Clinical profile of predefined asthma phenotypes in a large cohort of UK primary care patients (Clinical Practice Research Datalink).
Distinct asthma phenotypes have previously been suggested, including benign asthma, atopic asthma and obese non-eosinophilic asthma. This study aims to establish if these phenotypes can be identified using data recorded in primary care clinical records and reports on patient characteristics and exacerbation frequency. A population-based cohort study identified 193,999 asthma patients in UK primary care from 2007 to 2017. We used linked primary and secondary care data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics. Patients were classified into predefined phenotypes or included in an asthma "not otherwise specified" (NOS) group. We used negative binomial regression to calculate the exacerbation rates and adjusted rate ratios. Rate ratios were further stratified by asthma treatment step. In our cohort, 3.9% of patients were categorized as benign asthma, 28.6% atopic asthma and 4.8% obese non-eosinophilic asthma. About 62.7% of patients were asthma NOS, including asthma NOS without treatment (10.4%), only on short-acting beta agonist (6.1%) and on maintenance treatment (46.2%). Crude severe exacerbation rates per 1,000 person-years were lowest for benign asthma (106.8 [95% CI: 101.2-112.3]) and highest for obese non-eosinophilic asthma (469.0 [451.7-486.2]). Incidence rate ratios for all phenotype groups decreased when stratified by treatment step but remained raised compared to benign asthma. Established phenotypes can be identified in a general asthma population, although many patients did not fit into the specific phenotypes which we studied. Phenotyping patients and knowledge of asthma treatment step could help anticipate clinical course and therefore could aid clinical management but is only possible in a minority of primary care patients based on current phenotypes and electronic health records (EHRs).


Nitrogen dioxide increases cardiorespiratory admissions in Torrelavega (Spain).
The objective of the study reported here was to analyze relationships between levels of air pollutants and emergency admissions for cardiorespiratory disease. Admission data from January 1, 1992, to December 31, 1995, were obtained from the Marques de Valdecilla University Hospital Admission Service; meteorological data (rainfall, temperatures wind speed, wind direction) were obtained from the National Meteorology Institute in Santander. Pollutant data on sulfur dioxide (SO2), hydrogen sulfide (H2S), total suspended particles (TSP), nitrogen oxide (NO), and nitrogen dioxide (NO2) were provided by the secretary of environment for the Cantabrian Regional Government. Rate ratios were estimated for each pollutant by Poisson regression; they were adjusted for meteorological variables. It was found that elevated NO2 increased by 20 percent the risk of having an admission for cardiorespiratory diseases; this effect was mainly due to respiratory diseases (rate ratio = 1.7, p < .001) and was negligible for cardiac diseases (rate ratio = 1.1, p = .28). In the one-pollutant model, elevated particulates and nitrogen monoxide were also related to admissions, but this effect disappeared when a five-pollutant model was used (p = .21 and p = 0.36, respectively. SO2 and SH2 did not show any relationship with admissions. Thus, nitrogen dioxide was the only pollutant the authors found to be related to emergency admissions for cardiorespiratory diseases. It is difficult to generalize from these results because of the small number of daily admissions and the variability in pollutant levels; therefore, more studies are necessary to improve knowledge about the relationship between air pollution and health in small towns.


Impact of a State Opioid Prescribing Limit and Electronic Medical Record Alert on Opioid Prescriptions: a Difference-in-Differences Analysis.
Prescribing limits are one policy strategy to reduce short-term opioid prescribing, but there is limited evidence of their impact. Evaluate implementation of a state prescribing limit law and health system electronic medical record (EMR) alert on characteristics of new opioid prescriptions, refill rates, and clinical encounters. Difference-in-differences study comparing new opioid prescriptions from ambulatory practices in New Jersey (NJ) to controls in Pennsylvania (PA) from 1 year prior to the implementation of a NJ state prescribing limit (May 2016-May 2017) to 10 months after (May 2017-March 2018). Adults with new opioid prescriptions in an academic health system with practices in PA and NJ. State 5-day opioid prescribing limit plus health system and health system EMR alert. Changes in morphine milligram equivalents (MME) and tablet quantity per prescription, refills, and encounters, adjusted for patient and prescriber characteristics. There were a total of 678 new prescriptions in NJ and 4638 in PA. Prior to the intervention, median MME/prescription was 225 mg in NJ and 150 mg in PA, and median quantity was 30 tablets in both. After implementation, median MME/prescription was 150 mg in both states, and median quantity was 20 in NJ and 30 in PA. In the adjusted model, there was a greater decrease in mean MME and tablet quantity in NJ relative to PA after implementation of the policy plus alert (- 82.99 MME/prescription, 95% CI - 148.15 to - 17.84 and - 10.41 tabs/prescription, 95% CI - 19.70 to - 1.13). There were no significant differences in rates of refills or encounters at 30 days based on exposure to the interventions. Implementation of a prescribing limit and EMR alert was associated with an approximately 22% greater decrease in opioid dose per new prescription in NJ compared with controls in PA. The combination of prescribing limits and alerts may be an effective strategy to influence prescriber behavior.


Intraperitoneal injection of PDTC on the NF-kB signaling pathway and osteogenesis indexes of young adult rats with anterior palatal suture expansion model.
In recent years, many studies have found that mechanical tension can activiate NF-kB signal pathway and NF-kB plays an important role in the process of osteogenesis. However, it is still unclear whether this process exists in the anterior palatal suture expansion. In this paper, we mainly studied the effect of intraperitoneal injection of PDTC on the NF-kB signaling pathway and osteogenesis index of the anterior palatal suture expansion model in young adult rats. The expansion model is grouped and established: 45 male 8-week-old Sprague-Dawley rats were randomly divided into three groups, an expansion only (EO) group, an expansion plus PDTC (PE) group, and a control group. The results revealed that PDTC inhibited the activity of NF-kB signaling pathway and promote one morphogenetic protein 2 (BMP-2), steocalatin (OCN) expression. Compared with the control group, the optical density (OD) value of BMP in the EO group and PE group rats increased significantly from the first day to the seventh day, and the difference was statistically significant (P<0.05). After 6.0Gy irradiation, PDTC administration group could slightly increase the total SOD level in the liver and serum of rats, and reduce the MDA level in the liver and serum, especially the effect of 60mg/kg and 90mg/kg was the most obvious.


Failure of OPHL type IIb due to undiagnosed Eagle syndrome.
A 52-year-old man with glottic-supraglottic tumour underwent open partial horizontal laryngectomy (OPHL) IIb. On the 12th day postoperative, laryngoscopy showed necrotic tissue at the level of pexy and an increased distance between tongue base and neoglottis; the neck CT showed cricoid arch rupture and rupture of the pexy. By re-examining the preoperative CT images, the ossification of stylohyoid ligament (Eagle syndrome) was detected and supposed as the possible cause of cricoid rupture due to its traction on the hyoid bone and therefore on the pexy. The stylohyoid ligaments were cut at their insertion on the hyoid bone and a tracheohyoidopexy was performed. Two months after surgery, the patient had only some swallowing impairments. This case represents a complication in OPHL II never reported in literature caused by an undiagnosed Eagle syndrome in preoperative, pointing out the importance to search for any anatomical anomaly that could jeopardise the success of the surgery.


Isolation and structural analysis of microsomal membrane proteins.
Investigation of the endoplasmic reticulum requires a methodological background in the solubilization, purification, and structural analysis of membrane proteins. The experience of one laboratory with microsomal proteins over 30 years is summarized in this review. We focus on the isolation and structure of the major proteins of rabbit liver microsomes. The special pitfalls encountered with fragile protein complexes, hydrophobic peptides, and post-translational modifications are emphasized.


Infrared-active vibrational modes of single-walled carbon nanotubes.
The IR-active vibrational modes of single-walled carbon nanotubes have been observed by optical transmission through thin films of bundled nanotubes. Because IR-active chemical functional groups, e.g., -COOH, -OH, might be attached to the tube walls and contribute additional spectral features, we have also studied the effects of chemical purification and long-term high-temperature vacuum annealing on the IR spectrum. Through comparison with theory, we are able to assign much of the sharp structure observed in our IR spectra.


