injection are required. In the case of complications the opinion of a specialist should be sought at anearly stage.


Hemispherical double-layer time reversal imaging in reverberant and noisy environments at audible frequencies.
Time reversal is a widely used technique in wave physics, for both imaging purposes and experimental focusing. In this paper, a complete double-layer time reversal imaging process is proposed for in situ acoustic characterization of non-stationary sources, with perturbative noise sources and reverberation. The proposed method involves the use of a hemispherical array composed of pressure-pressure probes. The complete set of underlying optimizations to sonic time reversal imaging is detailed, with regard to space and time reconstruction accuracy, imaging resolution and sensitivity to reverberation, and perturbative noise. The proposed technique is tested and compared to more conventional time reversal techniques through numerical simulations and experiments. Results demonstrate the ability of the proposed method to back-propagate acoustic waves radiated from non-stationary sources in the volume delimited by the measurement array with a high precision both in time and space domains. Analysis of the results also shows that the process can successfully be applied in strongly reverberant environments, even with poor signal-to-noise ratio.


Establishment of a multicomponent dietary bioactive human equivalent dose to delete damaged Lgr5+ stem cells using a mouse colon tumor initiation model.
Multicomponent therapy has gained interest for its potential to synergize and subsequently lower the effective dose of each constituent required to reduce colon cancer risk. We have previously showed that rapidly cycling Lgr5 stem cells are exquisitely sensitive to extrinsic dietary factors that modulate colon cancer risk. In the present study, we quantified the dose-dependent synergistic properties of dietary n-3 polyunsaturated fatty acids (PUFA) and curcumin (Cur) to promote targeted apoptotic deletion of damaged colonic Lgr5 stem cells. For this purpose, both heterogeneous bulk colonocytes and Lgr5 stem cells were isolated from Lgr5-EGFP-IRES-CreER knock-in mice injected with azoxymethane (AOM). Isolated cells were analyzed for DNA damage (γH2AX), apoptosis (cleaved caspase-3), and targeted apoptosis (both γH2AX and cleaved caspase-3) at 12 h post-AOM injection. Comparison of the percentage of targeted apoptosis in Lgr5 stem cells (GFP) across a broad bioactive dose-range revealed an ED50 of 16.0 mg/day n-3 PUFA + 15.9 mg/day Cur. This corresponded to a human equivalent dose of 3.0 g n-3 PUFA + 3.0 g Cur. In summary, our results provide evidence that a low dose (n-3 PUFA + Cur) combination diet reduces AOM-induced DNA damage in Lgr5 stem cells and enhances targeted apoptosis of DNA-damaged cells, implying that a lower human equivalent dose can be utilized in future human clinical trials.


Simultaneous immunoassays of dual prostate cancer markers using a SERS-based microdroplet channel.
The simultaneous detection of multiple biomarkers plays an important role in the accurate diagnosis of cancer. In this study, we developed a novel, surface-enhanced Raman scattering (SERS)-based microfluidic device for the simultaneous detection of free prostate-specific antigen (f-PSA) and total PSA (t-PSA) markers. A fully automatic droplet-based microfluidic platform for the rapid and sensitive detection of f-PSA and t-PSA was designed. Magnetic immunocomplexes were aligned on one side of the channel using a permanent magnet embedded in the microfluidic device, and parent microdroplets containing magnetic immunocomplexes and supernatant solutions were split into two smaller daughter droplets at the Y-shaped junction of the channel. Then, Raman signals of sequential droplets including supernatant solutions were measured for the quantitative analysis of the PSA markers. Two parallel microfluidic channels were designed and fabricated for the simultaneous detection of f-PSA and t-PSA. Our results showed a good linear response for both PSA markers in the range from 0.05 to 100 ng mL-1. The limits of detection were estimated to be below 0.1 ng mL-1 for both the f-PSA and t-PSA. This SERS-based assay in a microfluidic channel was completed in 10 min without any manual incubation and washing steps. Our method is a very promising clinical tool for PSA-based screening test of prostate cancer.


Thyroidectomy of SHR: effects on ventricular relaxation and on SR calcium uptake activity.
Ventricular hypertrophy and hypothyroidism are each characterized by impaired cardiac muscle relaxation and sarcoplasmic reticulum (SR) calcium uptake activity. A previous report also showed that hypothyroidism does not reverse ventricular hypertrophy (left-to-right ventricular weight ratios) of spontaneously hypertensive rats (SHR). We characterized the effects of thyroidectomy of 8 wk duration on relaxation of ejecting hearts and on SR calcium uptake activity from SHR and nonhypertrophic Wistar-Kyoto rat (WKY) controls. Relaxation was quantified by plotting maximum left ventricular pulse pressure (Pmax) vs. the area under the falling phase of the left ventricular pressure wave at three different pressure loads. Ventricles of euthyroid SHR were characterized by impaired relaxation and depressed SR calcium uptake activity compared with those of euthyroid WKY, confirming earlier studies. Thyroidectomy reduced ventricular relaxation and SR calcium uptake activities to about the same extent in SHR and WKY strains so that these measurements were most depressed in the SHR hypothyroid group. When all groups were considered, the extent of mechanical relaxation ex vivo and the rate of SR calcium uptake in vitro were well correlated.


