Cigarette packet warning labels can prevent relapse: findings from the International Tobacco Control 4-Country policy evaluation cohort study.
To investigate the links between health warning labels (WLs) on cigarette packets and relapse among recently quit smokers. Prospective longitudinal cohort survey. Australia, Canada, the UK and the USA. 1936 recent ex-smokers (44.4% male) from one of the first six waves (2002-2007) of the International Tobacco Control 4-Country policy evaluation survey, who were followed up in the next wave. Whether participants had relapsed at follow-up (approximately 1 year later). In multivariate analysis, very frequent noticing of WLs among ex-smokers was associated with greater relapse 1 year later (OR: 1.52, 95% CI 1.11 to 2.09, p<0.01), but this effect disappeared after controlling for urges to smoke and self-efficacy (OR: 1.29, 95% CI 0.92 to 1.80, p=0.135). In contrast, reporting that WLs make staying quit 'a lot' more likely (compared with 'not at all' likely) was associated with a lower likelihood of relapse 1 year later (OR: 0.65, 95% CI 0.49 to 0.86, p<0.01) and this effect remained robust across all models tested, increasing in some. This study provides the first longitudinal evidence that health warnings can help ex-smokers stay quit. Once the authors control for greater exposure to cigarettes, which is understandably predictive of relapse, WL effects are positive. However, it may be that ex-smokers need to actively use the health consequences that WLs highlight to remind them of their reasons for quitting, rather than it being something that happens automatically. Ex-smokers should be encouraged to use pack warnings to counter urges to resume smoking. Novel warnings may be more likely to facilitate this.


Fluorescent nanomaterials combined with molecular imprinting polymer: synthesis, analytical applications, and challenges.
Fluorescent nanomaterials (FNMs) and molecular imprinted polymers (MIPs) have been widely used in analytical chemistry for determination. However, low selectivity of FNMs and low sensitivity of MIPs hinder their applications. Combining the merits of FNMs and MIPs, FNMs coated with MIPs (FNMs@MIPs) were proposed to solve those problems. Carbon dots, semiconductor quantum dots, noble metal nanoparticles, silica nanoparticles, and covalent-organic frameworks have been reported to be coated with MIPs. In order to overcome challenges for FNMs@MIPs, such as the lack of handy synthesis routes, incompatibility with aqueous solutions, heterogeneous size of particles, leakage of template molecules, the biocompatibility of FNMs@MIPs, and the inference between FNMs and MIPs, scientists proposed some solutions in recent years. We comprehensively review the newest advances of the FNMs@MIPs, and predict the direction of the future development. Graphical abstract.


Mononuclear phagocyte accumulates a stearic acid derivative during differentiation into macrophages. Effects of stearic acid on macrophage differentiation and Mycobacterium tuberculosis control.
The fatty acid composition of monocytes changes substantially during differentiation into macrophages, increasing the proportion of saturated fatty acids. These changes prompted us to investigate whether fatty acid accumulation in the extracellular milieu could affect the differentiation of bystander mononuclear phagocytes. An esterified fatty acid derivative, stearate, was the only fatty acid that significantly increased in macrophage supernatants, and there were higher levels when cells differentiated in the presence of Mycobacterium tuberculosis H37Rv or purified protein derivative (PPD). Exogenous stearic acid enhanced the expression of HLA-DR and CD64; there was also accumulation of IL-12, TNF-α, IL-6, MIP-1 α and β and a reduction in MCP-1 and the bacterial load. These results suggested that during differentiation, a derivative of stearic acid, which promotes the process as well as the effector mechanisms of phagocytes against the mycobacterium, accumulates in the cell supernatants.


Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related sclerosing cholangitis: a Japanese cohort.
IgG4-related sclerosing cholangitis (IgG4-SC) must be precisely distinguished from primary sclerosing cholangitis and cholangiocarcinoma (CC) because the treatments are completely different. However, the pathological diagnosis of IgG4-SC is difficult. Therefore, highly specific non-invasive criteria such as serum IgG4 should be established. This study established a cut-off for serum IgG4 to differentiate IgG4-SC from respective controls using serum IgG4 levels measured in Japanese centers. A total of 344 IgG4-SC patients were enrolled in this study. As controls, 245, 110, and 149 patients with pancreatic cancer, primary sclerosing cholangitis, and CC, respectively, were enrolled. IgG4-SC patients were classified into three groups: type 1 (stenosis only in the lower part of the common bile duct), type 2 (stenosis diffusely distributed throughout the intrahepatic and extrahepatic bile ducts), and types 3 and 4 (stenosis in the hilar hepatic region) with 246, 56, and 42 patients, respectively. Serum IgG4 levels were compared, and the cut-offs were established. The cut-off obtained from receiver operator characteristic curves showed similar sensitivity and specificity to that of 135 mg/dL when all IgG4-SC and controls were compared. However, a new cut-off value was established when subgroups of IgG4-SC and controls were compared. A cut-off of 182 mg/dL can increase the specificity to 96.6% (4.7% increase) for distinguishing types 3 and 4 IgG4-SC from CC. A cut-off of 207 mg/dL might be useful for completely distinguishing types 3 and 4 IgG4-SC from all CC. Serum IgG4 is useful for the differential diagnosis of IgG4-SC and controls.


Clinical features and prognosis of severe-to-profound sudden sensorineural hearing loss.
Sudden sensorineural hearing loss (SSNHL) is an otologic emergency. Despite multiple efforts to clarify the factors affecting the prognosis of severe-to-profound SSNHL, various studies showed inconsistent results and lack of clinical significance. Therefore, we examined the clinical features and outcomes of severe-to-profound SSNHL. We included patients who experienced SSNHL between 2018 and 2021 and were diagnosed according to the American Academy of Otolaryngology-Head and Neck Surgery criteria; hearing loss over 70 dB on initial pure tone audiometry (PTA) was used to define severe-to-profound SSNHL. We retrospectively examine the demographic, laboratory, radiologic, and audiometric data of SSNHL patients. We also evaluated the final hearing gain of these patients by assessing their PTA findings and word-recognition scores. Of the 178 patients, 94 (52.81%) and 84 (47.19%) showed profound (>90 dB) and severe (>70 to 90 dB) hearing loss, respectively. The presence of vertigo and hypertension differed significantly between the severe and profound groups (p < 0.001 and p = 0.012, respectively), as did the initial serum creatinine level (p = 0.043). Recovery in PTA showed a reliable correlation with the interval between onset and treatment in the severe group and periventricular white-matter findings in the profound group (p < 0.001 and p = 0.011, respectively). The presence of hypertension was related to recovery of low tone (p = 0.023 for 250 Hz; p = 0.034 for 500 Hz), while glycated hemoglobin level was related to recovery of high tone in the severe group (p = 0.049 for 4000 Hz; p = 0.047 for 8000 Hz). Severe-to-profound SSNHL showed poor prognosis for hearing gain. The interval from onset to treatment was a significant prognostic factor for severe SSNHL, while the presence of vertigo, estimated glomerular filtration rate, and periventricular white-matter findings were significant prognostic factors for profound SSNHL.


Optimized photocatalytic regeneration of adsorption-photocatalysis bifunctional composite saturated with Methyl Orange.
Photo-responsive adsorption-photocatalysis nanocomposites are generally used in water and wastewater decontamination; however, the prolonged adsorption capacity of composites and the role of adsorption in concomitant photocatalysis are typically neglected. These composites can be regenerated under light irradiation as their adsorption capacity decreases. Herein, a novel adsorption-photocatalysis bifunctional nanocomposite, Bi-doped TiO2 supported on powdered activated carbon (Bi2O3/TiO2/PAC), was prepared using the sol-impregnation-hydrothermal procedure. Bi2O3/TiO2/PAC with a secondary calcination temperature of 700°C under a nitrogen atmosphere was selected for maximum adsorption capacity on Methyl Orange (MO). The composite displayed an excellent adsorption capacity and was easily separated and recycled. The results demonstrate that 71.2% photocatalytic regeneration efficiency could be attained under visible light irradiation for 1 hr at an intensity of 750 W/m2 and pH 7. Characterization of the as-prepared Bi2O3/TiO2/PAC nanocomposite (700°C) indicates that it possesses a highly specific surface area and great optical properties, showing bifunctional adsorption-photocatalysis characteristics. The p-n heterojunction of the composite played a dominant role in the photocatalytic regeneration process, and effective degradation of MO could be achieved along with composite regeneration.


Broadband homonuclear TOCSY with amplitude and phase-modulated RF mixing schemes.
We have explored the design of broadband scalar coupling mediated (13)C-(13)C and cross-relaxation suppressed (1)H-(1)H TOCSY sequences employing phase/amplitude modulated inversion pulses. Considering a variety of supercycles, pulsewidths and a RF field strength of 10 kHz, the Fourier coefficients defining the amplitude and phase modulation profiles of the 180 degrees pulses were optimised numerically so as to obtain efficient magnetisation transfer within the desired range of resonance offsets. The coherence transfer characteristics of the mixing schemes were assessed via numerical simulations and experimental measurements and were compared with commonly used sequences based on rectangular RF pulses. The efficacies of the clean (1)H-(1)H TOCSY sequences were also examined via numerical simulations for application to weakly oriented systems and sequences with efficient, broadband and clean dipolar transfer characteristics were identified. In general, the amplitude and phase modulated TOCSY sequences presented here have moderately better performance characteristics than the sequences currently employed in biomolecular NMR spectroscopy.


Calculation of odds ratios on the TI-59 from logistic regression output.
A program for the Texas Instruments TI-59 and, optionally, a print cradle is described that allows calculation of point estimates and confidence intervals for odds ratios using information included in the output from most logistic regression programs. The program considers up to fifteen continuous and/or dichotomous independent variables.


Beta structures of alternating polypeptides and their possible prebiotic significance.
A survey of the commonest amino acids formed in prebiotic conditions suggests that the earliest form of genetic coding may have specified polypeptides with a strong tendency to form stable Beta-sheet structure. Poly(Val-Lys), like other polypeptides in which hydrophobic and hydrophilic residues alternate, tends to form Beta structures. We show that bilayers with a hydrophobic interior and a hydrophilic exterior may be present in aqueous solution.


Histone deacetylases (HDACs) as the promising immunotherapeutic targets for hematologic cancer treatment.
Bone marrow transplantation is regarded as the most effective immunotherapy for hematologic cancer, but it generally faces difficulties in matching. Aberrant expression of histone deacetylases (HDACs) is closely related to the occurrence and development of hematological cancer. Recent studies suggested that HDACs might play a critical role in initiating anti-cancer immune response or enhancing anti-cancer immunotherapy. Besides, combining HDAC inhibition and immunotherapy could prevent immunotherapy resistance in some degree and reach an extended treatment window. This review summarized the relationship between HDACs and immune and described the current understanding of HDACs in immunotherapy for hematologic cancer.