Does cooperation increase helpers' later success as breeders? A test of the skills hypothesis in the cooperatively displaying lance-tailed manakin.
Experience improves individual performance in many tasks. Pre-breeding cooperation may provide important experience that improves later success as a breeder, offering one compelling explanation for why some individuals delay reproduction to help others breed (the 'skills hypothesis'). However, confounding effects of age, quality and alternative selective benefits have complicated rigorous tests of this hypothesis. Male lance-tailed manakins perform cooperative courtship displays involving partnerships between unrelated alpha and beta males, and alphas monopolize resulting copulations. Beta males therefore do not receive immediate direct or indirect fitness benefits, but may gain skills during cooperation that increase their later success as an alpha. To date, however, the effect of cooperative experience on later success as a breeder has never been tested in any cooperatively displaying taxon. The effects of prior cooperative experience on reproductive success of alpha lance-tailed manakins were analysed in a mixed model framework using 12 years of information on cooperative experience and annual and lifetime genetic reproductive success for 57 alpha males. Models included previously identified effects of age and alpha tenure. Individual-level random effects controlled for quality differences to test for an independent influence of beta experience on success. Males accumulated up to 5 years of beta experience before becoming alphas, but 42·1% of alphas had no prior beta experience. Betas became alphas later in life, and experienced significantly lower reproductive success in their final year as alpha than males that were never beta, but did not have higher lifetime success or longer alpha tenures. Differences in patterns of annual siring success were best explained by age-dependent patterns of reproductive improvement and senescence among alphas, not beta experience. Cooperative experience does not increase relative breeding success for male lance-tailed manakins. Importantly, beta cooperation seems to be an alternative reproductive tactic that yields fitness payoffs equivalent to a non-cooperative route to alpha status, if population growth rate is stable.


Inquiring Voluntary Turnover For Female Nurses In Pakistan Through Focused Ethnography.
Pakistan is a country with very low nurses to population rate. This problem becomes more prominent due to voluntary turnover; especially among female nurses. This problem could be attributed to several social and demographic factors. This study sought to identify the factors affecting voluntary turnover of female nurses in Pakistan. This study is qualitative in nature. Focused ethnography was used for detailed exploration of the issue of voluntary turnover among female nurses. Ethnographic interviews of informants were conducted to identify the social and organizational determinants of voluntary turnover among female nursing staff. Social factors affecting voluntary turnover include religious beliefs, cultural values, lack of social respect, marital disruption, and lack of psychological support. While organizational factors affecting voluntary turnover include sexual harassment, work-family conflicts, workload and job stress, emotional labour, undefined career path and lack of promotion opportunities and bullying behaviour of co-workers. Both social and organizational issues affect voluntary turnover among female nursing staff. Policymakers at national and organizational level must identify and address these issues to provide congenial work environment and to reduce turnover of female nurses in Pakistan.


Interaction of blood flow and oxygen delivery affects peak VO2 and fatigue in canine muscle in situ.
This investigation was designed to examine the interactive effects of blood flow (Q) and oxygen delivery (QO2) on peak oxygen consumption (VO2peak) and fatigue in the gastrocnemius-plantaris dog muscle in situ. Arterial oxygen content (CaO2) was manipulated by varying the fraction of inspired O2 to create a high- and a low-QO2 treatment at each of three levels of Q (approximately/=800, 1100 and 1500 ml x kg(-1) x min(-1)). Isometric contraction was achieved by stimulation with one tetanic contraction per second (200 ms at 70 Hz) at supramaximal voltage for 10 min to achieve VO2peak under each condition. Arterial and venous blood were sampled, and Q and tension development (TD) were measured at 1, 5 and 10 min into the contractions. Fatigue was calculated as the percentage (%) change in TD from min 1 to min 10. While VO2peak was highly correlated to QO2 (R = 0.97) in both the moderate- and high-Q conditions, both low-Q conditions had a significantly (P < 0.05) higher VO2peak than predicted by the QO2-VO2 relationship. In addition, VO2 peak was significantly greater in the low-Q versus the high-Q condition. Fatigue (% decrease in TD) was significantly different between the two low-Q conditions [Low-QO2=38.4 (6.9); Norm QO2=27.9 (1.8)] and the two moderate-Q conditions [low-QO2=31.1 (7.3); high-QO2 = 20.9 (4.1)] but not between the two high-Q conditions [normal-QO2 = 10.4 (6.9); high-QO2 = 11.9 (4.5)]. In the two conditions of equal QO2, fatigue was significantly less in the high-Q condition (10.4%) compared to the low (27.9%). Thus, it seems that there is a unique interaction between Q and QO2 which determine the VO2peak and rate of fatigue in contracting muscle.


Vestibular schwannoma or tanycytic ependymoma: Immunohistologic staining reveals.
The cerebellopontine angle (CPA) is a common location for primary tumors, most often vestibular schwannomas, and also meningiomas, dermoids, and a host of other neoplasms. Our case report illustrates how radiologic and histopathologic presentations of an unusual variant of ependymal neoplasm can be diagnostically challenging and how accurate diagnosis can affect treatment protocols. Our patient had a CPA mass that was a variant of ependymoma known as tanycytic ependymoma that mimicked vestibular schwannoma radiologically and during intraoperative pathologic examination. Diagnosis as a World Health Organization (WHO) grade II tanycytic ependymoma was supported by its appearance on evaluation of the permanent sections, its diffuse immunoreactivity for glial fibrillary acidic protein (GFAP), and the perinuclear dot-and-ring-like staining for epithelial membrane antigen (EMA). Our patient's CPA mass initially believed to be a vestibular schwannoma on preoperative evaluation, surgical appearance, and intraoperative pathologic consultation was then correctly diagnosed as a WHO grade II tanycytic ependymoma on permanent histologic sections with the assistance of immunohistochemical stains, including EMA. After this definitive diagnosis, our patient's adjuvant treatment was adjusted. Earlier diagnosis could have provided guidance for goals of resection and prompt initiation of adjuvant treatment.


[Recent advances in liposomes and nanoparticles as drug carriers for drug delivery].
Liposomes and nanoparticles have been used as drug carriers to increase solubility, prolong drug duration in vivo, target drug delivery, reduce toxicity and combat multi-drug resistance. With major advances in the preparation techniques, preparation material, and surface modifiers in recent years, liposomes and nanoparticles delivery systems have achieved success in fields including cancer therapy, overcoming biological barriers, and biological drugs and vaccine carriage.


[HOOF genotyping characteristics of Brucella melitensis strains isolated in Ulanqab of Inner Mongolia Autonomous Region].
Objective: To investigate the HOOF genotyping characteristics of 83 Brucella (B.) melitensis strains isolated in Ulanqab of Inner Mongolia Autonomous Region from 2012 to 2015. Methods: A total of 83 B. melitensis strains were detected by convention identification and AMOS-PCR, then HOOF protocol with eight VNTR locus were used for the genotyping of the strains, and the allelic diversity of each VNTR locus and the discriminatory power of VNTR typing of HOOF were assessed by Hunter-Gaston Discriminatory index. BioNumerics 5.0 was used for phylogenetic analysis and constructing dendrogram. Results: All of the isolates were identified as B. melitensis strains by two identification methods. The complete eight VNTR locus had higher polymophism and diversity index was 0.998; and diversity index of six locus (1, 2 and 4-7) were ≥0.678, discriminatory power of HOOF was mainly from this six higher diversity index locus. The 83 B. melitensis strains were classified into eight clusters and 76 genotypes, 6 shared genotypes included 13 isolates, indicating that these brucellosis cases had epidemiological link, the other 70 strains had distinct genotypes, indicating that these cases had no epidemiological link. Conclusions: The epidemic of human brucellosis in Ulanqab was characterized by local and sporadic outbreaks. Cross infection was related with the transfer of the sources of infection.


Reverse causality and confounding and the associations of overweight and obesity with mortality.
To examine the effect of reverse causality and confounding on the association of BMI with all-cause and cause-specific mortality. Data from two large prospective studies were used. One (a community-based cohort) included 8327 women and 7017 men who resided in two Scottish towns at the time of the baseline assessment in 1972-1976; the other (an occupational cohort) included 4016 men working in the central belt of Scotland at the time of the baseline assessment in 1970-1973. Participants in both cohorts were ages 45 to 64 years at baseline; the follow-up period was 28 to 34 years. In age-adjusted analyses that did not take account of reverse causality or smoking, there was no association between being overweight (BMI 25 to <30 kg/m(2)) and mortality, and weak to modest associations between obesity (BMI > or =30 kg/m(2)) and mortality. There was a strong association between smoking and lower BMI in women and men in both cohorts (all p < 0.0001). Among never-smokers and with the first 5 years of deaths removed, overweight was associated with an increase in all-cause mortality (relative risk ranging from 1.12 to 1.38), and obesity was associated with a doubling of risk in men in both cohorts (relative risk, 2.10 and 1.96, respectively) and a 60% increase in women (relative risk, 1.56). In both never-smokers and current smokers, being overweight or obese was associated with important increases in the risk of cardiovascular disease. These findings demonstrate that with appropriate control for smoking and reverse causality, both overweight and obesity are associated with important increases in all-cause and cause-specific mortality, and in particular with cardiovascular disease mortality.