Kinetics of exchange between zero-, one-, and two-hydrogen-bonded states of methyl and ethyl acetate in methanol.
It has recently been shown that the ester carbonyl stretching vibration can be used as a sensitive probe of local electrostatic field in molecular systems. To further characterize this vibrational probe and extend its potential applications, we studied the kinetics of chemical exchange between differently hydrogen-bonded (H-bonded) ester carbonyl groups of methyl acetate (MA) and ethyl acetate (EA) in methanol. We found that, while both MA and EA can form zero, one, or two H-bonds with the solvent, the population of the 2hb state in MA is significantly smaller than that in EA. Using a combination of linear and nonlinear infrared measurements and numerical simulations, we further determined the rate constants for the exchange between these differently H-bonded states. We found that for MA the chemical exchange reaction between the two dominant states (i.e., 0hb and 1hb states) has a relaxation rate constant of 0.14 ps(-1), whereas for EA the three-state chemical exchange reaction occurs in a predominantly sequential manner with the following relaxation rate constants: 0.11 ps(-1) for exchange between 0hb and 1hb states and 0.12 ps(-1) for exchange between 1hb and 2hb states.


Simultaneous implant placement and restoration with guided bone regeneration in the mandibular anterior region.
Restoring the mandibular anterior teeth by implants can be difficult due to potential complications arising from using prosthetic implant connections that are larger than the incisors at the cementoenamel junction level. This retrospective study is aimed at determining the survival and esthetic outcomes of anterior mandible implants immediately placed and restored in patients diagnosed with stages 3-4 periodontitis. The study included 75 implants that were inserted along with guided bone regeneration in 42 patients. Over a follow-up period of 3 to 8 years (mean of 6.95 ± 1.78 years), the study evaluated esthetic, marginal bone loss (MBL), and biological and prosthetic complications. No failures were recorded during the follow-up period; after eight years, the survival rate was 100%. Patient's age and gender did not have a statistically significant impact on MBL, but smokers had a greater MBL than non-smokers at the 8-year (2.98 mm vs. 1.23 mm, respectively, p = 0.016) time-point. At 3 years, only 13.3% of the implants had mesial papillae, 36.0% had distal papillae, and 16.0% had the cervical metallic part of the abutment exposed. Peri-implantitis was diagnosed in 20.7% of the patients at the 8-year follow-up time. Based on the limitations of this study, immediate placement and restoration of the mandibular incisors can be a feasible procedure, but only a few implants achieved the complete restoration of the papillae.


Chronic shifts in the length and phase of the light cycle increase intermittent alcohol drinking in C57BL/6J mice.
Shift workers-e.g., health care professionals, truck drivers, and factory workers-are forced to maintain daily cycles at odds with their natural circadian rhythms and as a consequence need to frequently readjust these cycles. This shift work-induced circadian desynchrony (CD) is associated with increased sleep disorders and with alcohol abuse. Nonetheless, it has proven difficult to model CD-induced changes in alcohol consumption in mouse models, which is an important step toward identifying the mechanisms by which CD increases alcohol intake. This study examined whether frequent changes in the light cycle could increase free access alcohol intake in a mouse line that readily consumes alcohol. Free access alcohol intake, water intake, and wheel-running activity patterns of male C57BL/6J mice were measured while the mice were maintained on a normal 12HR photoperiod for baseline data for 2 weeks. The mice were then exposed to an alternating photoperiod of 12 h and 18 h, with light onset advanced 8 h during the 18HR photoperiod. The photoperiods rotated every 3 days, for 21 days total. The repeated pattern of phase advances and delays, with a concurrent change in the length of the photoperiod, shifted mice to a pattern of intermittent alcohol drinking without altering water intake. Wheel running activity demonstrated that mice were unable to reset their behavioral clocks during CD, showing constant, low-level activity with no peak in activity at the start of the dark phase and greater activity during the morning light phase. It is possible to model CD effects on alcohol intake in C57BL/6J mice using a pattern of phase shifts and changes in the photoperiod. Using this model, we demonstrate that mice begin intermittent drinking during CD, and this increase in alcohol intake does not correlate with an increase in overall activity or in overall fluid intake.