Dynamics of ion currents in the membrane of the isolated mollusc neuron under high pressure.
The action of helium (up to 101 abs. atm.) under high pressure on ionic currents through the cellular membrane was studied in experiments on isolated neurons of a gastropod. A method of intracellular dialysis which is new for physiological investigations under hyperbaric conditions was used. A substantial decrease in the inward (sodium) current with increased pressure was found. Its amplitude was decreased by 10-15% at 25 abs. atm. and by 64% at 101 abs. atm. as compared with the control. At the same time, a shift in the currentvoltage characteristics along the abscissa was not observed. Significant changes in the outward (potassium) current were not appreciable. The inhibition of the sodium current observed in these experiments with increased pressure is associated with a possible change in the structure of the cell membrane under the influence of pressure; this leads in its turn to shifts in the functioning of the membrane components participating in the generation of the nerve impulse.


Autonomic nervous reflexes in respiration elicited by mechanical stimulation of the velopharyngeal region in rabbits.
Reflex increases in peak activity of the diaphragm and expiratory pharyngeal muscles were recorded in lightly anesthetized and vagotomized rabbits by gentle mechanical stimulation of the nasal surface of the soft palate and of the posterior wall of the nasopharynx. No noticeable change in diaphragmatic activity was evoked by gentle mechanical stimulation of the oral surface of the soft palate and of the posterior wall of the oropharynx. The present results suggest that afferent signals from mechanoreceptors of the velopharyngeal region may contribute to reflex augmentation of respiration.


Modulating the mixed potential for developing biosensors: Direct potentiometric determination of glucose in whole, undiluted blood.
The growing demand for tools to generate chemical information in decentralized settings is creating a vast range of opportunities for potentiometric sensors, since their combination of robustness, simplicity of operation and cost can hardly be rivalled by any other technique. In previous works, we have shown that the mixed potential of a Pt electrode can be controlled with analytical purposes using a coating of Nafion, thus providing a way to develop a potentiometric biosensor for glucose. Unfortunately, the linear range of this device did not match the relevant clinical range for glucose in blood. This work presents a novel strategy to control the mixed potential that allows the development of a potentiometric biosensor for the direct detection of glucose in whole, undiluted blood without any sample pretreatment. By changing the ionomer, the analytical response can be tuned, shifting the linear range while keeping the sensitivity. Aquivion, a polyelectrolyte from the same family as Nafion, is used to stabilize the mixed potential of a platinized paper-based electrode, to entrap the enzyme and to reduce the interference from negatively charged species. Factors affecting the generation of the signal and the principle of detection are discussed. Optimization of the biosensor composition was achieved with particular focus on the characterization of the linear range and sensitivity. The accurate measurement of blood sugar levels in a single drop of whole blood with excellent recovery is presented.


A possible covalent xanthine oxidase inhibitor TS10: Inhibition mechanism, metabolites identification and PDPK assessment.
Xanthine oxidase (XO) inhibitors are widely used in the control of serum uric acid levels in the clinical management of gout. Our continuous efforts in searching novel amide-based XO inhibitors culminated in the identification of N-(4-((3-cyanobenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)isonicotinamide (TS10), which exhibited comparable in vitro inhibition to that of topiroxostat (TS10, IC50 = 0.031 μM; topiroxostat, IC50 = 0.020 μM). According to the molecular modeling, we speculated that, as well as topiroxostat, TS10 would be biotransformed by XO to yield TS10-2-OH. In this work, TS10-2-OH was successfully identified in XO targeted metabolism study, demonstrated that TS10 underwent a covalent binding with XO via a TS10-O-Mo intermediate after anchoring in the XO molybdenum cofactor pocket. Furthermore, TS10-2-OH is a weak active metabolite, and its potency was explained by the molecular docking. In metabolites identification, TS10 could be oxidized by CYP2C9, CYP3A4 and CYP3A5 to generate two mono-hydroxylated metabolites (not TS10-2-OH); and could occur degradation in plasma to mainly generate a hydrolytic metabolite (TS10-hydrolysate). In pharmacokinetic assessment, the low oral system exposure was observed (Cmax = 14.73 ± 2.66 ng/mL and AUClast = 9.17 ± 1.42 h⋅ng/mL), which could be explained by the poor oral absorption property found in excretion studies. Nonetheless, in pharmacodynamic evaluation, TS10 exhibited significant uric acid-lowering effect after oral administration in a dose-dependent manner. Briefly, in addition to allopurinol and topiroxostat, TS10 is possibly another explicitly mechanism-based XO inhibitor with powerful covalent inhibition.


[Epidemiology and clinical aspects of sarcoidosis as a cyclic infection disease with low penetrance].
Report on the epidemiology of sarcoidois in a town within the period of 1950-1983. The author tries to explain occurrence and distribution of his observation by assuming a cyclic infectious disease with a limited radius and penetrating power of infection.


Organic matter and concentrated nitrogen removal by shortcut nitrification and denitrification from mature municipal landfill leachate.
An UASB+Anoxic/Oxic (A/O) system was introduced to treat a mature landfill leachate with low carbon-to-nitrogen ratio and high ammonia concentration. To make the best use of the biodegradable COD in the leachate, the denitrification of NOx- -N in the recirculation effluent from the clarifier was carried out in the UASB. The results showed that most biodegradable organic matters were removed by the denitrification in the UASB. The NH4+ -N loading rate (ALR) of A/O reactor and operational temperature was 0.28-0.60 kg NH4+ -N/(m3 x d) and 17-29 degrees C during experimental period, respectively. The short-cut nitrification with nitrite accumulation efficiency of 90%-99% was stabilized during the whole experiment. The NH4+ -N removal efficiency varied between 90% and 100%. When ALR was less than 0.45 kg NH4+ -N/(m3 x d), the NH4+ -N removal efficiency was more than 98%. With the influent NH4+ -N of 1200-1800 mg/L, the effluent NH4+ -N was less than 15 mg/L. The shortcut nitrification and denitrification can save 40% carbon source, with a highly efficient denitrification taking place in the UASB. When the ratio of the feed COD to feed NH4+ -N was only 2-3, the total inorganic nitrogen (TIN) removal efficiency attained 67%-80%. Besides, the sludge samples from A/O reactor were analyzed using FISH. The FISH analysis revealed that ammonia oxidation bacteria (AOB) accounted for 4% of the total eubacterial population, whereas nitrite oxidation bacteria (NOB) accounted only for 0.2% of the total eubacterial population.


Corticotropin releasing hormone related behavioral and neuroendocrine responses to stress in Lewis and Fischer rats.
We have recently shown that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is related to a lack of glucocorticoid restraint of inflammation while the relative SCW arthritis resistance in histocompatible Fischer (F344/N) rats is related to their greater hypothalamic-pituitary-adrenal (HPA) axis response. The difference in pituitary-adrenal responsiveness results from decreased inflammatory mediator-induced hypothalamic corticotropin-releasing hormone (CRH) biosynthesis and secretion in LEW/N rats. Because CRH not only activates the pituitary-adrenal axis, but also is associated with behavioral responses that are adaptive during stressful situations, we wished to determine if the differential LEW/N and F344/N CRH responsiveness to inflammatory mediators could also be associated with differences in neuroendocrine and behavioral responses to physical and emotional stressors. In this study, LEW/N rats exhibited significant differences compared to F344/N rats, in plasma adrenocorticotropin hormone (ACTH) and corticosterone responses during exposure to an open field, swim stress, restraint or ether. Furthermore, hypothalamic paraventricular CRH mRNA expression was also significantly lower in LEW/N compared to F344/N rats after restraint. These differences in neuroendocrine responses were associated with differences in behavioral responses in LEW/N compared to F344/N rats in the open field. Outbred HSD rats, which have intermediate and overlapping arthritis susceptibility compared to LEW/N and F344/N rats, exhibited intermediate and overlapping plasma corticosterone and behavioral responses to stressful stimuli compared to the two inbred strains. These data suggest that the differences in CRH responses in these strains may contribute to the behavioral and neuroendocrine differences we have observed. Therefore these strains may provide a useful animal model for studying the relationship between behavior, neuroendocrine and inflammatory responses.


Development of biochar-based nanocatalysts for tar cracking/reforming during biomass pyrolysis and gasification.
Gasification and pyrolysis have been considered as potential routes for the production of fuel gas from abundant, low-cost and renewable biomass materials. Tar is the undesirable but inevitable byproduct during these processes, which not only lowers the overall energy conversion efficiency but also leads to potential contamination and clogging problems. Catalytic reforming has been seen as one of the most promising methods for tar elimination, and biochar-based nanocatalysts (BBNs) show promise as an efficient tar reforming catalyst. Extensive research efforts have been devoted to the development of BBNs to reduce biomass tar below tolerable limits. This current study reviews the recent progress in the preparation and application of BBNs for converting tar into fuel gas during biomass gasification or pyrolysis. The formation and chemical characteristics of the BBNs are introduced for a better understanding of the catalytic mechanism; prospects for success, as well as challenges, are also discussed.


Quantitative microsatellite analysis to delineate the commonly deleted region 1p22.3 in mantle cell lymphomas.
The molecular pathogenesis of mantle cell lymphomas (MCL), a subset of B-cell non-Hodgkin's lymphomas with a poor prognosis, is still poorly understood. In addition to the characteristic primary genetic alteration t(11;14)(q13;q32), several further genetic changes are present in most cases. One of the most frequent genomic imbalances is the deletion of 1p22.1-p31.1 observed in nearly one-third of MCL cases. This might indicate the presence of tumor suppressor gene(s) in this critical region of deletion. Quantitative microsatellite analysis (QuMA) is a real-time PCR-based method to detect DNA copy number changes. Since QuMA has the resolving power to detect subtle genomic alterations, including homozygous deletions, this may help to identify candidate tumor suppressor genes from deleted regions. To gain more insight into the molecular pathogenesis of MCL, QuMA was performed on genomic DNA from 57 MCL cases. Eight microsatellite loci mapping to the chromosomal region 1p22.3 were analyzed. Losses were observed in 51 of the 57 ( approximately 89.5%) samples. Two cases showed a homozygous deletion at the locus containing the gene SH3GLB1, which plays a key role in Bax-mediated apoptosis. Two hotspots with copy number losses were detected at chromosomal localizations 85.4 and 86.6 Mb encompassing BCL10 and CLCA2. Both the genes seem to be attractive candidates to study tumor suppressor function in MCL.