Potent Activities of Roemerine against Candida albicans and the Underlying Mechanisms.
Roemerine (RM) is an aporphine alkaloid isolated from the fresh rattan stem of Fibraurea recisa, and it has been demonstrated to have certain antifungal activity. This study aimed to investigate the antifungal activity of RM and the underlying mechanisms in Candida albicans (C. albicans). The in vitro antifungal activity of RM was evaluated by a series of experiments, including the XTT reduction assay, confocal laser scanning microscopy assay, scanning electron microscope assay. Results showed that 1 μg/mL RM inhibited biofilm formation significantly (p < 0.01) both in Spider medium and Lee's medium. In addition, RM could inhibit yeast-to-hyphae transition of C. albicans in a dose-dependent manner. The biofilm-specific and hypha-specific genes such as YWP1, SAP5, SAP6, HWP1, ECE1 were up-regulated and EFG1 was down-regulated after 8 μg/mL RM treatment. Furthermore, the toxicity of RM was investigated using C. elegans worms, three cancer cells and one normal cell. The date showed that RM had no significant toxicity. In conclusion, RM could inhibited the formation of C. albicans biofilm in vitro, but it had no fungicidal effect on planktonic C. albicans cells, and the anti-biofilm mechanism may be related to the cAMP pathway.


Special Ultrasound Phantom for Interventional Training: Construction, Advantages, and Application.
Interventional radiology procedures are becoming more challenging over time; thus, there is a need for excellent and reliable training methods. Training on live patients is neither safe nor an ethical solution. Alternatives are many and varied, but the most popular is ultrasound guided simulators. This report shows how a simple, homemade, low-cost phantom material, and construction modules can provide several advantages over ordinary gelatin phantoms. A new layering technique and target synthesis are described for the biopsy phantom, including tips on decreasing the needle pass artifact as well as controlling the mixture echogenicity.


Biochemical and functional properties of wheat middlings bioprocessed by lactic acid bacteria.
The present study aimed to investigate the bioprocessing of wheat middlings with different lactic acid bacteria (LAB) in order to improve biological activities of this by-product of wheat flour production. The concentration of lactic acid, reducing sugars, and total phenolics, as well as antioxidant, antibrowning, antibacterial and prebiotic activities of fermented samples were analyzed. All LAB strains were capable to growth on wheat middlings, and pH decreased in the medium associated with lactic acid production during cultivation. Samples inoculated with Lactobacillus plantarum DSM20174 presented the maximum growth, lactic acid concentration above 2 mg/ml, and pH values around 3.8. The amount or reducing sugars decreased after 24 hr growth, except for maltose. Bioprocessed wheat middlings exhibited antioxidant, antibrowning, antibacterial, and prebiotic properties, related with the increase of total phenolic content. Highest values for antioxidant activities were obtained for L. plantarum and Streptococcus thermophilus strains, reaching values around 400 and 640 μM Trolox equivalents (TE) ml-1 for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric ion reducing antioxidant power (FRAP) assays, respectively. Bioprocessing techniques using LAB can be an interesting approach to improve the availability of compounds with health-promoting properties from lignocellulosic waste material. PRACTICAL APPLICATIONS: The processing of secondary products from wheat milling can represent an important benefit to the industry. Wheat middlings bioprocessed with LAB showed improved biological activities and may represent an interesting ingredient to be incorporated in food and feed formulations.


[Cytokines in Kawasaki disease].
We analyzed plasma levels of 14 cytokines in patients with Kawasaki disease (KD) before intravenous infusion of immunoglobulin (WIG) therapy using multiplex bead assay system. The results demonstrated that both inflammatory(TNF-α, IL-6, IL-8, IL-17, IFN-γ, G-CSF, MCP-1 and sIL-2Rα) and anti-inflammatory(IL-10, sTNFR1 and sTNFR2) cytokine levels were simultaneously elevated in patients refractory to the initial IVIG therapy. System-level understanding of the cytokine networks would be the key to develop a new therapeutic strategy to prevent coronary artery injuries in KD.


Survey to Assess Knowledge and Reported Practices Regarding Blood Transfusion Among Cancer Physicians in Uganda.
Optimal decision making regarding blood transfusion for patients with cancer requires appropriate knowledge of transfusion medicine among physicians. We assessed blood transfusion knowledge, attitudes, and reported practices among physicians working at Uganda Cancer Institute (UCI). A cross-sectional self-administered survey of UCI physicians on their knowledge, attitudes, and practices regarding blood transfusion was conducted from June to September 2014. In consultation with transfusion medicine experts, 30 questions were developed, including 10 questions for each of the following three domains: knowledge, attitudes, and practices. For the knowledge domain, we created a knowledge score equal to the number of questions correctly answered out of 10. Of 31 physicians approached, 90% participated. The mean knowledge score was 5.3 (median, 5.5), and 32% correctly answered at least seven of 10 questions. Almost all (96%) understood the importance of proper patient identification before transfusion and indicated identification error as the most common cause of fatal transfusion reactions. More than 60% of physicians acknowledged they lacked knowledge and needed training in transfusion medicine. Most physicians reported sometimes changing their mind about whether to provide a patient with a transfusion on the basis of opinion of colleagues and sometimes administering unnecessary transfusions because of influence from others. Although UCI physicians have some basic knowledge in transfusion, most reported gaps in their knowledge, and all expressed a need for additional education in the basics of blood transfusion. Transfusion training and evidence-based guidelines are needed to reduce inappropriate transfusions and improve patient care. Greater understanding of peer influence in transfusion decision making is required.


Breakup of a fluid thread in a confined geometry: droplet-plug transition, perturbation sensitivity, and kinetic stabilization with confinement.
We investigate the influence of geometrical confinement on the breakup of long fluid threads in the absence of imposed flow using a lattice Boltzmann model. Our simulations primarily focus on the case of threads centered coaxially in a tube filled with another Newtonian fluid and subjected to both impulsive and random perturbations. We observe a significant slowing down of the rate of thread breakup ("kinetic stabilization") over a wide range of the confinement, Lambda= R(tube)/R(thread) < or =10 and find that the relative surface energies of the liquid components influence this effect. For Lambda<2.3, there is a transition in the late-stage morphology between spherical droplets and tube "plugs." Unstable distorted droplets ("capsules") form as transient structures for intermediate confinement (Lambda approximately equal 2.1-2.5). Surprisingly, the thread breakup process for more confined threads (Lambda< or =1.9 ) is found to be sensitive to the nature of the initial thread perturbation. Localized impulsive perturbations ("taps") cause a "bulging" of the fluid at the wall, followed by thread breakup through the propagation of a wave-like disturbance ("end-pinch instability") initiating from the thread rupture point. Random impulses along the thread, modeling thermal fluctuations, lead to a complex breakup process involving a competition between the Raleigh and end-pinch instabilities. We also briefly compare our tube simulations to threads confined between parallel plates and to multiple interacting threads under confinement.


A Bioinorganic Approach to Fragment-Based Drug Discovery Targeting Metalloenzymes.
Metal-dependent enzymes (i.e., metalloenzymes) make up a large fraction of all enzymes and are critically important in a wide range of biological processes, including DNA modification, protein homeostasis, antibiotic resistance, and many others. Consequently, metalloenzymes represent a vast and largely untapped space for drug development. The discovery of effective therapeutics that target metalloenzymes lies squarely at the interface of bioinorganic and medicinal chemistry and requires expertise, methods, and strategies from both fields to mount an effective campaign. In this Account, our research program that brings together the principles and methods of bioinorganic and medicinal chemistry are described, in an effort to bridge the gap between these fields and address an important class of medicinal targets. Fragment-based drug discovery (FBDD) is an important drug discovery approach that is particularly well suited for metalloenzyme inhibitor development. FBDD uses relatively small but diverse chemical structures that allow for the assembly of privileged molecular collections that focus on a specific feature of the target enzyme. For metalloenzyme inhibition, the specific feature is rather obvious, namely, a metal-dependent active site. Surprisingly, prior to our work, the exploration of diverse molecular fragments for binding the metal active sites of metalloenzymes was largely unexplored. By assembling a modest library of metal-binding pharmacophores (MBPs), we have been able to find lead hits for many metalloenzymes and, from these hits, develop inhibitors that act via novel mechanisms of action. A specific case study on the use of this strategy to identify a first-in-class inhibitor of zinc-dependent Rpn11 (a component of the proteasome) is highlighted. The application of FBDD for the development of metalloenzyme inhibitors has raised several other compelling questions, such as how the metalloenzyme active site influences the coordination chemistry of bound fragments, how one can identify the best fragments for a given metalloenzyme, and many others. Among the most significant, and concerning, questions for metalloenzyme inhibition are those that reside around issues of specificity and whether metalloenzyme inhibitors can be as selective and specific as other small molecule inhibitors (i.e., compounds that inhibit enzymes that do not utilize a metal at their active site). This also leads to the question of whether metalloenzyme inhibitors might interfere more broadly with the metallome. Efforts to address these and related questions are discussed, with the expectation that our findings will illuminate some of these topics, alleviate some of these concerns, and encourage greater interest in this important, undervalued class of drug targets.