Abdominal Stiffness Evaluation in Massage for Constipation.
According to the experience of nurses and physiotherapists, the abdomen of constipated people becomes softer after abdominal massage. However, the relationship between the decrease in abdominal stiffness and the benefits of abdominal massage has not been examined quantitatively and is unclear. Furthermore, devices for measuring stiffness have been designed to measure relatively hard areas such as the shoulders and do not take into account the lateral outflow of the target tissue, which can be a problem when measuring the stiffness of soft areas such as the abdomen. To address these issues, this study presents a stiffness sensor suitable for measuring abdominal stiffness and investigates the relationship between the reduction in abdominal stiffness and the benefits of abdominal massage. The solution to prevent the lateral outflow of the target is the realization of a stopper, including a contact detection device, which enables a wide-area contact around the targeted area. The sensor consists of a stopper, probe, spring, and time-of-flight (ToF) sensors. The probe and spring provide appropriate pressure and deformation to the abdomen, whereas the stopper prevents the probe from being pushed into the abdomen more than necessary. The ToF sensor measures the deformation length when the deformation is stopped by the stopper. The abdominal stiffness can be derived from the deformation length. The investigation results indicate that the reduction in abdominal stiffness corresponds to the improvement of the stool condition or the maintenance of a healthy stool condition, whereas the maintenance of abdominal stiffness indicates the maintenance or deterioration of the stool condition.


Role of adenosine and nitric oxide on the mechanisms of action of dipyridamole.
The combination of dipyridamole and aspirin has been shown to be more effective than aspirin alone in the secondary prevention of stroke. Dipyridamole may act by inhibiting adenosine uptake, thus potentiating its actions. Dipyridamole also inhibits cGMP-specific phosphodiesterases (PDE) and, through this mechanism, could potentiate cGMP-mediated actions of nitric oxide. To define the mechanism of action of dipyridamole, we studied the local vascular effects of adenosine, acetylcholine (NO-mediated dilation), and nitroprusside (cGMP-mediated dilation) in a double-blind study after treatment with dipyridamole/aspirin (200 mg dipyridamole/25 mg aspirin twice a day) or aspirin control for 7 days in 6 normal volunteers. Vasodilators were administered into the brachial artery in the nondominant arm in random order and forearm blood flow (FBF) was measured by venous occlusion plethysmography. Adenosine at a dosage of 125 mug/min increased FBF from 4.6+/-0.9 to 29.4+/-5.3 (539% increase) with dipyridamole/aspirin and from 3.9+/-0.8 to 12+/-2.5 mL/100 mL forearm/min (208% increase) with aspirin alone (P=0.007). In contrast, dipyridamole/aspirin did not alter the response to acetylcholine or to nitroprusside. The magnitude of adenosine-induced vasodilation correlated with plasma dipyridamole concentrations (r2=0.6); no correlation was observed with acetylcholine- or nitroprusside-induced vasodilation. Similar potentiation of adenosine, but not acetylcholine or nitroprusside, was observed in 7 additional subjects when adenosine, acetylcholine, and nitroprusside were given in random order before and 2 hours after a single dose of dipyridamole/aspirin. The effects of dipyridamole on resistance vessels are preferentially explained by potentiation of adenosine mechanisms rather than potentiation of nitric oxide or other cGMP-mediated actions.


Argyrophilic nucleolar organizing region associated protein synthesis in hair root cells of humans at different developmental stages and sex.
Argyrophilic nucleolar organizing region (AgNORs) associated proteins are important for cell proliferation and various diseases. We investigated AgNOR protein synthesis in hair root cells of males and females at different ages using two-dimensional image analysis. Experiments were performed on 58 healthy male and 24 healthy female volunteers in three groups according to age and sex. Hair root cells obtained from hair follicles were stained with silver. Total AgNOR number/total nuclear number (TAN/TNN) and total AgNOR area/nuclear area (TAA/NA) for each nucleus were analyzed. The only significant difference was observed in TAA/NA values for males and females from 6 to 12 years old. We suggest that the difference is due to high NOR activity caused by increased growth hormone production in hair root cells.


Let's talk about it: an exploration of the comparative use of three different digital platforms to gather patient-reported outcome measures.
Patient-reported outcome (PRO) measures provide valuable evidence in clinical trials; however, poor compliance with PRO measures is a notable and long-standing problem, resulting in missing data that potentially impact the interpretation of trial results. Interactive, patient-centric platforms may increase participants' motivation to complete PRO measures over the course of a clinical trial. Thus, the aim of this study was to evaluate and optimize the usability of 3 popular consumer technologies-a traditional app-based interface, a chatbot interface, and a speech-operated interface-that may be used to improve user engagement and compliance with PRO measures. Participants aged 18-75 years from the general United States population tested the usability of 3 ePRO platforms: a traditional app-based interface using Datacubed Health Platform (Datacubed), a web-based chatbot interface using the Orbita platform, and a speech-operated Alexa interface using an Alexa Skill called "My Daily Wellness." The usability of these platforms was tested with 2 PRO measures: the EQ-5D-5 L and the SF-12v2 Health Survey (SF-12v2), Daily recall. Using a crossover design, 3 cohorts of participants tested each ePRO platform daily for 1 week. After testing, interviews were conducted regarding the participants' experience with each platform. A total of 24 adults participated in the study. The mean age of participants was 45 years (range, 21-71 years), and half were female (n = 12; 50%). Overall, participants prioritized speed, ease of use, and device portability in selecting their preferred platform. The Datacubed app met these criteria and was the preferred platform among most participants (n = 20; 83%). Participants also suggested various modifications to the platforms, such as programmable notifications, adjustable speed, and additional daily reminders. These data demonstrate the importance of speed, ease of use, and device portability, features that are currently incorporated in the Datacubed app, in ePRO platforms used in future clinical trials. Additionally, the usability of ePRO platforms may be optimized by adding programmable notifications, adjustable speed, and increased daily reminders. The results of this study may be used to enhance the usability and patient centricity of these platforms to improve user compliance and engagement during clinical trials.