Cytokine responses to quantiferon peptides in pediatric tuberculosis: a pilot study.
Detailed understanding of tuberculosis (TB) immunopathology and cytokine/chemokine responses can ultimately lead to the development of new diagnostic tools, especially useful in children where TB diagnosis remains challenging. Nineteen cytokine/chemokine responses to Mycobacterium tuberculosis (M.tb) antigens were analyzed in 47 children distributed as follow: 28 with TB-disease (TD), 12 with latent TB and 7 uninfected controls. All the cytokines and chemokines were quantified in a multiplexed microsphere-based assay by using residual plasma from the quantiFERON kit (IFNγ release assay). IP-10, IL-2, IL-5 and IL-13 were among the best cytokines to diagnose infection as related by the area under ROC curve for IP-10 (0.96, 95%CI: 0.91-1.00), IL-2 (0.98, 95%CI: 0.93-1.02), IL-5 (0.91, 95%CI: 0.81-1.01) and IL-13 (0.97, 95%CI: 0.93-1.00). None of the 5 biomarkers, however, discriminated TB-disease from latent-TB. Finally, lower IL-5 (p = 0.02) and IL-13 (p = 0.02) levels were observed in severe opposed to non-severe TB. These results suggest that IP-10, IL-2, IL-5 and IL-13 may find a diagnostic application in pediatric tuberculosis and argue against the paradigm of a negative influence of Th2 responses in severe pediatric M.tb infection.


Draft Genome Sequences of Historical Strains of Coxiella burnetii Isolated from Cow's Milk and a Goat Placenta.
Here, we report draft genome sequences of historical strains of Coxiella burnetii derived from cow's milk and the placenta of a goat that had aborted. The California and Ohio milk strains display a different sequence type than do contemporary milk strains.


Water status and dynamics of high-moisture Mozzarella cheese as affected by frozen and refrigerated storage.
High-moisture Mozzarella is one of the most exported cheeses worldwide, but affected by short shelf-life. Freezing can help to reduce waste, but its effect on quality needs to be considered. In this study, the physico-chemical changes of Mozzarella occurring during frozen storage and subsequent refrigerated storage (after thawing) were evaluated. Frozen cheeses stored at -18 °C between 1 and 4 months showed microstructural damage and different physical, textural, sensory properties. With NMR relaxometry it was possible to observe freeze-related dehydration of caseins, by measuring the changes in water relaxation times within the matrix. These modifications were confirmed by microstructural observations that showed the formation of larger serum channels in samples subjected to freezing, compared with fresh cheeses. Sensory evaluation showed skin peeling off in frozen samples. By observing the changes at various length scales it was therefore possible to identify the critical points affecting HM Mozzarella cheese quality during frozen storage.


Septic arthritis in adults in a tertiary care center.
To describe the history, clinical features and microorganisms involved in a group of adult subjects with and without septic arthritis (SA) at a tertiary care in Mexico. A cross-sectional descriptive study was conducted on 96 adults with clinical suspicion of AS in one or more joints. In all cases synovial fluid arthrocentesis and culture was performed. The comparison group subjects were culture negative. A descriptive statistical analysis and binary logistic regression model was performed between the variables associated with the development of AS. A value of P≤.05 was significant. A total of 49 out of 96 subjects had a positive culture, mostly of the monoarticular type (96%; P=.02). The knee was the most common site (61%; P=.06) and pain was the main clinical manifestation (59%; P=.001). Staphylococcus was the most common etiological agent (65%; P<.001). The risk factors revealed in the final regression model were SA the history of joint disease (OR=25; P=.03) and volume increase (OR=13.16; P=.06). Functional limitation (OR=8.54; P=.04) showed a significant risk among borderline for SA. Our results are consistent with previous studies, and can be generalized to geographical areas with similar clinical features to those observed in this study.


Tyrosinemia.
A case of tyrosinemia in a three-month-old boy is presented. The patient appeared jaundiced initially with markedly elevated levels of serum tyrosine and a positive Millon-reacting urine. Jaundice persisted and hepatosplenomegaly gradually increased. He died due to liver failure on the 51st day after admission. At autopsy, the liver showed the features of severe giant cell hepatitis including giant cell formation, fibrosis and bile retention. The pancreas and the brain showed characteristic postmortem findings as previously reported in patients with tyrosinemia.


Using project management methodology to plan and track inpatient care.
Effective care of each patient throughout a hospital admission involves executing a specific set of tasks to produce a favorable outcome within an appropriate time frame. The ProjectRounds methodology, which can be implemented using widely available software, incorporates the principles of project management in planning and control hospital inpatient care. It consists of four stages--clinical assessment, planning, scheduling, and tracking. OVERVIEW OF PROJECTROUNDS AND EXAMPLE: As an example, a 68-year-old-man is admitted with pneumonia. In clinical assessment, the admitting physician uses an assessment tool that prompts her to list all the patient's clinical issues, define the conditions that need to be met to discharge the patient, highlight special problems, and list any consultations, diagnostic tests, and procedures that are planned. In planning, the work breakdown structure--a tabulation of all the tasks in the "project" (the admission)--is created. In scheduling, a project schedule is generated, and in tracking, the clinical team evaluates and monitors the project's course. During interdisciplinary clinical rounds, the progress of the patient's hospital care can be tracked and quantified by employing the percent complete method. Tracking can be used as a "dashboard," providing a concise summary of the care that needs to be and has been rendered to the patient. Applying the tenets of project management can optimize the process of providing health care to hospital inpatients.


Peroxidase-like activity of vanadium tetrasulfide submicrospheres and its application to the colorimetric detection of hydrogen peroxide and L-cysteine.
It is demonstrated that vanadium tetrasulfide (VS4) exhibits peroxidase (POx)-like activity which follows Michaelis-Menten kinetics when using H2O2 as a co-substrate. Electron spin resonance spectroscopy was use to analyze the catalytic mechanism. It suggests that the enzyme mimicking activity is caused by decomposing H2O2 into hydroxyl radicals. The method was used to quantify H2O2 by using 3,3',5,5'-tetramethylbenzidine as the substrate which results in the formation of a blue coloration (with an absorption peak at 652 nm). H2O2 can be detected in the 50 to 300 μM concentration range, and the detection limit is 5.0 μM. The assay for L-cysteine (L-cys) is based on the capability of oxTMB to oxidize L-cys to form L-cystine. The colorimetric L-cys assay has a linear response in the 5 to 100 μM concentration range and a 2.5 μM detection limit. Graphical abstractSchematic representation of the enzyme mimicking activity of vanadium tetrasulfide (VS4) submicrospheres originated from the decomposition of hydrogen peroxide (H2O2) to generate reactive hydroxyl radical (·OH) and the colorimetric detection of L-cysteine.


Comparison of two different lysozyme types under native and crystallization conditions using two-dimensional NMR and dynamic light scattering.
In order to elucidate differences observed in the aggregation kinetics of hen-egg white lysozyme under crystallization conditions we have undertaken a comparative study of the enzyme marketed by Seikagaku and Sigma companies. When the crystallization of the two lysozyme preparations is followed by time-resolved dynamic light scattering, the structural differences are also observed under native conditions in the early nucleation kinetics. The differences are manifested in the formation rates of macroscopic crystals, but do not influence the morphology of the typical tetragonal lysozyme crystal. Using two-dimensional NMR we have followed the differences in the native-like solution structure of the two preparations, while the primary sequence and molecular mass are identical. According to the published structure of tetragonal lysozyme crystal the largest deviations were found for the residues involved in the intermolecular interactions in crystal structure.


Evolution of NAD biosynthetic enzymes.
Two research groups have solved crystal structures of nicotinic acid phosphoribosyltransferase (PRTase) and made the argument that PRTases in three distinct pathways of nicotinamide adenine dinucleotide (NAD) biosynthesis evolved from a common ancestor (Shin et al., 2005 and Chappie et al., 2005).


G protein-coupled receptor 183 facilitates endothelial-to-hematopoietic transition via Notch1 inhibition.
In vertebrates, embryonic hematopoietic stem and progenitor cells (HSPCs) are derived from a subset of endothelial cells, the hemogenic endothelium (HE), through the endothelial-to-hematopoietic transition (EHT). Notch signaling is essential for HSPC development during embryogenesis across vertebrates. However, whether and how it regulates EHT remains unclear. Here, we show that G protein-coupled receptor 183 (Gpr183) signaling serves as an indispensable switch for HSPC emergence by repressing Notch signaling before the onset of EHT. Inhibition of Gpr183 significantly upregulates Notch signaling and abolishes HSPC emergence. Upon activation by its ligand 7α-25-OHC, Gpr183 recruits β-arrestin1 and the E3 ligase Nedd4 to degrade Notch1 in specified HE cells and then facilitates the subsequent EHT. Importantly, 7α-25-OHC stimulation promotes HSPC emergence in vivo and in vitro, providing an attractive strategy for enhancing the in vitro generation of functional HSPCs.


NextGen nuclear DNA sequencing in cyclic vomiting syndrome reveals a significant association with the stress-induced calcium channel (RYR2).
Cyclic vomiting syndrome (CVS) is a common, frequently disabling, 'functional' condition characterized by recurring, stereotypical attacks of intense nausea, vomiting, and lethargy, with the essential absence of these symptoms between episodes. Although the pathogenesis of CVS is yet unexplained, evidence has accumulated which suggest pathogenic roles for stress-related, autonomic, neuroendocrine, and mitochondrial factors. The objective of this pilot study was to elucidate mechanism(s) by identifying genes involved in the presumed multifactorial pathogenesis of CVS. In this pilot study, DNA from 75 unrelated CVS cases and 60 healthy controls were assayed by Courtagen Life Science's next-generation sequencing platform (nucSEEK(™) ), including over 1100 nuclear-encoded genes involved with mitochondria, metabolism, or ion channels. Significant sequence variants were defined as evolutionary conservation at least to Xenopus (frog) per the UCSC Genome Browser. The RYR2 gene, encoding a stress-induced calcium channel present in many neurons, was the only gene demonstrating a statistically significant difference in the proportion of conserved sequence variants among the groups (18/75 CVS, 24%, vs 3/60 controls, 5%; p = 0.0018, OR = 6.0, 95% CI = 1.7-22). We propose a mechanism in which RYR2 sequence variants result in aberrant stress-induced calcium release into the mitochondria of autonomic neurons, resulting in an increased risk to develop autonomic/functional disease such as CVS, and related conditions such as migraine and gut dysmotility. This model incorporates the existing hypotheses regarding CVS pathogenesis into a cohesive mechanism, and might have treatment implications.