Metal-Chelated Polymeric Nanomaterials for the Removal of Penicillin G Contamination.
We developed selective and relatively low-cost metal-chelated nanoparticle systems for the removal of the penicillin G (Pen G) antibiotic, presented for the first time in the literature. In the nanosystem, poly(glycidyl methacrylate) nanoparticles were synthesized by a surfactant-free emulsion polymerization method and covalently bound with a tridentate-chelating ligand, iminodiacetic acid, based on the immobilized metal chelate affinity technique. It was modified with Cu2+, a chelating metal, to make Pen G specific. Metal-chelated nanoparticles were characterized by Fourier-transform infrared spectroscopy, energy dispersive spectrometry, zeta dimensional analysis, and scanning electron microscopy technology. Optimization studies of the Pen G removal were conducted. As a result of this study, Pen G removal with the p(GMA)-IDA-Cu2+ nanoparticle reached its maximum adsorption capacity of 633.92 mg/g in the short time of 15 min. The Pen G adsorption of p(GMA)-IDA-Cu2+ was three times more than that of the p(GMA) nanoparticles and two times more than that of the ampicillin adsorption. In addition, there was no significant decrease in the adsorption capacity of Pen G resulting from the repeated adsorption-desorption process of metal-chelated nanoparticles over five cycles. The metal-chelated nanoparticle had an 84.5% ability to regain its ability to regenerate the product with its regeneration capability, making the widespread use of the system very convenient in terms of reducing cost, an important factor in removal processes.


Vanishing adrenal mass.
Adrenal involvement by primary lymphomatous disorders is quite rare. Primary adrenal lymphoma is usually associated with bilateral adrenal involvement and presents as adrenal insufficiency or class B symptoms. The authors report a case who presented with pain in the abdomen and was diagnosed to have unilateral primary adrenal lymphoma. The patient responded to chemotherapy with near-complete resolution of the adrenal mass.


A review on endoscopic palliation of obstructive jaundice before surgery.
Since its development, endoscopic retrograde cholangiopancreatography (ERCP) has evolved from a simple diagnostic technique to an important therapeutic procedure. Obstructive jaundice is often the first and most common complication in patients with malignant disease of the extrahepatic biliary tract. Although preoperative biliary drainage (PBD) may be instituted in many centers, different studies have reported divergent results regarding its benefits in reducing the complications of hepatopancreatobiliary surgery, especially with regard to pancreatoduodenectomy for pancreatic cancer. In this review, we will summarize the current literature of PBD and describe its indications, possible benefits, and, when indicated, the appropriate interval before surgery.


A case of Rosai-Dorfman disease involving the lacrimal gland in an elderly patient.
Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) is a rare disease characterised by benign proliferation of histiocytes, with painless lymph node enlargement and frequent extranodal involvement. Orbital involvement occurs in 11% of cases and onset of the disease is typically in the first two decades of life. A benign course is usual, but in some cases blindness or fatality may result. We present a case with late onset at age 78 years and lacrimal gland involvement, and review the literature on this disease.


General diastereoselective synthetic approach toward isospongian diterpenes. Synthesis of (-)-marginatafuran, (-)-marginatone, and (-)-20-acetoxymarginatone.
This work describes a synthetic approach to the carbocyclic skeleton of isospongian diterpenes that uses the commercially available monoterpene (S)-carvone as a C-ring synthon, which is incorporated into the tetracyclic isospongian framework via a C→ABC→ABCD ring annulation strategy using intramolecular Diels-Alder and ring-closing metathesis reactions. This approach has been successfully used to prepare both the title natural isospongians and several nonnatural oxygenated analogues. A preliminary evaluation of the inhibitory activity of the small collection of synthesized isospongians on the mammalian mitochondrial respiratory chain revealed that most were able to inhibit the integrated electron transfer chain (NADH oxidase activity) in the micromolar range.


An LRR receptor kinase regulates growth, development and pathogenesis in Phytophthora capsici.
Leucine-rich repeats (LRRs) domain containing kinase proteins (LRR-RK) perform various functions in eukaryotic organisms. However, their functions in Oomycetes are still largely unknown. Here, we identified an LRR-RK (PcLRR-RK1) gene and characterized its functions in Phytophthora capsici, a model oomycete specie and a major plant destroyer of solanaceous and cucurbitaceous vegetable crops. We showed that PcLRR-RK1-silenced P. capsici transformants exhibited reduced growth and produced highly branched fluffy hyphae. The shape and size of sporangia were also altered along with the reduced production of number of sporangia and zoospores. Moreover, silencing of the gene affected the cyst germination and penetration of germ tube into the host tissues, and led to the reduced virulence of P. capsici. Thus, we suggest that PcLRR-RK1 was essentially required for zoospores development, and successful infection of the P. capsici.


Chronic illness: psychosocial effects on siblings--I. Chronically ill boys.
Focusing on the adjustment of the siblings of three groups of male children: with pervasive developmental disability, diabetes and no known chronic illness, the present study failed to support the view that siblings of ill children are uniformly at greater risk for psychosocial impairment. However, several domains were identified in which siblings as well as parents of sick children were more susceptible to adjustment problems, though 'risk' seemed to relate more closely to illness-specific variables than the presence or absence of illness. Several sex differences were found suggesting that same-sexed siblings may be more vulnerable to maladjustment than opposite-sexed pairs. The results are discussed in terms of their implications for investigation and intervention for families with an ill member.


'Internet+' comprehensive nursing training course in the post-epidemic era-an exploration of the mixed teaching mode: a randomized trial.
To explore the effect of the application of the 'Internet+' nursing teaching mode on the comprehensive teaching 'Fundamentals of Nursing'. Parallel design and convenient sampling were used to select vocational nursing students from the Nursing College of Capital Medical University. Selected students were randomly divided into two groups. The control group consisted of 30 students in Grade 2020 higher vocational nursing education (traditional teaching mode). The observation group consisted of 30 students in Grade 2021 higher vocational nursing education (Internet+ mixed teaching mode). Training assessment results, automatic learning ability, professional identity, and satisfaction were compared between the two groups. Compared with the control group, the students in the observation group scored higher in the following operation practices: venous blood sampling, intradermal injection, cardiopulmonary resuscitation (CPR), sputum aspiration, and putting on and taking off robes (84.01 ± 0.87 vs. 92.14 ± 1.23; 91.41 ± 0.82 vs. 96.86 ± 0.27; 87.56 ± 0.31 vs. 93.91 ± 2.79; 88.11 ± 0.51 vs. 93.75 ± 0.29; and 82.29 ± 0.29 vs. 90.96 ± 0.34, respectively, with p < 0.05 for all scores). The total scores for autonomous learning ability and subjective satisfaction were also higher in the observation group compared with the control group (82.98 ± 4.72 vs. 93.17 ± 5.01 and 96.67% vs. 90.00%, respectively, with p < 0.05 for all scores). In the post-epidemic era, the 'Internet+ hybrid teaching mode' was applied to comprehensive nursing teaching. This changed the traditional education mode, which focuses only on professional knowledge. The 'Internet+' teaching mode results showed that the professional, ideological, and political courses exhibited the same value guidance, which improved students' independent learning ability, practical operation ability, professional identity, and satisfaction.