The influence of dietary intake on the insulin-like growth factor (IGF) system across three ethnic groups: a population-based study.
The insulin-like growth factor (IGF) system has been implicated in the aetiopathogenesis of cancer, cardiovascular disease and diabetes. Since dietary factors and ethnicity are considered contributory to the development of these diseases, we examined the IGF system in relation to nutritional intake by ethnic group. Dietary intake in 257 subjects of White European, African-Caribbean and Pakistani ethnic origin living in Manchester, UK was assessed using ethnic-group-specific food-frequency questionnaires to assess habitual nutrient intake over the previous 12 months. Fasting IGF-I, IGF-II and IGF-binding protein-1 (IGFBP-1) concentrations were determined and their relationship to specific dietary constituents was analysed. Analysis by quintiles of nutrient intake showed a significant increase in circulating IGF-I concentration with increasing dietary fat intake (F for trend=3.9, ), saturated fat intake and for protein intake There was also a significant increase in IGF-II by quintiles of dietary protein intake There was a trend for increasing IGF-I with increasing energy intake. The relationships between circulating concentration of IGFBP-1, an acute regulator of IGF action, and fat/protein intake were opposite to those for IGF-I and IGF-II. Multiple linear regression modelling showed that people of Pakistani origin and older subjects had lower levels of IGF-I (Pakistani origin vs. others, ) (age, for both). There was an independent inverse relationship between IGF-I and dietary carbohydrate intake This study provides evidence for a dietary contribution to regulation of the IGF system, although the effects of ethnicity on circulating IGF levels remain dominant. We propose that the IGF system's influences on cancer risk in specific ethnic groups are potentially modifiable by dietary intervention.


Purification to homogeneity of Charonia lampas alpha-fucosidase by using sequential ligand-affinity chromatography.
An alpha-fucosidase from the liver of the marine gastropod Charonia lampas was purified to homogeneity using a procedure that included cation-exchange and gel-filtration chromatography, chromatofocusing and a final series of affinity-chromatography steps which involved the following gel-immobilized ligands: N-(5-carboxy-1-pentyl)-1,5-dideoxy-1,5-imino-L-fucitol, N-(5-carboxy-1-pentyl)-2-acetamido-1,5-imino-1,2,5-trideoxy-D-glucitol and thio-beta-D-galactoside. The enzyme was found to be a tetrameric glycoprotein with a native Mr of 208,000, and to exist in a number of isoforms displaying pI values in the range 6.0-6.4. Substrate-specificity studies using a number of fucosylated oligosaccharides of the lacto-N and lacto-N-neo series and a synthetic disaccharide confirmed that the enzyme catalyses the hydrolysis of a broad range of fucosidic linkages, and established the following hierarchy of susceptibility: Fuc alpha 2Gal beta 4Glc much much greater than Fuc alpha 6GlcNAc greater than Fuc alpha 2Gal beta 4GlcNAc greater than Gal beta 3(Fuc alpha 4)GlcNAC much much greater than Gal beta 4(Fuc alpha 3)GlcNAc. Similar relative rates of hydrolysis were also demonstrated using biantennary oligosaccharide alditols as substrates which contained fucose linked either alpha 3 or alpha 6 to the N-acetylglucosaminitol residue of the chitobiosyl core.


[Progressive familial intrahepatic cholestasis type 3].
Progressive familial intrahepatic cholestasis is caused by mutations in the ABCB4 gene and belongs to the family of familial intrahepatic cholestais disorders inherited in an autosomal recessive pattern. To date, about 200 patients with various hepatobiliary disorders associated with ABCB4 gene mutations have been described in the literature. The aim of this manuscript was to describe the pathogenesis, clinical presentation, diagnostic process and treatment of progressive familial intrahepatic cholestais type 3, based on the literature review.