Trends in opioid use following balloon kyphoplasty or vertebroplasty for the treatment of vertebral compression fractures.
This retrospective analysis of insurance claims evaluated real-world trends in prescription fills among patients treated with balloon kyphoplasty (N = 6,656) or vertebroplasty (N = 2,189) following diagnosis of vertebral compression fracture. Among those with evidence of opioid use, nearly half of patients discontinued or reduced prescription fills relative to pre-operative levels. Vertebral compression fractures (VCF) are associated with debilitating pain, spinal misalignment, increased mortality, and increased healthcare-resource utilization in elderly patients. This study evaluated the effect of balloon kyphoplasty (BKP) or vertebroplasty (VP) on post-procedure opioid prescription fills and payer costs in patients with VCF. This was a retrospective analysis of a large, nationally representative insurance-claims database. Clinical characteristics, opioid prescription patterns, and payer costs for subjects who underwent either BKP or VP to treat VCF were evaluated beginning 6 months prior to surgery through 7-month follow-up that included a 30-day, postoperative medication washout. Patient demographics, changes in opioid utilization, and payer costs were analyzed. A total of 8,845 patients met eligibility criteria (75.3% BKP and 24.7% VP) with a mean of age 77 and 74% female. Among the 75% of patients who used opioids, 48.7% of patients discontinued opioid medication and 8.4% reduced prescription fills versus preoperative baseline. Patients who reduced or discontinued prescriptions exhibited a decrease in all-cause payer costs relative to pre-intervention levels, which was a significantly greater change relative to patients with no change, increase, or new start of opioids. Interventional treatment for VCF was associated with decreased or discontinued opioid prescription fills and reduced payer costs in follow-up in a significant proportion of the study population. Reduction of opioid-based harms may represent a previously unrecognized benefit of vertebral augmentation for VCF, especially in this elderly and medically fragile population.


[Use of hormone loading tests for assessing the source of hyperestrogenism and the functional state of the ovaries in breast cancer patients in menopause].
The source of hyperestrogenia was ascertained in 12 patients by dexametasone-infecundin test, and the ovarian hormonal activity in 5 patients by dexametasone-choriogonin test. The source of hyperestrogenia was found to be the adrenal glands in 50%, ovaries--in 30% and the adrenal together with ovaries--in 20%. Ovarian hormonal activity was retained in 3 of 5 patients under examination. The response to the test concerned was changed in two of them. It is felt that application of hormonal stress tests will make it possible to get detailed indications to castration in menopausal patients with breast cancer.


In vitro stimulation of lymphocytes in leprosy patients, healthy contacts of leprosy patients, and subjects not exposed to leprosy. Comparison of an antigen fraction prepared from Mycobacterium leprae and tuberculin-purified protein derivative.
In vitro lymphocyte stimulation was performed on peripheral blood lymphocytes from 48 leprosy patients, 15 healthy contacts of leprosy patients, and 16 normal controls who lived in a leprosy-free area and who had not been exposed to leprosy. Tuberculin PPD and an antigen fraction. MLW 1, prepared from M. leprae, were used as stimulants. The MLW 1 preparation contained one antibody-precipitable component when tested in crossed immunoelectrophoresis against a polyvalent anti-M. leprae immunoglobulin preparation, namely the ML 7 antigen. MLW 1 induced strong lymphocyte responses in patients with tuberculoid leprosy and healthy contacts of leprosy patients, but only a weak or no responses in lepromatous leprosy patients and non-exposed controls. A marked depression of the response to tuberculin PPD was observed in lepromatous leprosy patients. The specificity of the MLW 1 antigen is discussed, and a new estimator of specific lymphocyte stimulation, the delta cpm', is introduced.


Diagnostic approach, therapeutic strategies, and surgical indications in intradural thoracic disc herniation associated with CSF leak, intracranial hypotension, and CNS superficial siderosis.
Intradural disc herniation (IDH) can manifest with radicular or medullary syndrome. In about 15% of cases, IDH may be responsible, through a dural laceration, for a CSF leak, determining spontaneous intracranial hypotension (SIH) and CNS superficial siderosis (CNSss). This paper attempts to present an overview on IDH as the cause for both CSF leak, and subsequent SIH, and CNSss, and to describe a peculiar clinical and neuroradiological scenario related to this condition. A search on the PUBMED database was performed. Although the investigation did not rigorously follow the criteria for a systematic review (we consider only articles about thoracic IDH), nonetheless, the best quality evidence was pursued. Furthermore, an illustrative case was presented. A 69-year-old woman was referred to our hospital for slowly progressive gait disturbances and hearing impairment. Brain imaging revealed diffuse bilateral supratentorial and infratentorial superficial siderosis, mostly of the cerebellum, the eighth cranial nerves, and the brainstem. Spinal imaging disclosed a posterior disc herniation determining a dural tear at D6-D7. Lumbar puncture revealed low opening pressure and hemorrhagic CSF with siderophages. A posterior transdural herniectomy and dural sealing determined a stabilization of hearing and a significant improvement in both gait and balance. The diagnostic workup of CNSss with suspected CNS leak demands whole neuraxis imaging, especially in cases presenting SIH or myelopathic symptoms. This may avoid delays in detection of IDH and spinal dural leaks. The different forms of treatment available depend on the type and severity of the clinical picture.


A review of the biology, ecology, and control of the northern fowl mite, Ornithonyssus sylviarum (Acari: Macronyssidae).
The northern fowl mite, Ornithonyssus sylviarum (Canestrini & Fanzago, 1877), is found on several continents and has been a major pest of poultry in the United States for nearly a century. Lack of earlier USA reports in the United States suggests an introduction or change to pest status in domestic poultry systems occurred in the early 1900s. Though predominantly a nest-parasite of wild birds, this obligate hematophagous mite is a permanent ectoparasite on domestic birds, especially egg-laying chickens. Economic damage is incurred by direct blood feeding and activation of the of host's immune responses. This in turn causes decreased egg production and feed conversion efficiency, and severe infestations can cause anemia or death to birds. Here we review the biology, ecology, and recent control measures for the northern fowl mite. Photomicrographs are included of adult males and females, protonymphs, and larvae with key characters indicated. Special emphasis is placed on current knowledge gaps of basic and applied science importance.


Determination of Aflatoxins in Milk by PS-MWCNT/OH Composite Nanofibers Solid-Phase Extraction Coupled with HPLC-FLD.
In this work, a sensitive analytical method based on packed-nanofiber solid-phase extraction (PFSPE), after derivatization with trichloroacetic acid and high-performance liquid chromatography with a fluorescence detector (HPLC-FLD), has been established for the determination of aflatoxins (AFs) in milk. Polystyrene polymeric multi-walled carbon nanotube (PS-MWCNT/OH) composite nanofibers were fabricated by electrospinning and used to prepare homemade extraction columns. The extraction efficiency of the HPLC-FLD analysis method was sufficiently investigated and validated. After the implementation of optimal conditions, all of the analytes were separated efficiently and the components of the milk matrix did not disturb the determination. The obtained linear ranges of the calibration curves were 0.2-20 ng/mL for AFTB1 and AFTG2, 0.1-10 ng/mL for AFTB2, and 0.4-40 ng/mL for AFTG1. The recoveries ranged between 80.22% and 96.21%. The relative standard deviations (RSDs) for the intra-day and inter-day results ranged from 2.81-6.43% to 3.42-7.75%, respectively. Generally, 11 mg of sorbent and 200 μL of elution solvent were used to directly extract all of the AFs from the milk matrix. Reported herein is the first utilization of PS-MWCNT/OH-PFSPE HPLC-FLD to simultaneously analyze the occurrence of aflatoxins in milk.


High specificity and efficiency electrochemical detection of poly(ADP-ribose) polymerase-1 activity based on versatile peptide-templated copper nanoparticles and detection array.
Poly(ADP-ribose) polymerase-1 (PARP-1) activity is closely related to tumor, which is a promising biomarker for cancer diagnosis. So far, only a few methods have been developed for PARP-1 activity assay because both PARP-1 and its catalytic products lack valuable optical or electrochemical property. Herein, we propose a more specific method to label probes on great deal of phosphate groups of PAR. Firstly, versatile peptides were used to prepare CuNPs. This peptide not only worked as reducing agent to prepare CuNPs but also had guanidine groups to label PAR autonomously and specifically. Unlike most previously reported methods based on unspecific electrostatic interactions, CuNPs probes covered by guanidine groups labelled PAR with phosphate groups via intense covalent-like interactions. On the other hand, PARP-1 catalyzed the formation of PAR in each isolated reaction container of the detection array, realizing the high-throughput detection and enhancing the detection efficiency. Ultimately, CuNPs were oxidized into Cu2+ and precisely detected by stripping voltammetry. Hence, selectivity and efficiency of PARP-1 detection were both improved. Meanwhile, this approach was successfully used to detect the efficiency of PARP-1 inhibitor and the PARP-1 contents in real cells, indicating its great potential for clinical diagnosis and high-throughput PARP-1 inhibitor screen.


Diversified diazotrophs associated with the rhizosphere of Western Indian Himalayan native red kidney beans (Phaseolus vulgaris L.).
Red kidney beans (RKBs) are one of the major components in the human diet of Western Indian Himalaya (WIH). Their cultivation in these habitats is strongly influenced by various biotic and abiotic stresses and therefore, there must be a selection of RKB associated microorganisms that are adapted to these harsh conditions. Seven cold adaptive diazotrophs from the same rhizosphere were isolated in our previous study to reveal the low-temperature associated proteins and mechanisms. However, the diversity and phylogenetic affiliations of these rhizosphere diazotrophs are still unknown. In this study, RKB rhizospheric soil from two different agro-ecosystems of WIH namely S1 (Chhiplakot, 30.70°N/80.30°E) and S2 (Munsyari, 30.60°N/80.20°E) were explored for the assessment of nitrogenase reductase gene (nifH) diversity by plating respective clone libraries SN1 and SN2. The RKB rhizosphere diazotroph assemblage was very diverse and apparently consists mainly of the genera Rhizobium, followed by unknown diazotrophic microorganisms. Deduced amino acid sequence analysis revealed the presence of diverse nifH sequences, affiliated with a wide range of taxa, encompassing members of the Proteobacteria, Actinobacteria and Firmicutes. Members of cyanobacteria, methanotrophs and archaea were also detected. To the best of our knowledge, this is the first major metagenomic effort that revealed the presence of diverse nitrogen-fixing microbial assemblages in indigenous RKB rhizospheric soil which can further be explored for improved crop yield/productivity.


Immunofluorescence studies for hepatitis A virus and hepatitis B surface and core antigen in liver biopsies from patients with acute viral hepatitis.
Immunofluorescence studies for hepatitis A virus and hepatitis B surface and core antigen were performed on liver biopsies from 48 patients with acute viral hepatitis. Hepatitis A virus was detected in 11 out of 17 patients with type A hepatitis and was not found in patients with type B or non-A non-B hepatitis. Hepatitis B surface and core antigens were detected in 2, hepatitis B core antigen alone in 1, and hepatitis B surface antigen alone in 4 out of 24 patients with type B hepatitis. Neither hepatitis B surface nor core antigen were found in patients with type A or non-A non-B hepatitis. One patient with both type A and B hepatitis were all negative for hepatitis A virus, and hepatitis B surface and core antigens. Immunofluorescence examination for hepatitis A virus in human liver biopsies appears to be a sensitive and specific technique and might be valuable in the search for possible chronic carriers of hepatitis A virus.