Multimodal Encoding of Goal-Directed Actions in Monkey Ventral Premotor Grasping Neurons.
Visuo-motor neurons of the ventral premotor area F5 encode "pragmatic" representations of object in terms of the potential motor acts (e.g., precision grip) afforded by it. Likewise, objects with identical pragmatic features (e.g., small spheres) but different behavioral value (e.g., edible or inedible) convey different "semantic" information and thus afford different goal-directed behaviors (e.g., grasp-to-eat or grasp-to-place). However, whether F5 neurons can extract distinct behavioral affordances from objects with similar pragmatic features is unknown. We recorded 134 F5 visuo-motor neurons in 2 macaques during a contextually cued go/no-go task in which the monkey grasped, or refrained from grasping, a previously presented edible or inedible target to eat it or placing it, respectively. Sixty-nine visuo-motor neurons showed motor selectivity for the target (35 food and 34 object), and about half of them (N = 35) exhibited congruent visual preference. Interestingly, when the monkey grasped in complete darkness and could identify the target only based on haptic feedback, visuo-motor neurons lost their precontact selectivity, but most of them (80%) showed it again 60 ms after hand-target contact. These findings suggest that F5 neurons possess a multimodal access to semantic information on objects, which are transformed into motor representations of the potential goal-directed actions afforded by them.


Study of the properties of ZnO:Zn thin films obtained from ZnO/Zn/ZnO structure deposited by DC sputtering.
A method to manage the resistivity of n-type ZnO films is presented. It involves the controlled diffusion of Zn at low temperature in N2 atmosphere into the ZnO/Zn/ZnO structure. The structures were made by DC sputtering technique. The diffusion periods were varied from 5 to 30 min. This process allow us to obtain ZnO films with excess of Zn (ZnO:Zn). The electrical characterization showed that the resistivity of the films can be varied from 0.01 to 100 omega-cm, the electron concentration from 10(19) to 10(17) cm(-3) and the carrier mobility from 10 to 40 cm2N-s. The films are nanocrystalline with preferred (002) orientation and crystal size that varies from 13 to 20 nm depending on the diffusion period. The films have a band gap of 3.18 eV and 70% of transmittance in the visible region, these properties were obtained from the transmittance measurements of low-resistivity films. Films have good structural, optical and electrical properties, and could be used in the manufacture of light emitting diodes.


A brief history of vascular access for hemodialysis: an unfinished story.
Progress in the development of permanent vascular access for hemodialysis has been much slower than progress in other areas of end-stage renal disease (ESRD) patient care. This article provides a brief historical overview of the major means used for vascular access since the start of chronic hemodialysis. These access modalities include external shunts, arteriovenous fistulae, prosthetic arteriovenous grafts, needle-less access devices, and tunneled central venous catheters. Despite the evolution of access methodology, vascular access complications remain a major impediment to the full rehabilitation of the chronic hemodialysis patient.


The National Home-Based Primary Care Learning Network: A Practice-Based Quality Improvement and Research Network.
Home-based primary care (HBPC) provides interdisciplinary, comprehensive care at home for homebound older adults and has been largely excluded from the national conversation on care quality and quality improvement. In this Pragmatic Innovations article, we describe the work of the National HBPC Learning Network (LN), which focuses on fostering a continuous learning culture among HBPC practices to improve practice quality, elevate the field of HBPC, and create a community of continuous growth and quality of care accountability. The LN recruits HBPC practices in waves of 9 to 10 practices. It currently comprises 38 HBPC practices that care for 58,000 patients across 25 states (approximately 26% of all patients receiving HBPC in the United States). In a Kickoff meeting, the HBPC practices in each wave are instructed in the basics of quality improvement, develop project aim statements and their first plan-do-study-act cycle, receive an introduction to the LN quality improvement software platform, and review plans for LN engagement. Each month, practices submit updates and receive real-time feedback on their quality improvement work. Monthly virtual workshops are held with all practices that include sharing results of a "1-minute survey" (a monthly 1-to 3-question survey sent to all LN participants on a topic relevant to HBPC practices), a didactic and discussion related to the 1-minute survey topic, and interactive progress updates from LN participants regarding their quality improvement work. Each wave ends with "Moving-up Day," where practices report on their overall project and reflect on how their practice has changed as a result of the LN. LN practices have addressed and improved performance in multiple HBPC-related quality areas including assessment of functional status and cognitive impairment, falls prevention, advanced care planning, COVID-19 vaccination, and others. We present case studies of 3 LN practices and how LN participation strengthened their practices.


The therapeutic potential of small-conductance KCa2 channels in neurodegenerative and psychiatric diseases.
KCa2 or small-conductance Ca(2+)-activated K(+) channels (SK) are expressed in many areas of the central nervous system where they participate in the regulation of neuronal afterhyperpolarization and excitability, and also serve as negative feedback regulators on the glutamate-NMDA pathway. This review focuses on the role of KCa2 channels in learning and memory and their potential as therapeutic targets for Alzheimer's and Parkinson's disease, ataxia, schizophrenia and alcohol dependence. There currently exists relatively solid evidence supporting the use of KCa2 activators for ataxia. Genetic KCa2 channel suppression in deep cerebellar neurons induces ataxia, while KCa2 activators like 1-EBIO, SKA-31 and NS13001 improve motor deficits in mouse models of episodic ataxia (EA) and spinal cerebellar ataxia (SCA). Use of KCa2 activators for ataxia is further supported by a report that riluzole improves ataxia in a small clinical trial. Based on accumulating literature evidence, KCa2 activators further appear attractive for the treatment of alcohol dependence and withdrawal. Regarding Alzheimer's disease, Parkinson's disease and schizophrenia, further research, including long-term studies in disease relevant animal models, will be needed to determine whether KCa2 channels constitute valid targets and whether activators or inhibitors would be needed to positively affect disease outcomes.


Haemophilus parainfluenzae Pyogenic Liver Abscess Associated With Cholangiocarcinoma.
Haemophilus parainfluenzae (H. parainfluenzae) is a commensal organism of the gastrointestinal tract. It rarely causes hepatobiliary infections; however, in the presence of underlying inflammation, immunosuppression, or malignancy, it can cause hepatobiliary infection via an ascending route. Herein, we report a case of pyogenic liver abscess secondary to H. parainfluenzae associated with cholangiocarcinoma, which was treated with ceftriaxone and metronidazole.


Antenna effect by organometallic chromophores in bimetallic d-f complexes.
The nature of the intermetallic bond in a series of complexes of the type [Cp2-TM-M-Cp2] (where TM = Re and M = Y, La, Lu, Yb, Ac; also TM = Os and M = Th; Cp = cyclopentadienyl ligand) have been studied by relativistic two-component density functional theory (DFT) calculations. The results obtained in this work show that the interaction between the transition metal and lanthanide atoms is mainly ionic in all cases, while for the case of actinide atoms this interaction becomes significantly more covalent. The effective direction of the electron transfer between the Re→Ac or Os→Th centers allows us to propose that the [Cp2ReAcCp2] and [Cp2OsThCp2] complexes are ideal candidates for near-infrared (NIR) technologies since their absorption spectra show some transitions over 600 nm. We also observed a shifting of the absorption spectrum of around 100 nm of the [Cp2Re] fragment when is compared against the absorption spectrum of the entire complex. This behavior allows us to argue that the [Cp2Re] fragment is a good antenna chromophore due to the possibility of charge transfer transitions from this fragment to the f shell in lanthanide or actinide elements studied here.


Molecular dynamics simulations of yeast F1-ATPase before and after 16° rotation of the γ subunit.
We have recently proposed the "packing exchange mechanism" for F1-ATPase, wherein the perturbation by a substrate binding/release or an ATP hydrolysis is followed by the reorganization of the asymmetric packing structure of the α3β3 complex, accompanying the γ subunit rotation. As part of a further investigation of this rotational mechanism, we performed all-atom molecular dynamics simulations for yeast F1-ATPase both before and after a 16° rotation of the γ subunit triggered by a Pi release. We analyzed the structural fluctuations, the subunit interface interactions, and the dynamics of the relative subunit arrangements before and after the rotation. We found that with the Pi release the αEβE subunit interface becomes looser, which also allosterically makes the αDPβDP subunit interface looser. This structural communication between these interfaces takes place through a tightening of the αTPβTP subunit interface. The γ subunit interacts less strongly with αDP and βDP and more strongly with αTP and βTP. After the Pi release, the tightly packed interfaces are reorganized from the interfaces around βDP to those around βTP, inducing the 16° rotation. These results, which are consistent with the packing exchange mechanism, allow us to deduce a view of the structural change during the 40° rotation.