Chronic salicylism in a patient with juvenile rheumatoid arthritis.
A patient who developed chronic salicylism associated with salicylate therapy for treatment of juvenile rheumatoid arthritis is described, and the clinical presentation and treatment of chronic salicylism are reviewed. A 5 1/2-year-old boy was receiving aspirin 150/mg/kg/day for treatment of juvenile rheumatoid arthritis. While on salicylate therapy, the patient developed tachypnea and became increasingly hyperthermic, lethargic, and disoriented. The patient developed a maculopapular rash, weakness, and a decreased level of consciousness during the 11 days before admission to the hospital. Physical examination and laboratory determinations revealed that the patient had hypoprothrombinemia, hypoglycemia, and severe hepatic encephalopathy secondary to long-term salicylate toxicity. The patient was treated for hypoglycemia, electrolyte imbalances, thrombocytopenia, and anemia and was discharged after 24 days. Diagnosing chronic salicylism with hepatic dysfunction was difficult because the symptoms are similar to those of stage I to stage II Reye's syndrome. Liver enzymes, including aspartate aminotransferase (also called SGOT), alanine aminotransferase (also called SGPT), alkaline phosphatase, and lactate dehydrogenase, may be elevated in juvenile arthritis patients with hepatic dysfunction. Liver dysfunction usually improves when salicylate therapy is discontinued. Supportive therapy should always be used in symptomatic patients. Children on long-term, high-dose salicylate therapy should be monitored closely, and baseline liver function tests should be performed. The clinical effectiveness of administering sodium bicarbonate in attempts to alkalinize urine and increase salicylate elimination is controversial. In patients with juvenile rheumatoid arthritis who develop chronic salicylism, careful analysis of the patient's medication history, laboratory values, and clinical presentation are necessary to rule out Reye's syndrome.


Activatable Photosensitizer for Targeted Ablation of lacZ-Positive Cells with Single-Cell Resolution.
To achieve highly selective ablation of lacZ-positive cells in a biological milieu in vivo, we developed an activatable photosensitizer, SPiDER-killer-βGal, targeted to β-galactosidase encoded by the lacZ reporter gene. Hydrolysis of SPiDER-killer-βGal by β-galactosidase simultaneously activates both its photosensitizing ability and its reactivity to nucleophiles, so that the phototoxic products generated by light irradiation are trapped inside the lacZ-positive cells. The combination of SPiDER-killer-βGal and light irradiation specifically killed lacZ-positive cells in coculture with cells without lacZ expression. Furthermore, β-galactosidase-expressing cells in the posterior region of cultured Drosophila wing discs and in pupal notum of live Drosophila pupae were selectively killed with single-cell resolution. This photosensitizer should be useful for specific ablation of targeted cells in living organisms, for example, to investigate cellular functions in complex networks.


Phosgene inhalation causes hemolysis and acute lung injury.
Phosgene (Carbonyl Chloride, COCl2) remains an important chemical intermediate in many industrial processes such as combustion of chlorinated hydrocarbons and synthesis of solvents (degreasers, cleaners). It is a sweet smelling gas, and therefore does not prompt escape by the victim upon exposure. Supplemental oxygen and ventilation are the only available management strategies. This study was aimed to delineate the pathogenesis and identify novel biomarkers of acute lung injury post exposure to COCl2 gas. Adult male and female C57BL/6 mice (20-25 g), exposed to COCl2 gas (10 or 20 ppm) for 10 min in environmental chambers, had a dose dependent reduction in PaO2 and an increase in PaCO2, 1 day post exposure. However, mortality increased only in mice exposed to 20 ppm of COCl2 for 10 min. Correspondingly, these mice (20 ppm) also had severe acute lung injury as indicated by an increase in lung wet to dry weight ratio, extravasation of plasma proteins and neutrophils into the bronchoalveolar lavage fluid, and an increase in total lung resistance. The increase in acute lung injury parameters in COCl2 (20 ppm, 10 min) exposed mice correlated with simultaneous increase in oxidation of red blood cells (RBC) membrane, RBC fragility, and plasma levels of cell-free heme. In addition, these mice had decreased plasmalogen levels (plasmenylethanolamine) and elevated levels of their breakdown product, polyunsaturated lysophosphatidylethanolamine, in the circulation suggesting damage to cellular plasma membranes. This study highlights the importance of free heme in the pathogenesis of COCl2 lung injury and identifies plasma membrane breakdown product as potential biomarkers of COCl2 toxicity.


Bringing light into the dark triplet space of molecular systems.
A molecule or a molecular system always consists of excited states of different spin multiplicities. With conventional optical excitations, only the (bright) states with the same spin multiplicity of the ground state could be directly reached. How to reveal the dynamics of excited (dark) states remains the grand challenge in the topical fields of photochemistry, photophysics, and photobiology. For a singlet-triplet coupled molecular system, the (bright) singlet dynamics can be routinely examined by conventional femtosecond pump-probe spectroscopy. However, owing to the involvement of intrinsically fast decay channels such as intramolecular vibrational redistribution and internal conversion, it is very difficult, if not impossible, to single out the (dark) triplet dynamics. Herein, we develop a novel strategy that uses an ultrafast broadband white-light continuum as a excitation light source to enhance the probability of intersystem crossing, thus facilitating the population flow from the singlet space to the triplet space. With a set of femtosecond time-reversed pump-probe experiments, we report on a proof-of-concept molecular system (i.e., the malachite green molecule) that the pure triplet dynamics can be mapped out in real time through monitoring the modulated emission that occurs solely in the triplet space. Significant differences in excited-state dynamics between the singlet and triplet spaces have been observed. This newly developed approach may provide a useful tool for examining the elusive dark-state dynamics of molecular systems and also for exploring the mechanisms underlying molecular luminescence/photonics and solar light harvesting.