Cytologic diagnosis and subtyping of rhabdomyosarcoma.
We reviewed the cytological findings of 38 cases of rhabdomyosarcoma (RMS) with histological confirmation performed during a period of 15 years and proposed a morphological subtyping based on the most prominent cytologic features. Seventeen of these cases were alveolar, 14 cases embryonal, and seven botryoid subtypes. From these cases, a total of 43 samples, of which 37 were fine needle aspiration (FNA) biopsies and six were touch imprints, were evaluated. Detailed cellular features were identified which enabled differentiation into histological subtypes. In the alveolar RMSs, most tumour cells were small and lymphocyte-like, having finely granular chromatin. The finding of cells with more abundant cytoplasm, eccentrically located nuclei and bi/multinucleated tumour cells in a background of mucosubstance helped in the differential diagnosis. Two cell types, including large, tadpole or ribbon-shaped tumour cells and small, round cells with scant cytoplasm, were seen in embryonal RMSs. In botryoid RMSs, a cell type with tightly grouped nuclei within elongated cytoplasm similar to a myotubular structure was observed in addition to the two cell types of embryonal RMSs. We conclude that with experience it will be possible to subtype these tumours by cytologic examination alone.


Silencing of α-complex protein-2 reverses alcohol- and cytokine-induced fibrogenesis in hepatic stellate cells.
α-complex protein-2 (αCP2) encoded by the poly (rC) binding protein 2(PCBP2) gene is responsible for the accumulation of type I collagen in fibrotic livers. In this study, we silenced the PCBP2 gene using a small interfering RNA (siRNA) to reverse alcohol-and cytokine-induced profibrogenic effects on hepatic stellate cells (HSCs). Primary rat HSCs and the HSC-T6 cell line were used as fibrogenic models to mimic the initiation and perpetuation stages of fibrogenesis, respectively. We previously found that a PCBP2 siRNA, which efficiently silences expression of αCP2, reduces the stability of type I collagen mRNA. We investigated the effects of the PCBP2 siRNA on cell proliferation and migration. Expression of type I collagen in HSCs was analyzed by quantitative real-time PCR and western blotting. In addition, we evaluated the effects of the PCBP2 siRNA on apoptosis and the cell cycle. PCBP2 siRNA reversed multiple alcohol- and cytokine-induced profibrogenic effects on primary rat HSCs and HSC-T6 cells. The PCBP2 siRNA also reversed alcohol- and cytokine-induced accumulation of type I collagen as well as cell proliferation and migration. Moreover, the combination of LY2109761, a transforming growth factor-β1 inhibitor, and the PCBP2 siRNA exerted a synergistic inhibitive effect on the accumulation of type I collagen in HSCs. Silencing of PCBP2 using siRNA could be a potential therapeutic strategy for alcoholic liver fibrosis.


Revisiting robotic approaches to endocrine neoplasia: do the data support their continued use?
Although the advent of the robot has revolutionized the modern treatment of endocrine neoplasia, substantial controversies exist on its applicability, safety and benefits over the conventional laparoscopic operations. The present review aims to review the recent literature on various robotic approaches in treating thyroid, parathyroid, adrenal and pancreatic endocrine neoplasia and see whether its continued use should be supported. In summary, the role of robotic thyroidectomy has been clearly established and should be continued by experienced surgeons on selected patients. Because of the limited availability of evidence, the feasibility of robotic parathyroidectomy has yet to be elucidated. With proven favorable perioperative outcomes, robotic adrenalectomy and pancreatectomy should be continued as potential alternatives to conventional surgery. Robotic endocrine procedures still play a pivotal role in minimally invasive endocrine surgery with demonstrable safety and effectiveness. Future research should embark on prospective randomized-controlled trials on robotic endocrine procedures to collect higher level of evidence and long-term survival data.


Modafinil improves monocrotaline-induced pulmonary hypertension rat model.
Pulmonary arterial hypertension (PAH) progressively leads to increases in pulmonary vasoconstriction. Modafinil plays a role in vasorelaxation and blocking KCa3.1 channel with a result of elevating intracellular cyclic adenosine monophosphate (cAMP) levels. The purpose of this study is to evaluate the effects on modafinil in monocrotaline (MCT)-induced PAH rat. The rats were separated into three groups: the control group, the monocrotaline (M) group (MCT 60 mg/kg), and the modafinil (MD) group (MCT 60 mg/kg + modafinil). Reduced right ventricular pressure (RVP) was observed in the MD group. Right ventricular hypertrophy was improved in the MD group. Reduced number of intra-acinar pulmonary arteries and medial wall thickness were noted in the MD group. After the administration of modafinil, protein expressions of endothelin-1 (ET-1), endothelin receptor A (ERA) and KCa3.1 channel were significantly reduced. Modafinil suppressed pulmonary artery smooth muscle cell (PASMC) proliferation via cAMP and KCa3.1 channel. Additionally, we confirmed protein expressions such as Bcl-2-associated X, vascular endothelial growth factor, tumor necrosis factor-α, and interleukin-6 were reduced in the MD group. Modafinil improved PAH by vasorelaxation and a decrease in medial thickening via ET-1, ERA, and KCa3.1 down regulation. This is a meaningful study of a modafinil in PAH model.


Fatty acid metabolism in human lymphocytes. II. Activation of fatty acid desaturase-elongase systems during blastic transformation.
The fatty acid desaturation-elongation ability of human T-lymphocytes during blastic transformation was determined both by gas-liquid chromatography and incubation with radiolabeled precursors. Human peripheral blood mononuclear cells (PBMC) were activated with phytohemagglutinin (PHA) and cultured in media supplemented with different fatty acids (18:0, 18:1(n - 9), 18:2(n - 6), 18:3(n - 3) and 20:4(n - 6)) at a final concentration of 30 microM. All the fatty acids added were elongated by activated PBMC and the maximal activity was observed on 20:4(n - 6) (a 25% of conversion to 22:4(n - 6)). Supplementation with stearic acid increased the proportion of oleic (from 21.4% to 23.7%) and eicosaenoic (from 3.1% to 5.7%) acids in cellular lipids, indicating the existence of a delta 9-desaturase activity. Supplementation with linoleic and linoleic acids increased slightly the cell content in their more unsaturated derivatives. Direct measurement of desaturase activities was performed by incubating quiescent and activated PBMC with [1-14C]stearic, [1-14C]linoleic and [1-14C]linolenic acids. Quiescent cells exhibited a very low delta 9-desaturase and no sign of delta 6-desaturase activity. A moderate and progressive activation of delta 9-, delta 6- and delta 5-desaturases was observed during blastic transformation of human PBMC. Up to 8% of 18:0 was converted to monoenes, 4% and 1.5% of 18:2(n - 6) was converted to trienes and tetraenes, respectively, and 14.5% of 18:3(n - 3) was converted to pentaenes. The maximal relative activities were found after 48 h of PHA-stimulation for delta 9-desaturase (around 90 pmol of 18:0 converted per 10(6) cells in the last 24 h) and at 72 h for delta 6- and delta 5-desaturases (around 75 and 140 pmol of 18:2 and 18:3, respectively, converted per 10(7) cells in the last 24 h). Although these activities are not enough to explain all the changes in fatty acid composition of human PBMC during blastic transformation, they may contribute to a more controlled cell phospholipid composition.


Alpha-methyltyrosine reduces the acute cardiovascular and behavioral sequelae in a murine model of traumatic brain injury.
Increased catecholamines contribute to heightened cardiovascular reactivity and behavioral deficits after traumatic brain injury (TBI); adrenergic receptor blockade has limited success in reducing adverse sequelae of TBI. Injury-induced increases in the synthesis of catecholamines could contribute to adverse outcomes in TBI. Inhibition of catecholamine synthesis with alpha-methyltyrosine (αMT) could offer a benefit after TBI. Original research trial in mice randomized to αMT (50 mg·kg -1 ·d -1 ) or vehicle for 1 week after TBI induced by controlled cortical impact. Primary outcomes of cardiovascular reactivity and behavioral deficits were assessed after 1 week. Secondary outcomes included blood brain barrier permeability and quantification of gene transcription whose products determine intraneuronal chloride concentrations, the release of catecholamines, and activation of the sympathetic nervous system. These genes were the alpha-2 adrenergic receptor ("Adra2c"), the sodium-potassium-chloride cotransporter ("Nkcc1"), and the potassium chloride cotransporter ("Kcc2"). We also assessed the effect of TBI and αMT on the neuronal chloride/bicarbonate exchanger ("Ae3"). Traumatic brain injury-induced increases in blood pressure and cardiac reactivity were blocked by αMT. Inhibition of catecholamine synthesis decreased blood brain barrier leakage and improved behavioral outcomes after TBI. Traumatic brain injury diminished the transcription of Adra2c and enhanced expression of Nkcc1 while reducing Kcc2 transcription; αMT prevented the induction of the Nkcc1 by TBI without reversing the effects of TBI on Kcc2 expression; αMT also diminished Ae3 transcription. Traumatic brain injury acutely increases cardiovascular reactivity and induces behavioral deficits in an αMT-sensitive manner, most likely by inducing Nkcc1 gene transcription. Alpha-methyltyrosine may prove salutary in the treatment of TBI by attenuating the enhanced expression of Nkcc1, minimizing blood brain barrier leakage, and diminishing central catecholamine and sympathetic output. We also found an unreported relationship between Kcc2 and the chloride/bicarbonate exchanger, which should be considered in the design of trials planned to manipulate central intraneuronal chloride concentrations following acute brain injury.


Effects of electromagnetic pulse on polydactyly of mouse fetuses.
There is an increasing public concern regarding potential health impacts from electromagnetic radiation exposure. Embryonic development is sensitive to the external environment, and limb development is vital for life quality. To determine the effects of electromagnetic pulse (EMP) on polydactyly of mouse fetuses, pregnant mice were sham-exposed or exposed to EMP (400 kV/m with 400 pulses) from Days 7 to 10 of pregnancy (Day 0 = day of detection of vaginal plug). As a positive control, mice were treated with 5-bromodeoxyuridine on Days 9 and 10. On Days 11 or 18, the fetuses were isolated. Compared with the sham-exposed group, the group exposed to EMP had increased rates of polydactyly fetuses (5.1% vs. 0.6%, P < 0.05) and abnormal gene expression (22.2% vs. 2.8%, P < 0.05). Ectopic expression of Fgf4 was detected in the apical ectodermal ridge, whereas overexpression and ectopic expression of Shh were detected in the zone of polarizing activity of limbs in the EMP-exposed group and in the positive control group. However, expression of Gli3 decreased in mesenchyme cells in those two groups. The percentages of programmed cell death of limbs in EMP-exposed and positive control group were decreased (3.57% and 2.94%, respectively, P < 0.05, compared with 7.76% in sham-exposed group). In conclusion, polydactyly induced by EMP was accompanied by abnormal expression of the above-mentioned genes and decreased percentage of programmed cell death during limb development.