Extracoronary collateral myocardial blood flow during cardioplegic arrest.
Extracoronary blood flow to the myocardium was studied in 54 patients during cold cardioplegic arrest. Coronary venous return was measured with the aorta and the pulmonary artery cross-clamped, both venae cavae occlusively snared, and the heart completely drained. Cold St. Thomas' cardioplegic solution was infused into either the aortic root or the coronary ostia. Myocardial septal temperature was continuously monitored. The amount of blood in the right atrial effluent was determined by means of the hematocrit and was considered to be the extracoronary collateral myocardial blood flow (QE), originating from the systemic circulation. QE ranged from 0 to 1470 ml-100 min-1 (x = 241.1 ml-100min-1). The myocardial spontaneous rewarming rate was not significantly correlated to QE. QE was lowest in pure mitral valve stenosis (x = 39.9 ml-100 min-1) and higher in aortic valve disease (x = 165.5 ml-100 min-1). Very high QE values (greater than 800 ml-100 min-1) were only observed in patients with severe three vessel coronary artery disease. Patients with angina at rest appear to have lower QE values than patients with equally severe coronary artery disease suffering from angina under excise only. It is concluded that extracoronary collateral blood flow may unpredictably influence the efficacy of clinical cardioplegia and may to some extent compensate for severe coronary artery disease.


Epidemiology and outcomes of multiple antibiotic-resistant bacterial infection in renal transplantation.
Mutiresistant bacterial infections are an emerging problem in the nosocomial setting. Our objectives were to describe the incidence, outcome, and risk factors for acquisition of multiresistant bacteria among renal transplant recipients. We prospectively followed patients undergoing kidney transplantation over a 3-year period. We collected demographic features, underlying chronic diseases, and main transplant characteristics and complications. Multiple antibiotic resistance was defined for the most important bacteria: Enteric gram-negative bacilli resistant to betalactamics, cephalosporins, and quinolones; Staphylococcus aureus resistant to methicillin, cotrimoxazole, and clindamcin; Enterococcus spp resistant to ampicillin and quinolones; nonfermentator bacilli resistant to all antibiotics except aminoglycosides and collistin. Overall, 416 patients included 65 double transplants (62 kidney-pancreas and three kidney-liver) of mean age 48.5 years, and 57% men. Infection with multiresistant bacteria was observed in 58 patients (14%). Most frequent multiresistant bacteria were: Escherichia coli (n = 33), Klebsiella spp (n = 15), Citrobacter spp (n = 8), Enterobacter spp (n = 5), Morganella morganii (n = 2), Pseudomonas aeruginosa (n = 16), Acinetobacter baumanii (n = 2), Enterococcus spp (n = 9) and methicillin-resistant S. aureus (MRSA, n = 2). Age greater than 50 years, hepatitis C virus infection, double kidney-pancreas transplantation, requirement for posttransplant hemodialysis, surgical reoperation, and requirement for nephrostomy were independent variables associated with multiresistant bacterial infection. Most used antibiotics for treatment were: carbapenems (65%), amikacin (12%), linezolid, piperacillin-tazobactam, vancomycin, collistin, and fosfomycin. Infection with multiresistant bacteria was associated with a worse prognosis (graft loss or death, 19% vs 8%, P = .009). The incidence of infection with multiresistant bacteria in our renal transplant cohort was high, being most frequently cephalosporin-resistant enteric gram-negative bacilli and multiresistant P aeruginosa. Methicillin-resistant S. aureus incidence was low. Infection with multiresistant bacteria conferred a worse prognosis.


[The effect of water immersion on humoral and urinary parameters in healthy persons and in patients with liver cirrhosis].
The authors subjected 10 healthy subjects and 13 patients inflicted by liver cirrhosis in the stage of vascular decompensation (ascites and/or oedemas) to water immersion (WI). The group of healthy subjects responded during WI by a significant increase of diuresis and sodium diuresis at its maximum in the third hour, which was accompanied by a decrease of plasma aldosterone (PA) and a decrease of atrial natriuretic factor (ANF) and digoxin-like activity (DLA). The decrease of plasma vasopressin (PAVP) was not statistically significant. In patients with liver cirrhosis a significant increase of diuresis and sodium diuresis took place, whilst the response was significant already in the first hour of WI. Only 3 non-respondents were among the ill patients. In the group of liver cirrhotics also a significant decrease of AVP, PA, and an increase of ANF and DLA were recorded, the response of humoral factors was not significant due to great variability. A long term administration of diuretics (Spirolakton+Furosemid) did not decrease the serum K in ill patients. Hence, WI by means of supervention of volume expansion evokes an increase of diuresis and natriuresis in both healthy and ill subjects, the latter with decompensated liver cirrhosis which is associated with a controversial reaction of sodium diuresis and sodium retention factors. It is possible to use it as a supplementary method in the therapy of oedemas due to liver cirrhosis besides diuretic therapy. (Tab. 2, Fig. 3, Ref. 22.)


Specific inhibition of hormone-sensitive lipase improves lipid profile while reducing plasma glucose.
Elevation of plasma free fatty acids has been linked with insulin resistance and diabetes. Inhibition of lipolysis may provide a mechanism to decrease plasma fatty acids, thereby improving insulin sensitivity. Hormone-sensitive lipase (HSL) is a critical enzyme involved in the hormonally regulated release of fatty acids and glycerol from adipocyte lipid stores, and its inhibition may thus improve insulin sensitivity and blood glucose handling in type 2 diabetes. In rat adipocytes, forskolin-activated lipolysis was blocked by in vitro addition of a potent and selective HSL inhibitor or by prior treatment of the animals themselves. Antilipolytic effects also were demonstrated in overnight-fasted mice, rats, and dogs with species-dependent effects on plasma free fatty acid levels but with similar reductions in plasma glycerol being observed in all species. Inhibition of HSL also reduced hyperglycemia in streptozotocin-induced diabetic rats. The data support a connection between adipose tissue lipolysis and plasma glucose levels.


Hepatocellular carcinoma metastatic to the mandible.
We describe the case of a 55-year-old man with known multifocal hepatocellular carcinoma (HCC) who presented with a painful mandibular mass. Fine-needle aspiration cytology of the mass revealed the presence of bile canaliculi and bile formation, an extremely rare finding. Findings on immunoperoxidase staining of the aspirate were consistent with an HCC. Since the patient was known to have multiorgan metastatic disease, he was administered palliative radiation therapy to the mandibular metastasis for pain control, which was achieved. One year after presentation, the patient died as a result of disease progression. HCC rarely metastasizes to the mandible, as only about 70 such cases have been reported in the literature. We discuss the histopathologic appearance of HCC metastatic to the mandible, the radiologic findings, and the established treatment modalities.


Malonate degradation in Acinetobacter baylyi ADP1: operon organization and regulation by MdcR.
Transcriptional regulators in the LysR or GntR families are typically encoded in the genomic neighbourhood of bacterial genes for malonate degradation. While these arrangements have been evaluated using bioinformatics methods, experimental studies demonstrating co-transcription of predicted operons were lacking. Here, transcriptional regulation was characterized for a cluster of mdc genes that enable a soil bacterium, Acinetobacter baylyi ADP1, to use malonate as a carbon source. Despite previous assumptions that the mdc-gene set forms one operon, our studies revealed distinct promoters in two different regions of a nine-gene cluster. Furthermore, a single promoter is insufficient to account for transcription of mdcR, a regulatory gene that is convergent to other mdc genes. MdcR, a LysR-type transcriptional regulator, was shown to bind specifically to a site where it can activate mdc-gene transcription. Although mdcR deletion prevented growth on malonate, a 1 nt substitution in the promoter of mdcA enabled MdcR-independent growth on this carbon source. Regulation was characterized by methods including transcriptional fusions, quantitative reverse transcription PCR, reverse transcription PCR, 5'-rapid amplification of cDNA ends and gel shift assays. Moreover, a new technique was developed for transcriptional characterization of low-copy mRNA by increasing the DNA copy number of specific chromosomal regions. MdcR was shown to respond to malonate, in the absence of its catabolism. These studies contribute to ongoing characterization of the structure and function of a set of 44 LysR-type transcriptional regulators in A. baylyi ADP1.


Sample size for comparing negative binomial rates in noninferiority and equivalence trials with unequal follow-up times.
We derive the sample size formulae for comparing two negative binomial rates based on both the relative and absolute rate difference metrics in noninferiority and equivalence trials with unequal follow-up times, and establish an approximate relationship between the sample sizes required for the treatment comparison based on the two treatment effect metrics. The proposed method allows the dispersion parameter to vary by treatment groups. The accuracy of these methods is assessed by simulations. It is demonstrated that ignoring the between-subject variation in the follow-up time by setting the follow-up time for all individuals to be the mean follow-up time may greatly underestimate the required size, resulting in underpowered studies. Methods are provided for back-calculating the dispersion parameter based on the published summary results.