Cavitation and the interaction between macroscopic hydrophobic surfaces.
The interaction in water of neutral hydrocarbon and fluorocarbon surfaces, prepared by Langmuir-Blodgett deposition of surfactant monolayers, has been investigated. The attraction between these hydrophobic surfaces can be measured at separations of 70 to 90 nanometers and thus is of considerably greater range than previously found. Spontaneous cavitation occurred as soon as the fluorocarbon surfaces were brought into contact but occurred between the hydrocarbon surfaces only after separation from contact. The very long range forces measured are a consequence of the metastability of water films between macroscopic hydrophobic surfaces. Thus the hydrophobic interaction between macroscopic surfaces may not be related to water structure in the same way that the hydrophobic effect between nonpolar molecules is related to water structure.


Chronic renal failure is accompanied by endothelial activation and a large increase in microparticle numbers with reduced procoagulant capacity.
In patients with chronic renal failure (CRF), cardiovascular disease is the leading cause of increased morbidity and mortality. We hypothesized a role for endothelial activation and microparticle (MP) numbers and procoagulant activity in the pre-thrombotic state of these patients. We analysed blood samples of 27 patients with CRF [8 chronic kidney disease Stage 4 (CKD4), 9 peritoneal dialysis (PD) and 10 haemodialysis (HD), samples taken before and after HD] and 10 controls. Degree and nature of endothelial activation were assessed by measuring mature von Willebrand factor (vWF) and vWF propeptide levels. Cellular MPs were characterized by flow cytometry and MP-specific thrombin generation (TG) measurements. CRF was accompanied by chronic (CKD4 and PD) or acute (HD) endothelial activation. Patients with CRF had substantially higher MP numbers than controls (median 9400 versus 4350×10(6)/L, P=0.001), without significant differences between the treatment subgroups or between pre- and post-HD. The vast majority of MPs were platelet derived. Of the minor populations, endothelial MPs and tissue factor-bearing MPs were more abundant in CRF. MPs were procoagulant, but the increase in numbers was not reflected in a proportional increase in MP-specific TG. Renal failure is accompanied by endothelial activation of a different nature in CKD4 and PD patients compared to HD patients, and results in all subgroups in an increase of mainly platelet-derived MPs that appear to be less procoagulant than in other disease states, possibly because of the uraemic functional defect of their cellular source.


Roles of icosahedral and crystal-like order in the hard spheres glass transition.
A link between structural ordering and slow dynamics has recently attracted much attention from the context of the origin of glassy slow dynamics. Candidates for such structural order are icosahedral, exotic amorphous and crystal-like. Each type of order is linked to a different scenario of glass transition. Here we experimentally access local structural order in polydisperse hard spheres by particle-level confocal microscopy. We identify the key structures as icosahedral and FCC-like order, both statistically associated with slow particles. However, when approaching the glass transition, the icosahedral order does not grow in size, whereas crystal-like order grows. It is the latter that governs the dynamics and is linked to dynamic heterogeneity. This questions the direct role of the local icosahedral ordering in glassy slow dynamics and suggests that the growing length scale of structural order is essential for the slowing down of dynamics and the non-local cooperativity in particle motion.


Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer.
Mesenchymal stem cells (MSCs) play an important role in chemoresistance. Exosomes have been reported to modify cellular phenotype and function by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from MSCs (MSC-exosomes) are involved in mediating the resistance to chemotherapy in gastric cancer and to explore the underlying molecular mechanism. We found that MSC-exosomes significantly induced the resistance of gastric cancer cells to 5-fluorouracil both in vivo and ex vivo. MSC-exosomes antagonized 5-fluorouracil-induced apoptosis and enhanced the expression of multi-drug resistance associated proteins, including MDR, MRP and LRP. Mechanistically, MSC-exosomes triggered the activation of calcium/calmodulin-dependent protein kinases (CaM-Ks) and Raf/MEK/ERK kinase cascade in gastric cancer cells. Blocking the CaM-Ks/Raf/MEK/ERK pathway inhibited the promoting role of MSC-exosomes in chemoresistance. Collectively, MSC-exosomes could induce drug resistance in gastric cancer cells by activating CaM-Ks/Raf/MEK/ERK pathway. Our findings suggest that MSC-exosomes have profound effects on modifying gastric cancer cells in the development of drug resistance. Targeting the interaction between MSC-exosomes and cancer cells may help improve the efficacy of chemotherapy in gastric cancer.