Circularly Polarized Light Probes Excited-State Delocalization in Rectangular Ladder-type Pentaphenyl Helices.
Ladder-type pentaphenyl chromophores have a rigid, planar π-system and show bright fluorescence featuring pronounced vibrational structure. Such moieties are ideal for studying interchromophoric interactions and delocalization of electronic excitations. We report the synthesis of helical polymers with a rigid square structure based on spiro-linked ladder-type pentaphenyl units. The variation of circular dichroism with increasing chain length provides direct evidence for delocalization of electronic excitations over at least 10 monomeric units. The change in the degree of circular polarization of the fluorescence across the vibronic side bands shows that vibrational motion can localize the excitation dynamically to almost one single unit through breakdown of the Born-Oppenheimer approximation. The dynamic conversion between delocalized and localized excited states provides a new paradigm for interpreting circular dichroism in helical polymers such as proteins and polynucleic acids.


Human haematopoietic stem cell lineage commitment is a continuous process.
Blood formation is believed to occur through stepwise progression of haematopoietic stem cells (HSCs) following a tree-like hierarchy of oligo-, bi- and unipotent progenitors. However, this model is based on the analysis of predefined flow-sorted cell populations. Here we integrated flow cytometric, transcriptomic and functional data at single-cell resolution to quantitatively map early differentiation of human HSCs towards lineage commitment. During homeostasis, individual HSCs gradually acquire lineage biases along multiple directions without passing through discrete hierarchically organized progenitor populations. Instead, unilineage-restricted cells emerge directly from a 'continuum of low-primed undifferentiated haematopoietic stem and progenitor cells' (CLOUD-HSPCs). Distinct gene expression modules operate in a combinatorial manner to control stemness, early lineage priming and the subsequent progression into all major branches of haematopoiesis. These data reveal a continuous landscape of human steady-state haematopoiesis downstream of HSCs and provide a basis for the understanding of haematopoietic malignancies.


Milk of calcium renal stone: a case report.
A case of milk of calcium renal stone was reported. It is an unusual condition in which there is suspension of calcium salt within a pyelogenic cyst. The diagnosis is difficult because of its rarity. Reviewing literature, plain abdominal X-ray in different positions were emphasized. We found that fluoroscopy with spot films in different positions is worthwhile. It has to be differentiated from gallstone and also from usual renal stone. Conservative treatment is advised if there is no suggestive malignancy.


Awareness survey of so-called Dappou drugs or Kiken drugs (New Psychoactive Substances) among University Students in Japan.
Spread of new psychoactive substances (NPS) is a worldwide problem. In Japan, NPSs with psychoactive ingredients are called as "dappou drugs" or "kiken drugs." Their potential effect on the Japanese society cannot be ignored. We conducted an awareness survey of So-called Dappou Drugs or Kiken Drugs among the students of Ibaraki University, a national university in Japan, in April 2014. 3976 students (2425 men, 1406 women and 145 unspecified) participated in this study. 2813 (70.7 %) respondents were aware of dappou drugs. Only 39.5 % of the respondents selected the option of "ingredients that cause delusions and/or hallucinations may be included" in dappou drugs. 23.4 % of the respondents selected "the number of (dappou drug) users requiring emergency hospitalization due to acute intoxication is increasing". Of the respondents, 19 (0.5 %) reported that they had been invited to use dappou drugs previously, and 40 (1.0 %) had witnessed and/or heard of somebody close to them using the drugs. Those who drank alcohol every day and those who smoked had a higher chance of witnessing and/or hearing of somebody close to them using dappou drugs than those who did not drink or smoke, respectively. Japanese university students do not have sufficient knowledge about dappou drugs or kiken drugs to protect themselves from potential drug misuse. It is both important and urgent to educate Japanese university students about the harmful effects of dappou drugs; in addition, it is important to provide such knowledge before the students are allowed to legally drink and smoke.


Rapid report on methodology: does loss to follow-up in a cohort study bias associations between early life factors and lifestyle-related health outcomes?
To examine the consequences of non-response in a follow-up survey for associations between early-life factors and lifestyle-related health outcomes in adulthood. In a cohort of 11532 Danish men born in 1953 we had nearly complete follow-up in the National Patient Register, but only 66% of 9507 eligible cohort members participated in a follow-up survey, in 2004. We examined whether characteristics measured early in life and discharge from hospital for alcohol abuse or tobacco-related lung diseases, were associated with survey response. Associations between the early-life characteristics and these two health outcomes were calculated in the entire cohort and among responders, and the effect of non-response was described by a Relative Odd Ratio (ROR=OR(responders)/OR(entire cohort)). A low response rate at age 50 years was related to having a single mother at birth, low educational attainment at age 18, and low cognitive function at ages 12 and 18. The risk of alcohol overuse and tobacco-related diseases was also highest among non-responders. However, the associations between early-life characteristics and the outcomes were nearly the same in responders as in the entire cohort. Although non-responders differed from responders in terms of early-life exposures and incidence of the lifestyle-related outcomes, we found no overt effects of this on the exposure-risk associations.


Posttranscriptional recoding by RNA editing.
The posttranscriptional recoding of nuclear RNA transcripts has emerged as an important regulatory mechanism during eukaryotic gene expression. In particular the deamination of adenosine to inosine (interpreted by the translational machinery as a guanosine) is a frequent event that can recode the meaning of amino acid codons in translated exons, lead to structural changes in the RNA fold, or may affect splice consensus or regulatory sequence sites in noncoding exons or introns and modulate the biogenesis of small RNAs. The molecular mechanism of how the RNA editing machinery and its substrates recognize and interact with each other is not understood well enough to allow for the ab initio delineation of bona fide RNA editing sites. However, progress in the identification of various physiological modification sites and their characterization has given important insights regarding molecular features and events critical for productive RNA editing reactions. In addition, structural studies using components of the RNA editing machinery and together with editing competent substrate molecules have provided information on the chemical mechanism of adenosine deamination within the context of RNA molecules. Here, I give an overview of the process of adenosine deamination RNA editing and describe its relationship to other RNA processing events and its currently established roles in gene regulation.


Enhancement of Neuromodulation with Novel Pulse Shapes Generated by Controllable Pulse Parameter Transcranial Magnetic Stimulation.
Standard repetitive transcranial magnetic stimulation (rTMS) devices generate bidirectional biphasic sinusoidal pulses that are energy efficient, but may be less effective than monophasic pulses that induce a more unidirectional electric field. To enable pulse shape optimization, we developed a controllable pulse parameter TMS (cTMS) device. We quantified changes in cortical excitability produced by conventional sinusoidal bidirectional pulses and by three rectangular-shaped cTMS pulses, one bidirectional and two unidirectional (in opposite directions), and compared their efficacy in modulating motor evoked potentials (MEPs) produced by stimulation of motor cortex. Thirteen healthy subjects completed four sessions of 1 Hz rTMS of the left motor cortex. In each session, the rTMS electric field pulse had one of the four shapes. Excitability changes due to rTMS were measured by applying probe TMS pulses before and after rTMS, and comparing resultant MEP amplitudes. Separately, we measured the latency of the MEPs evoked by each of the four pulses. While the three cTMS pulses generated significant mean inhibitory effects in the subject group, the conventional biphasic cosine pulses did not. The strongest inhibition resulted from a rectangular unidirectional pulse with dominant induced current in the posterior-anterior direction. The MEP latency depended significantly on the pulse shape. The pulse shape is an important factor in rTMS-induced neuromodulation. The standard cosine biphasic pulse showed the smallest effect on cortical excitability, while the greatest inhibition was observed for an asymmetric, unidirectional, rectangular pulse. Differences in MEP latency across the various rTMS pulse shapes suggest activation of distinct subsets of cortical microcircuitry.


Photodynamic therapy for carcinoma in situ of the anus.
Photodynamic therapy (PDT) for carcinoma in situ of the anus is an alternative to surgical excision in patients who are seropositive for human immunodeficiency virus (HIV). Before-after trial. Settings Tertiary referral center. Twelve HIV-seropositive patients who were actively being treated for AIDS with high-grade dysplasia on anal Papanicolaou test results had site-directed biopsies of acetowhitening foci immediately after application of dilute acetic acid. Biopsy results showed that 5 patients had anal carcinoma in situ. These patients were given the photosensitizer delta-aminolevulinic acid orally. Four to 4.25 hours later, the entire anal circumference was treated with PDT. All 5 patients, after being treated with PDT, had repeated Papanicolaou tests at monthly intervals. If acetowhitening occurred at the fifth month, site-directed biopsy was done. Anal cytologic examination by Papanicolaou test and site-directed biopsy if acetowhitening was found at 5 months in order to determine effectiveness of PDT in downstaging cytologic findings. All patients had a consistent downgrading of cytologic findings during the 5 months of follow-up. Papanicolaou test results showed 2 patients had no dysplasia, 2 had mild dysplasia, and 1 had moderate dysplasia. Moderate dysplasia was confirmed by site-directed biopsy results. No complications of PDT occurred, but all 5 patients developed various abnormalities in liver function test results that returned to baseline values within 2 weeks; this also has been noted in patients ingesting delta-aminolevulinic acid who are presumably HIV seronegative. In a group of patients who are at high risk for recurrence irrespective of initial treatment, PDT can be used as a successful alternative to surgical excision for anal carcinoma in situ.


Epidemiology of multimorbidity in Iran: An investigation of a large pharmacy claims database.
Multimorbidity (MM) (presence of more than one chronic condition within a same patient) imposes a heavy burden on patients and health care systems. In contrast to high-income countries, the epidemiology of this phenomenon is unclear in low- and middle-income countries, particularly among Iranian population. This was a retrospective cohort study using Iranian Health Insurance Organization claims database. A framework was developed for identifying a set of 18 chronic conditions from the pharmacy claims data in Iran. All 2013 outpatient utilizers (aged 18 years or older) were included. Data were analyzed according to number of chronic conditions, gender, and age. The association between MM and utilizations of health services was examined for 2013 to 2016. In total, 481 733 people were included. Cardiovascular diseases (including hypertension) (19.1%), depression/anxiety/sleep disorders (13.7%), and acid-related disorders (10.3%) were the three most prevalent conditions. MM was present in 21.1%. Although prevalence of MM is higher in older age groups and was present in 40% of individuals aged 65 and older, the absolute number of multimorbid patients was higher in those younger than 65 years (66 271 vs 35 386). MM was more prevalent among women (22.1%) compared with men (19.5). After multivariate adjustment for age group and sex, each additional chronic condition was associated with an increase of 2.23 physician visits, 2.86 drugs dispensed, 2.32 laboratory tests, and 1.6 medical imaging. Our findings challenge the current single-disease-based assumption implicit in Iranian health care system. To take account of MM, complementary strategies should be designed and implement in health care system.


Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial.
Almonertinib (HS-10296) is a novel, third-generation EGFR tyrosine kinase inhibitor (EGFR TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy, and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive NSCLC that had progressed after pevious EGFR TKI therapy. This phase 1, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220, and 260 mg) and dose-expansion cohorts (55, 110, and 220 mg) with once daily oral administration of almonertinib. In each expansion cohort, tumor biopsies were obtained for the determination of EGFR T790M status. The safety, tolerability, antitumor activity, and pharmacokinetics of almonertinib were evaluated. A total of 120 patients (26 patients in the dose-escalation cohort and 94 patients in the dose-expansion cohort) were enrolled. The maximum tolerated dose was not defined in the dose-escalation phase; the 260 mg regimen was not further evaluated in the dose-expansion phase owing to safety concerns and saturation of exposure. The most common treatment-related grade greater than or equal to 3 adverse events were increased blood creatine phosphokinase (10%) and increased alanine aminotransferase (3%). Among 94 patients with the EGFR T790M mutation in the dose-expansion cohort, the investigator-assessed objective response rate and disease control rate were 52% (95% confidence interval [CI]: 42-63) and 92% (95% CI: 84-96), respectively. Median progression-free survival was 11.0 months (95% CI: 9.5-not reached) months. Almonertinib is safe, tolerable and effective for patients with locally advanced or metastatic NSCLC harboring the EGFR T790M mutation who were pretreated with EGFR TKIs.


Cloning, expression and functional characterization of two sesquiterpene synthase genes from moso bamboo (Phyllostachys edulis).
The purpose of this work was to characterize the functions of two sesquiterpene synthase genes from moso bamboo (Phyllostachys edulis). Two novel sesquiterpene synthase genes, belonging to the Tpsa subfamily, were isolated from moso bamboo. MoTPS2 was 1641 bp in length and encoded a protein of 63 kDa, whereas MoTPS6 was 1626 bp in length, encoded protein 62.4 kDa. Both genes were expressed in Pichia pastoris for heterologous expression, and protein contents reached 0.243 μg μL(-1) for MoTPS2 and 0.088 μg μL(-1) for MoTPS6. The soluble enzymes were catalytically active, and capable of converting farnesyl pyrophosphate to two distinct sesquiterpene compounds. The MoTPS2 gene encoded a farnesol synthase which was responsible for the production of (E, E)-farnesol. MoTPS6 showed nerolidol synthase activity, catalyzing the formation of (E)-nerolidol. Functional characterization of both MoTPSs should prove beneficial for future research into large-scale fermentation of sesquiterpenes.


Inhibitory Potential of Resveratrol in Cancer Metastasis: From Biology to Therapy.
Cancer metastasis is a significant challenge in cancer treatment, and most existing drugs are designed to inhibit tumor growth but are often ineffective in treating metastatic cancer, which is the leading cause of cancer-related deaths. Resveratrol, a polyphenol found in grapes, berries, and peanuts, has shown potential in preclinical studies as an anticancer agent to suppress metastasis. However, despite positive results in preclinical studies, little progress has been made in clinical trials. To develop resveratrol as an effective anticancer agent, it is crucial to understand its cellular processes and signaling pathways in tumor metastasis. This review article evaluates the current state and future development strategies of resveratrol to enhance its potency against cancer metastasis within its therapeutic dose. In addition, we critically evaluate the animal models used in preclinical studies for cancer metastasis and discuss novel techniques to accelerate the translation of resveratrol from bench to bedside. The appropriate selection of animal models is vital in determining whether resveratrol can be further developed as an antimetastatic drug in cancer therapy.


Femoral morphology due to impingement influences the range of motion in slipped capital femoral epiphysis.
Femoroacetabular impingement due to metaphyseal prominence is associated with the slippage in patients with slipped capital femoral epiphysis (SCFE), but it is unclear whether the changes in femoral metaphysis morphology are associated with range of motion (ROM) changes or type of impingement. We asked whether the femoral head-neck junction morphology influences ROM analysis and type of impingement in addition to the slip angle and the acetabular version. We analyzed in 31 patients with SCFE the relationship between the proximal femoral morphology and limitation in ROM due to impingement based on simulated ROM of preoperative CT data. The ROM was analyzed in relation to degree of slippage, femoral metaphysis morphology, acetabular version, and pathomechanical terms of "impaction" and "inclusion." The ROM in the affected hips was comparable to that in the unaffected hips for mild slippage and decreased for slippage of more than 30 degrees. The limitation correlated with changes in the metaphysic morphology and changed acetabular version. Decreased head-neck offset in hips with slip angles between 30 degrees and 50 degrees had restricted ROM to nearly the same degree as in severe SCFE. Therefore, in addition to the slip angle, the femoral metaphysis morphology should be used as criteria for reconstructive surgery.


The glutathione transferase activity and tissue distribution of a cloned Mr28K protective antigen of Schistosoma mansoni.
A protective Mr28K antigen of Schistosoma mansoni, expressed from its cDNA, has been purified in a single step and shown to possess glutathione (GSH) transferase activity as predicted from sequence homologies with two mammalian GSH transferase multigene families. It is notable for its high 1-chloro-2,4-dinitrobenzene GSH transferase and linoleic acid hydroperoxide GSH peroxidase activities. The major GSH transferase of S. mansoni has been purified and its subunit is identical to this Mr28K antigen by criteria of Mr, immunochemistry, substrate specificity and peptide sequence analysis. In the parasite, the antigen is present in the tegument, protonephridial cells and subtegumental parenchymal cells. No significant immunological cross-reactivity between the S.mansoni and mammalian (human and rat) GSH transferases was observed.


Carbonization of waste PVC to develop porous carbon material without further activation.
Efficient removal of chlorine from PVC achieved by two-stage heat-treatment (280 and 410 degrees C) provided chlorine-free isotropic pitch containing additive. The pitch was stabilized and carbonized into porous carbons with surface areas of approximately 300 m2/g. Resultant porous carbons showed three pore structures of supermicropore, micropore and mesopore. The generation of CO2 from the decomposition of the CaCO3 additive in waste PVC is responsible for the development of porous structures. The surface area of the carbonized product increased after the removal of CaO.


Dynamic changes of peritoneal macrophages and subpopulations during ulcerative colitis to metastasis of colorectal carcinoma in a mouse model.
Patients with ulcerative colitis have increased risk of colorectal carcinoma, but little is known about how peritoneal macrophages are involved in ulcerative colitis-associated carcinogenesis. We investigated the alteration of peritoneal macrophages and M1/M2 subpopulations during ulcerative colitis-associated carcinogenesis. Expression and functional changes in peritoneal macrophages and M1/M2 subpopulations were investigated by histopathology, flow cytometry, immunofluorescence, cytokines expression by ELISA and QRT-PCR in an azoxymethane (AOM)- and dextran sodium sulfate (DSS)-induced chemical colitis-associated carcinoma mouse model using male Crj:CD-1 (ICR) mice. Striking evidence observed in histopathology, flow cytometry, cytokine detection, and gene expression analysis all revealed that inflammation-associated cytokines (IL-1β, IL-10, IL-12, IL-6, TNF-α) and migration/invasion-associated factors (G-CSF, GM-CSF, CXCR4, VEGF, TGF-β, ICAM-1) induced by peritoneal M2 macrophages increased significantly during the progression from inflammatory hyperplasia to carcinoma and metastasis. Similar functional changes occurred during peritoneal metastasis in M1 macrophages without changed polarization. These results suggested that peritoneal M2 macrophages played a critical role in ulcerative colitis-associated carcinogenesis, including unbalanced pro-inflammatory and anti-inflammatory axis and enhanced expression of migration/invasion-associated factors. Furthermore, functional changes of M1 macrophages occurred without changed polarization during carcinogenesis and metastasis.


Immortalized human urothelial cells as a model of arsenic-induced bladder cancer.
Arsenical-induced carcinogenesis in human bladder has been established through epidemiological evidence, and UROtsa cells, a normal, immortalized cell culture model of human urothelium, have proven to be a good model for the bladder epithelium. This cell line does not form tumors when injected into immuno-compromised mice nor does it have anchorage-independent growth. UROtsa can be easily manipulated for acute studies related to arsenical exposure. They have been shown to be sensitive to all arsenicals, in particular, the trivalent species, arsenite and monomethylarsonous acid. UROtsa cells have also opened the area of cellular signaling alterations following subcytotoxic exposure to arsenicals in both the acute and long-term time points. In addition, UROtsa cells were shown to be malignantly transformed following low-level exposure to both As(III) and MMA(III) providing additional models for studying arsenical-induced carcinogenesis of the bladder. These transformed cell lines allow researchers the ability to investigate the process of urothelial tumorigenesis at multiple time points of arsenical exposure. Overall, UROtsa cells are an effective model for cellular insult following arsenical exposure.


Comparisons of the inotropic effects of the beta 1-adrenoceptor partial agonists SL 75.177.10 and ICI 118,587 with digoxin on the intact canine heart.
The effects of the beta 1-adrenoceptor partial agonists ICI 118,587 (xamoterol) and SL 75.177.10 on the left ventricular inotropic state and relaxation rate were compared with those of digoxin in open-chest dogs. These agents were administered to three separate groups of dogs (5, 6, and 7 dogs, respectively). In each animal, the inotropic effects were assessed at fixed heart rate (atrial pacing) and at similar end-diastolic left ventricular diameter. Under these controlled conditions, ICI 118,587 (200 micrograms/kg) increased peak (+) dP/dt by 3176 +/- 363 mm Hg/s (p less than 0.005) and the slope of the end-systolic pressure/end-systolic diameter relation rose by 190% above the control value (p less than 0.01). These changes were significantly greater than after digoxin (100 micrograms/kg) which increased these indexes, respectively, by 2132 +/- 248 mm Hg/s (p less than 0.003) and by 31 +/- 4% (p less than 0.05). SL 75.177.10 (200 micrograms/kg) also increased dP/dt, but significantly less than did digoxin or ICI 118,587 (+428 +/- 105 mm Hg/s; p less than 0.007); the increase in end-systolic pressure/diameter slope was not different from that observed after digoxin. In contrast to ICI 118,587 which accelerated isovolumic relaxation (-7.6 ms in time constant of isovolumic pressure fall; p less than 0.01), neither SL 75.177.10 nor digoxin modified this phase of the cardiac cycle. Finally, at the dose used in the study, digoxin induced ventricular arrhythmias in all animals, a side effect which was never observed after ICI 118,587 or SL 75.177.10.(ABSTRACT TRUNCATED AT 250 WORDS)


Uptake Prediction of Ten Heavy Metals by Eruca sativa Mill. Cultivated in Soils Amended with Sewage Sludge.
This study was carried out to develop mathematical regression equations for predicting the uptake of ten heavy metals (HMs) (cadmium, Cd; cobalt, Co; chromium, Cr; copper, Cu; iron, Fe; manganese, Mn; molybdenum, Mo; nickel, Ni; lead, Pb; zinc, Zn) by a vegetable species (Eruca sativa Mill.) in the Abha region (Saudi Arabia) based on the concentration of these HMs in soils amended with sewage sludge, organic matter (OM) content and soil pH. The resultant regression equations indicated that the three soil factors were significant predictors for the uptake of the ten HMs in the plant tissues. By applying a t test, we found that there are no significant differences between the actual and predicted values of the ten HMs in the E. sativa roots and leaves (P > 0.05), which reflects the goodness of fit of these equations for predicting the uptake of these HMs. Such types of equations may be helpful for evaluating the risk of cultivation of E. sativa plants in soils amended with sewage sludge.