Adherence to Clinical Practice Guidelines.
Clinical practice guidelines are designed to synthesize and disseminate the best available evidence to guide clinical practice. The goal is to increase high-quality care and reduce inappropriate interventions. Clinical practice guidelines that systematically review evidence and synthesize it into recommendations are important because the available scientific evidence is normally neither rapidly nor broadly incorporated into practice. It is important to understand and improve the impact of our American Academy of Otolaryngology-Head and Neck Surgery Foundation clinical practice guidelines on this uptake of scientific knowledge. Considering the barriers to guideline adherence is a central part of this. This understanding can guide clinicians, future guideline authors, and researchers when using guidelines, writing them, and planning clinically relevant research.


Polyclonal antibody production against rGPC3 and their application in diagnosis of hepatocellular carcinoma.
Glypican-3 (GPC3) is an integral membrane proteoglycan, which contains a core protein anchored to the cytoplasmic membrane through a glycosylphosphatidylinositol linkage. The glypican-3 can regulate the signaling pathways, thereby enhances cell division, growth, and apoptosis in certain cell types. It is almost nonexistent on the surface of the human normal cell membrane and highly expresses on the membrane of hepatocellular carcinoma (HCC) cells. It has been well established that GPC3 provides a useful diagnostic marker. For generating the polyclonal antibody of GPC3, we expected that GPC3 N-terminal region (amino acid sequence 26-358) could be expressed in Escherichia coli system, however, no active expression was observed after IPTG induction. Interestingly, after deletion of six proline residues from position 26 to 31 in the N-terminus, expression of recombinant GPC3 was clearly detected. We further analyzed the expressed protein deprived of six prolines, to immunize the New Zealand male rabbits for production of active antibodies. The binding affinity of antibody was analyzed by immunofluorescence analysis, immunohistochemical detection, and western blotting. The functional GPC3 N-terminal protein recombinant development, expression, purification, and the polyclonal antibody have been generated provide the basis for the diagnosis of HCC in cancer therapy.


Effect of pregnenolone-16alpha-carbonitrile on the rat liver.
In female rats, pregnenolone-16alpha-carbonitrile [PCN (a known microsomal enzyme inducer)] augmented liver weight and significantly increased hepatic protein, total lipid, phospholipid and ATP concentrations. These changes were correlated with hepatic drug-metabolizing enzyme induction. PCN did not alter body weight, or water, ash, triglyceride and cholesterol levels in the liver, but caused a mild reduction of hepatic glycogen.


High Matrix Metalloproteinase 28 Expression is Associated with Poor Prognosis in Pancreatic Adenocarcinoma.
Pancreatic adenocarcinoma (PAAD) is a devastating disease with high mortality and morbidity. Matrix metalloproteinase 28 (MMP28) has been associated with carcinogenesis of many human cancers. However, little is known about the potential prognostic value and underlying regulatory mechanisms of MMP28 in PAAD. The relationship between MMP28 expression level and various clinicopathological parameters was analyzed in TCGA-PAAD cohorts. MMP28-correlated genes in the TCGA-PAAD cohort were identified and enrichment analysis according to the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes was conducted using LinkedOmics. Protein-protein interaction and transcription factors-miRNA co-regulatory networks were constructed with the use of NetworkAnalyst. Then, the distribution of immune cells related to MMP28 expression in blood was analyzed using the Human Protein Atlas, and the tumor microenvironment of PAAD was analyzed by the TIMER 2.0 database. To investigate the biological function of MMP28 in PAAD, siRNA was constructed to knock down the MMP28 gene in vitro. High MMP28 expression is associated with poor overall survival and disease-free survival in PAAD patients. The expression of MMP28 in PAAD is most significantly correlated with KRT19, IL1RN, and ANXA2 genes. Network analysis revealed that MIR-181 family, TAFs, and CDC6 are potential regulators of MMP28. Furthermore, naive CD4+ T cell, naive CD8+ T cell, and mucosal-associated invariant T cell enrichment in blood were correlated with MMP28 expression. Furthermore, high MMP28 expression was correlated with a decrease in B cell, naive CD4+ T cell, naive CD8+ T cell, and endothelial cell presence in the tumor microenvironment in PAAD. Finally, genetic knockdown of MMP28 could restrain the proliferation, migration, and invasion of PAAD cells. Our findings indicate that high MMP28 expression in PAAD is associated with cancer progression, invasion, and metastasis. Hence, MMP28 might serve as an independent prognostic biomarker and a prospective therapeutic target for PAAD.


Enhancement of gp130-mediated tyrosine phosphorylation of STAT3 and its DNA-binding activity in dexamethasone-treated AIDS-associated Kaposi's sarcoma cells: selective synergy between dexamethasone and gp130-related growth factors in Kaposi's sarcoma cell proliferation.
The soluble IL-6R (slL-6R alpha)/IL-6 complex and oncostatin M (OM), which exert biologic activities through the signal-transducing protein gp130, are potent growth factors for AIDS-associated Kaposi's sarcoma (KS) cells. Clinical observations indicate that glucocorticoid therapy is a possible risk factor in KS; however, little is known of specific interactions in KS cells between glucocorticoid and gp130-related growth factors. We obtained evidence that dexamethasone (Dex), in a synergistic manner, enhances gp130-mediated growth of KS cells. Anti-gp130 Abs or the glucocorticoid antagonist RU-486 abolished this synergistic effect. In addition, Dex had additive but not synergistic effects on stimulation of KS cell growth with IL-1beta or TNF-alpha, the signals of which are not mediated through gp130. Immunoblot analysis revealed sIL-6R alpha/IL-6- or OM-induced tyrosine phosphorylation of a similar set of proteins in KS cells, and which was augmented significantly in Dex-treated KS cells. Stimulation of KS cells with sIL-6R alpha/IL-6 or OM induced rapid tyrosine phosphorylation of the transcription factor STAT3, and Dex significantly enhanced the accumulation of tyrosine-phosphorylated STAT3. Electrophoretic mobility shift assays showed sIL-6R alpha/IL-6- or OM-induced DNA-binding activity of STAT3 in KS cells, and Dex further increased this activity. Thus, Dex appears to participate in the gp130-STAT3 signaling and transcriptional events by enhancing STAT3 activation, thereby leading to selective synergistic stimulation of KS cell growth with Dex and the gp130-related growth factors.


Influence of the Surface Acidity of the Alumina on the Sustained Release of Ketoprofen.
This work reports the immobilization of ketoprofen into mesoporous alumina, prepared in different way, to assess their possible applications as a matrix for controlled drug release. The acids' surface properties of the aluminas and their effect on the drug content and release rate were also analyzed. The systems have been characterized by powder X-ray diffractometry, Fourier transformer infrared spectroscopy (FT-IR), N2 adsorption desorption, transmission electron microscopy, and FT-IR of pyridine adsorption. The results show that the drug is incorporated inside the pores of mesoporous alumina, and the content and release rate depend of surface acidity, when increase the surface acidity decrease the drug content and increase the release rate.


Chronic depletion of gonadal testosterone leads to blood-brain barrier dysfunction and inflammation in male mice.
A dysfunction in the blood-brain barrier (BBB) is associated with many neurological and metabolic disorders. Although sex steroid hormones have been shown to impact vascular tone, endothelial function, oxidative stress, and inflammatory responses, there are still no data on the role of testosterone in the regulation of BBB structure and function. In this context, we investigated the effects of gonadal testosterone depletion on the integrity of capillary BBB and the surrounding parenchyma in male mice. Our results show increased BBB permeability for different tracers and endogenous immunoglobulins in chronically testosterone-depleted male mice. These results were associated with disorganization of tight junction structures shown by electron tomography and a lower amount of tight junction proteins such as claudin-5 and ZO-1. BBB leakage was also accompanied by activation of astrocytes and microglia, and up-regulation of inflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), interleukin 1 beta (IL-1β), and tumor necrosis factor (TNF). Supplementation of castrated male mice with testosterone restored BBB selective permeability, tight junction integrity, and almost completely abrogated the inflammatory features. The present demonstration that testosterone transiently impacts cerebrovascular physiology in adult male mice should help gain new insights into neurological and metabolic diseases linked to hypogonadism in men of all ages.