An enhanced care package to improve asthma management in Malawian children: a randomised controlled trial.
Shortages of clinical staff make chronic asthma care challenging in low-income countries. We evaluated an outpatient asthma care package for children, including task-shifting of asthma management roles. We conducted a non-blinded individually randomised controlled trial at a tertiary-level government hospital in Blantyre, Malawi. Children aged 6-15 years diagnosed with asthma were recruited from outpatient clinic, stratified by Childhood Asthma Control Test (cACT) score and allocated 1:1 from a concealed file, accessed during electronic questionnaire completion. The intervention, delivered by non-physicians, comprised clinical assessment, optimisation of inhaled treatment, individualised asthma education. The control group received standard care from outpatient physicians. Primary outcome for intention-to-treat analysis was change in cACT score at 3 months. Secondary outcomes included asthma exacerbations requiring emergency healthcare and school absence. Between September 2018 and December 2019, 120 children (59 intervention; 61 control) were recruited; 65.8% males, with mean (SD) age 9.8 (2.8) years, mean (SD) baseline cACT 20.3 (2.6). At 3 months, intervention children (n=56) had a greater mean (SD) change in cACT score from baseline (2.7 (2.8) vs 0.6 (2.8)) compared with standard care participants (n=59); a difference of 2.1 points (95% CI: 1.1 to 3.1, p<0.001). Fewer intervention children attended emergency healthcare (7.3% vs 25.4%, p=0.02) and missed school (20.0% vs 62.7%, p<0.001) compared with standard care children. The intervention resulted in decreased asthma symptoms and exacerbations. Wider scale-up could present substantial benefits for asthmatic patients in resource-limited settings. PACTR201807211617031.


Early Prognosticators for Induction of Therapeutic Hypothermia Following Cardiac Arrest.
The American Heart Association recommends therapeutic hypothermia for comatose patients with return of spontaneous circulation after out-of-hospital ventricular fibrillation cardiac arrest. While there is a growing body of evidence for the general efficacy of therapeutic hypothermia, the individualized benefit of therapy is not currently predictable. Ninety-one consecutive patients, from April 2011 to July 2014, were treated at the University of Kentucky Medical Center with the therapeutic hypothermia protocol. Medical records were reviewed retrospectively. Data, such as preexisting comorbidities, cardiac arrest characteristics, and hospital course, were used to compose a multivariate logistic regression with mortality serving as the primary endpoint. The overall in-hospital mortality was 64% (n = 58) in this group. The arrest was considered cardiac etiology in 84% (n = 76) of patients, of which 49% (n = 45) were classed as ventricular fibrillation and 9% (n = 8) as ventricular tachycardia. The presence of a shockable rhythm, as well as shorter duration of cardiac arrest, was associated with increased survival, whereas time to target temperature was not. The presence of a preexisting neurologic disease was associated with a 10-fold increase in estimated odds of mortality. Age, serum lactate, ionized calcium, arterial pH, estimated glomerular filtration rate, and APACHE score were all predictors of mortality. Cardiac arrest is a devastating condition with a high mortality rate. Given the limited resources of the resuscitation community, the ability to predict survivors based on routinely obtained measures upon admission would be of tremendous value. In this study, we show a series of admission parameters that demonstrate predictive ability in identifying patients more likely to survive with therapeutic hypothermia.


A mechanism for the evolution of phosphorylation sites.
Protein phosphorylation provides a mechanism for the rapid, reversible control of protein function. Phosphorylation adds negative charge to amino acid side chains, and negatively charged amino acids (Asp/Glu) can sometimes mimic the phosphorylated state of a protein. Using a comparative genomics approach, we show that nature also employs this trick in reverse by evolving serine, threonine, and tyrosine phosphorylation sites from Asp/Glu residues. Structures of three proteins where phosphosites evolved from acidic residues (DNA topoisomerase II, enolase, and C-Raf) show that the relevant acidic residues are present in salt bridges with conserved basic residues, and that phosphorylation has the potential to conditionally restore the salt bridges. The evolution of phosphorylation sites from glutamate and aspartate provides a rationale for why phosphorylation sometimes activates proteins, and helps explain the origins of this important and complex process.


Quantitative DNA methylation analysis detects cervical intraepithelial neoplasms type 3 and worse.
DNA methylation may be used a potential biomarker for detecting cervical cancer. The authors of this report used quantitative methylation analysis of 4 genes in a full spectrum of cervical lesions to test its potential clinical application. This hospital-based, retrospective, case-control study was conducted in 185 patients and included patients who had a normal uterine cervix (n = 53), cervical intraepithelial neoplasm type 1 (CIN1) (n = 37), CIN2 (n = 22), CIN3 (n = 24), carcinoma in situ (CIS) (n = 22), squamous cell carcinoma (SCC, n = 20), and adenocarcinoma (AC) (n = 7). Methylation levels of the genes sex-determining region Y, box 1 (SOX1); paired box gene 1 (PAX1); LIM homeobox transcription factor 1α (LMX1A), and NK6 transcription factor-related locus 1 (NKX6-1) were determined by using real-time methylation-specific polymerase chain reaction (PCR) amplification. Cutoff values of the percentage of methylation reference (PMR) for different diagnoses were determined to test the sensitivity and specificity and to generate receiver operating characteristic (ROC) curves. Two-sided Mann-Whitney U tests were used to test differences in PMR between groups. The PMRs of the 4 genes were significantly higher in CIN3 and worse (CIN3+) lesions than the PMRs in specimens of normal cervix and CIN1 or CIN2 (P < .001). ROC curve analysis demonstrated that the sensitivity, specificity, and accuracy for detecting CIN3+ lesions were 0.88, 0.82, and 0.95, respectively, for SOX1; 0.78, 0.91, and 0.89, respectively, for PAX1; 0.77, 0.88, and 0.90, respectively, for LMX1A; and 0.93, 0.97, and 0.97, respectively, for NKX6-1. The current results indicated that quantitative PCR-based testing for DNA methylation of 4 genes holds great promise for cervical cancer screening and warrants further population-based studies using standardized DNA methylation testing.