Mefloquine inhibits cholinesterases at the mouse neuromuscular junction.
Mefloquine is effective against drug-resistant Plasmodium falciparum. This property, along with its unique pharmacokinetic profile, makes mefloquine a widely prescribed antimalarial drug. However, mefloquine has neurologic effects which offset its therapeutic advantages. Cellular actions underlying mefloquine's neurologic effects are poorly understood. Here, we demonstrate that mefloquine inhibits human recombinant acetylcholinesterase. To explore the consequences of this action, we investigated mefloquine's actions at a model cholinergic synapse, the mouse neuromuscular junction. Sharp electrode recording was used to record miniature endplate potentials (mepps) in the Triangularis sterni muscle. Within 30 min of exposure to 10 microM mefloquine, mepps were altered in three ways: 10-90% rise time, 90-10% decay time and amplitude significantly increased. Mepp decay time increased linearly with mefloquine concentration. Pretreatment of muscles with the cholinesterase inhibitor physostigmine (3 microM) precluded the mefloquine-induced prolongation of mepp decay. Mefloquine also prolonged mepps at endplates of acetylcholinesterase knock-out mice. Since the selective butyrylcholinesterase inhibitor iso-OMPA (100 microM) also prolonged mepp decay at the neuromuscular junction of acetylcholinesterase knock-out mice, mefloquine inhibition of this enzyme is physiologically relevant. The non-selective anti-cholinesterase action can contribute to the neurologic effects of mefloquine.


Nomogram for predicting survival in patients with advanced hepatocellular carcinoma treated with PD-1 inhibitors: incorporating pre-treatment and post-treatment clinical parameters.
Immunotherapy has transformed cancer treatment patterns for advanced hepatocellular carcinoma (aHCC) in recent years. Therefore, the identification of predictive biomarkers has important clinical implications. We collected medical records from 117 aHCC patients treated with anti-PD-1 antibody. Kaplan-Meier analysis and Cox proportional hazard regression were used to evaluate the association between peripheral blood biomarkers and overall survival (OS) and progression-free survival (PFS). Finally, the prognostic nomogram was constructed. The mPFS and mOS were 7.0 months and 18.7 months, respectively. According to Kaplan-Meier analysis and Cox regression analysis, we regarded the treatment regimen (p = 0.020), hemoglobin (Hb) at 6-week (p = 0.042), neutrophil-to-lymphocyte ratio (NLR) at 6-week (p < 0.001), system immune inflammation index (SII) at 6-week (p = 0.125) as predictors of PFS, and alpha fetoprotein (AFP) (p = 0.035), platelet-to-lymphocyte ratio (PLR) (p = 0.012), Hb at 6-week (p = 0.010) and NLR at 6-week (p = 0.020) as predictors of OS. Furthermore, the results suggest that the OS and PFS nomogram model were in agreement with actual observations. Biomarkers in peripheral blood can predict the prognosis of patients with aHCC treated with anti-PD-1 antibody. The development of nomogram models can help us to screen potential patients who can benefit from immunotherapy.


Coping styles in asthma.
Some patients with asthma cope with their disease in ways that are deleterious to them. The coping styles used by these patients often were used by them before the onset of the asthma, but the asthma amplifies these styles, and the coping styles can amplify the asthma. There are striking similarities between these coping styles and those described in cancer victims. Like the latter, they may reflect denial, anger, bargaining, and depression. Recognition that patients are using these coping styles and appropriate intervention will prevent them from continuing to act in these self-destructive manners.


A hospital-based palliative care service for patients with advanced organ failure in sub-Saharan Africa reduces admissions and increases home death rates.
Despite emerging data of cost savings under palliative care in various regions, no such data have been generated in response to the high burden of terminal illness in Africa. This evaluation of a novel hospital-based palliative care service for patients with advanced organ failure in urban South Africa aimed to determine whether the service reduces admissions and increases home death rates compared with the same fixed time period of standard hospital care. Data on admissions and place of death were extracted from routine hospital activity records for a fixed period before death, using standard patient daily expense rates. Data from the first 56 consecutive deaths under the new service (intervention group) were compared with 48 consecutive deaths among patients immediately before the new service (historical controls). Among the intervention and control patients, 40 of 56 (71.4%) and 47 of 48 (97.9%), respectively, had at least one admission (P < 0.001). The mean number of admissions for the intervention and control groups was 1.39 and 1.98, respectively (P < 0.001). The mean total number of days spent admitted for intervention and control groups was 4.52 and 9.3 days, respectively (P < 0.001). For the intervention and control patients, a total of 253 and 447 admission days were recorded, respectively, with formal costs of $587 and $1209, respectively. For the intervention and control groups, home death was achieved by 33 of 56 (58.9%) and nine of 48 (18.8%), respectively (P ≤ 0.001). These data demonstrate that an outpatient hospital-based service reduced admissions and improved the rate of home deaths and offers a feasible and cost-effective model for such settings.


Recognition and treatment of cluster headache in the emergency department.
Cluster headache has a dramatic presentation marked by rapidly escalating intensity of pain and prominent signs of autonomic dysfunction. Despite its distinctive features, diagnostic delay and misdiagnosis are common. Prompt recognition of this headache disorder provides an opportunity for effective treatment. This article provides a practical approach to the diagnosis and management of patients with cluster headache in the emergency room setting.


Metadata Correction: A Comparison of Different Modeling Techniques in Predicting Mortality With the Tilburg Frailty Indicator: Longitudinal Study.
[This corrects the article DOI: 10.2196/31480.].


Dendritic spine morphology and memory formation depend on postsynaptic Caskin proteins.
CASK-interactive proteins, Caskin1 and Caskin2, are multidomain neuronal scaffold proteins. Recent data from Caskin1 knockout animals indicated only a mild role of Caskin1 in anxiety and pain perception. In this work, we show that deletion of both Caskins leads to severe deficits in novelty recognition and spatial memory. Ultrastructural analyses revealed a reduction in synaptic profiles and dendritic spine areas of CA1 hippocampal pyramidal neurons of double knockout mice. Loss of Caskin proteins impaired LTP induction in hippocampal slices, while miniature EPSCs in dissociated hippocampal cultures appeared to be unaffected. In cultured Caskin knockout hippocampal neurons, overexpressed Caskin1 was enriched in dendritic spine heads and increased the amount of mushroom-shaped dendritic spines. Chemically induced LTP (cLTP) mediated enlargement of spine heads was augmented in the knockout mice and was not influenced by Caskin1. Immunocytochemistry and immunoprecipitation confirmed that Shank2, a master scaffold of the postsynaptic density, and Caskin1 co-localized within the same complex. Phosphorylation of AMPA receptors was specifically altered by Caskin deficiency and was not elevated by cLTP treatment further. Taken together, our results prove a previously unnoticed postsynaptic role of Caskin scaffold proteins and indicate that Caskins influence learning abilities via regulating spine morphology and AMPA receptor localisation.


Optimization of the chiral separation of a Ca-sensitizing drug on an immobilized polysaccharide-based chiral stationary phase: case study with a preparative perspective.
Sample solubility in the mobile phase and enantioselectivity are key factors in chiral preparative chromatography. In the search for a high throughput process for production of pure enantiomers, the rational design of the mobile phase and the selection of a suitable chiral stationary phase (CSP) are essential. However, one may sometimes be faced with the incompatibility between the CSP and the preferential eluent for sample solubility. Such a limitation may be circumvented by using an immobilized CSP such as CHIRALPAK IA. In this manuscript, the chiral separation of a Ca-sensitizing drug (EMD 53986) is optimized on CHIRALPAK IA in terms of sample solubility, enantioselectivity and preparative productivity. The approaches for method optimization and the impact of sample solubility on productivity are discussed. The preparative potential of CHIRALPAK IA is also demonstrated.


Open complete intrafascial nerve-sparing retropubic radical prostatectomy: technique and initial experience.
To report our refinement of open intrafascial retropubic radical prostatectomy (OIF-RP) and 1-year follow-up results. OIF-RP was performed in 231 cases of clinically localized Prostate cancer in a prospective study from January 2007 to December 2009. Inclusion criteria were good potency (IIEF-5 score ≥ 15), Gleason score ≤ 6, prostate-specific antigen (PSA) ≤ 10, and clinical T1-2 tumors. Endopelvic fascia was not incised, and the prostate capsule was freed laterally from surrounding fasciae and dorsally from Denonvillier's fascia, keeping all periprostatic fasciae/nerves intact. Functional outcomes were followed at 3 and 12 months (3 M and 12 M). Continence defined as complete (no pads), grade I (1-2 pads/day) and grade II (>2 pads/day). Median age was 63.3 years, body mass index 25.6, and PSA 5.4 ng/mL. Median operating time was 65 minutes (range 50-250), blood loss was 150 mL (range 50-1000), preoperative IIEF-score was 23 (range 15-25). Pathologic stage was pT2 (91%) and pT3 (9%). Gleason score was ≤ 6 (73%) and ≥ 7 (27%). Positive margins were 10% (pT2) and 65% (pT3). There were no postoperative complications/reinterventions. At 3 M, 60% of patients had full continence, and 86% had full continence at 12 M (≤ 60 years, 64% and 95% after 3 M and 12 M, respectively). At 3 M and 12 M, median IIEF-score was 14 (range 0-25) and 19 (range 0-25), respectively. Baseline IIEF-score was reached by 50% (3 M) and 78% (12 M) (P<.001). IIEF-score was inversely correlated to patients' age (≤ 60 years 92%, 60-69 years 77%, ≥ 70 years 60%). OIF-RP follows rationales of radical prostatectomy and might be considered for selected patients. Preserving all periprostatic fasciae/nerves recuperates early continence and maintains potency without affecting oncological outcomes.