Trypanosoma brucei gambiense group 1 is distinguished by a unique amino acid substitution in the HpHb receptor implicated in human serum resistance.
Trypanosoma brucei rhodesiense (Tbr) and T. b. gambiense (Tbg), causative agents of Human African Trypanosomiasis (sleeping sickness) in Africa, have evolved alternative mechanisms of resisting the activity of trypanosome lytic factors (TLFs), components of innate immunity in human serum that protect against infection by other African trypanosomes. In Tbr, lytic activity is suppressed by the Tbr-specific serum-resistance associated (SRA) protein. The mechanism in Tbg is less well understood but has been hypothesized to involve altered activity and expression of haptoglobin haemoglobin receptor (HpHbR). HpHbR has been shown to facilitate internalization of TLF-1 in T.b. brucei (Tbb), a member of the T. brucei species complex that is susceptible to human serum. By evaluating the genetic variability of HpHbR in a comprehensive geographical and taxonomic context, we show that a single substitution that replaces leucine with serine at position 210 is conserved in the most widespread form of Tbg (Tbg group 1) and not found in related taxa, which are either human serum susceptible (Tbb) or known to resist lysis via an alternative mechanism (Tbr and Tbg group 2). We hypothesize that this single substitution contributes to reduced uptake of TLF and thus may play a key role in conferring serum resistance to Tbg group 1. In contrast, similarity in HpHbR sequence among isolates of Tbg group 2 and Tbb/Tbr provides further evidence that human serum resistance in Tbg group 2 is likely independent of HpHbR function.


Nicotine ameliorates NMDA receptor antagonist-induced deficits in contextual fear conditioning through high-affinity nicotinic acetylcholine receptors in the hippocampus.
NMDA glutamate receptors (NMDARs) and nicotinic acetylcholine receptors (nAChRs) are both involved in learning and synaptic plasticity. Increasing evidence suggests processes mediated by these receptors may interact to modulate learning; however, little is known about the neural substrates involved in these interactive processes. The present studies investigated the effects of nicotine on MK-801 hydrogen maleate (MK-801) and DL-2-Amino-5-phosphonovaleric acid (APV)-induced disruption of contextual fear conditioning in male C57BL/6J mice, using direct drug infusion and selective nAChR antagonists to define the brain regions and the nAChR subtypes involved. Mice treated with MK-801 showed a deficit in contextual fear conditioning that was ameliorated by nicotine. Direct drug infusion demonstrated that the NMDAR antagonists disrupted hippocampal function and that nicotine acted in the dorsal hippocampus to ameliorate the deficit in learning. The high-affinity nAChR antagonist Dihydro-β-erythroidine hydrobromide (DhβE) blocked the effects of nicotine on MK-801-induced deficits while the α7 nAChR antagonist methyllycaconitine citrate salt hydrate (MLA) did not. These results suggest that NMDARs and nAChRs may mediate similar hippocampal processes involved in contextual fear conditioning. Furthermore, these results may have implications for developing effective therapeutics for the cognitive deficits associated with schizophrenia because a large subset of patients with schizophrenia exhibit cognitive deficits that may be related to NMDAR dysfunction and smoke at much higher rates than the healthy population, which may be an attempt to ameliorate cognitive deficits.


Medical image segmentation using analysis of isolable-contour maps.
A common challenge for automated segmentation techniques is differentiation between images of close objects that have similar intensities, whose boundaries are often blurred due to partial-volume effects. We propose a novel approach to segmentation of two-dimensional images, which addresses this challenge. Our method, which we call intrinsic shape for segmentation (ISeg), analyzes isolabel-contour maps to identify coherent regions that correspond to major objects. ISeg generates an isolabel-contour map for an image by multilevel thresholding with a fine partition of the intensity range. ISeg detects object boundaries by comparing the shape of neighboring isolabel contours from the map. ISeg requires only little effort from users; it does not require construction of shape models of target objects. In a formal validation with computed-tomography angiography data, we showed that ISeg was more robust than conventional thresholding, and that ISeg's results were comparable to results of manual tracing.