Pathology of glomerular basement membrane nephropathy.
Studies of the molecular pathology of glomerular basement membrane have led to the discovery of four novel chains of type IV collagen, the latest of which is the alpha 6(IV) chain. Three chains have been shown to be directly involved in the pathogenesis of Goodpasture syndrome, Alport syndrome, and Alport posttransplantation antiglomerular basement membrane nephritis. This review focuses on the novel chains with respect to recent advances in their structure, gene organization, and involvement in the pathogenesis of these glomerulopathies.


Implementation of cystic fibrosis services in developing countries: memorandum from a Joint WHO/ICF(M)A meeting.
A Joint WHO/ICF(M)A meeting defined strategies for the implementation and development of cystic fibrosis (CF) services in countries where CF is thought to be more common than is appreciated by the medical profession or the public and where CF services are either non-existent or in the early stages of development. The following common problems in such countries were identified: underdiagnosis; reduced life expectancy (relative to developed countries) among those diagnosed; a clinical profile that may vary from the "classic" description; poor availability of necessary drugs; and a lack of CF services or basic research on the condition. The following recommendations were made concerning CF: neonatal screening projects should be set up to determine its incidence and identify affected infants; national and regional laboratories should be encouraged to identify the specific mutations responsible for the condition in their populations; centres for diagnosis and treatment should be developed, using a team approach; a national organization, involving families and friends of individuals with CF and other volunteers, should be established; a national registry should be set up; awareness about the condition should be improved and knowledge about it developed among medical professionals, public health authorities, and the general public; and increased collaboration between groups and organizations (including pharmaceutical companies) at the national, regional, and international levels should be developed in order to exchange information about and promote knowledge of CF, and to stimulate the development of CF services in developing countries.


Inbred lines of mice derived from long-term growth selected lines: unique resources for mapping growth genes.
Lines of mice selected for many generations for high or low growth in several laboratories around the world have been collected, and from these, inbred lines are being developed by recurrent full-sib mating in Edinburgh. There are seven high selected lines and four low lines (each low line is from the same base population as one of the high lines), and the histories of each are summarized. Mean body weight of males at 70 days of age in the Edinburgh laboratory in the heaviest inbred line (77 g) is 4.8-fold higher than in the lightest line (16 g), and 1.9-fold higher than in the least extreme high line (41 g). Litter size, food intake, and fat content also differ substantially. These inbred extreme selected lines are a uniquely valuable resource for QTL or gene mapping, candidate gene identification, and elucidation of epistatic effects.


All-Microwave Manipulation of Superconducting Qubits with a Fixed-Frequency Transmon Coupler.
All-microwave control of fixed-frequency superconducting quantum computing circuits is advantageous for minimizing the noise channels and wiring costs. Here we introduce a swap interaction between two data transmons assisted by the third-order nonlinearity of a coupler transmon under a microwave drive. We model the interaction analytically and numerically and use it to implement an all-microwave controlled-Z gate. The gate based on the coupler-assisted swap transition maintains high drive efficiency and small residual interaction over a wide range of detuning between the data transmons.


Biases in the Visual and Haptic Subjective Vertical Reveal the Role of Proprioceptive/Vestibular Priors in Child Development.
Investigation of the perception of verticality permits to disclose the perceptual mechanisms that underlie balance control and spatial navigation. Estimation of verticality in unusual body orientation with respect to gravity (e.g., laterally tilted in the roll plane) leads to biases that change depending on the encoding sensory modality and the amount of tilt. A well-known phenomenon is the A-effect, that is a bias toward the body tilt often interpreted in a Bayesian framework to be the byproduct of a prior peaked at the most common head and body orientation, i.e., upright. In this study, we took advantage of this phenomenon to study the interaction of visual, haptic sensory information with vestibular/proprioceptive priors across development. We tested children (5-13 y.o) and adults (>22 y.o.) in an orientation discrimination task laterally tilted 90° to their left-ear side. Experimental conditions differed for the tested sensory modality: visual-only, haptic-only, both modalities. Resulting accuracy depended on the developmental stage and the encoding sensory modality, showing A-effects in vision across all ages and in the haptic modality only for the youngest children whereas bimodal judgments show lack of multisensory integration in children. A Bayesian prior model nicely predicts the behavioral data when the peak of the prior distribution shifts across age groups. Our results suggest that vision is pivotal to acquire an idiotropic vector useful for improving precision when upright. The acquisition of such a prior might be related to the development of head and trunk coordination, a process that is fundamental for gaining successful spatial navigation.


Agency in young clients' narratives of counseling: "it's whatever you want to make of it".
Although there is a growing body of research that looks at how adult clients are active agents in their own counseling, there is little similar research that looks at the experiences of young people in counseling. This research explores how client agency is constructed in retrospective accounts of a school counseling experience provided by 22 young people (aged 16-18). The narrative analysis shows how participants constructed their agency as clients in a number of different ways: in asserting their choice over whether to see a counselor; in their evaluations of counselors; in the selection or rejection of aspects of counseling and by portraying themselves as primarily responsible for the benefits obtained from counseling. In these ways, young clients seemed able to shape their construction of counseling to better match their own priorities. But participants also seemed aware of potential threats to their ability to exercise their agency and described how they struggled to express their needs overtly to their counselors. This raises the possibility that young people's assertions of agency may be best understood in the context of their relative powerlessness in counseling situations. Although there is potential to harness young clients' agency in the service of better counseling outcomes, their strong commitment to a view of themselves as agents may result in them experiencing greater accountability without a corresponding access to power in counseling.


DNACPR ('do not attempt cardiopulmonary resuscitation') orders in patients with a fractured neck of femur who lack capacity.
Nationally, half of all deaths occur in hospital, with 94% having a 'do not attempt cardiopulmonary resuscitation' (DNACPR) notice in place at the time of death. Recent court rulings have raised the profile of practices surrounding DNACPR orders where patients lack capacity. Failure to consult with those close to the patient in relation to DNACPR decisions is a breach of the right to respect for private and family life under article 8 of the Human Rights Act. A report from 2016 found that those close to the patient were not consulted before one out of every five DNACPR orders are placed. We advocate addressing the issue of resuscitation in patients with a fractured neck of femur who are approaching the end of their lives. Where the patient lacks capacity, there is a legal duty to consult with those close to the patient where it is practicable and appropriate to do so. There must be a convincing and well evidenced reason to proceed without consultation, and the orthopaedic surgeon should exercise extreme caution before doing so.


A retrospective hospital study of human cystic echinococcosis in Egypt.
We performed a retrospective study to determine annual clinical incidence of human cystic echinococcosis (CE) in 14 Egyptian hospitals between January 1997 and December 1999. From 492 353 records examined, 133 (0.027%) new human CE cases were recorded. Of these, 50 (37.6%) were from Alexandria and Matrouh hospitals, 33 (24.8%) from Giza Chest Hospital and 50 from other regions. Matrouh governorate had the highest annual clinical incidence (1.34-2.60 per 100 000) followed by Giza governorate (0.80-1.16 per 100 000). About a third of those affected were aged < or = 20 years. Liver and lungs were the organs most affected. Although human CE is of low endemicity in Egypt, it may-represent a public health concern in Matrouh and Giza governorates.


Spinopelvic Hypermobility Corrects After Staged Bilateral Total Hip Arthroplasty.
Background: Spinopelvic hypermobility may be secondary to a stiff osteoarthritic hip with a compliant spine. Purpose: We sought to determine if spinopelvic hypermobility resolves after total hip arthroplasty (THA) and when it resolves in patients with bilateral hip osteoarthritis (OA) undergoing staged bilateral THA. We also sought to analyze the change in spinopelvic parameters before and after the second THA. Methods: We conducted a retrospective review of 2047 THAs that were performed by 2 fellowship-trained arthroplasty surgeons from 2014 to 2018. Patients with preoperative spinopelvic hypermobility undergoing staged bilateral THA were identified. Radiographic spinopelvic parameters, including sacral slope (SS), pelvic incidence (PI), lumbar lordosis (LL), PI-LL mismatch, anterior pelvic plane tilt (APPt), and spinopelvic tilt (SPT), were measured on preoperative, 6-week postoperative, and 1-year postoperative lateral standing and sitting radiographs. Bilateral hip OA was graded using Kellgren-Lawrence criteria. Results: We identified 42 patients with preoperative spinopelvic hypermobility who underwent staged bilateral THA. Mean time (standard deviation) between surgeries was 9.4 months (±10.0). After the first THA, spinopelvic hypermobility resolved in 29% of the patients. After the second THA, it resolved in 67% at 6 weeks, increasing to 98% at 1 year postoperatively. Conclusion: Spinopelvic hypermobility resolves after staged bilateral THA in 98% of the patients, occurring most often only after the second THA. Less than one-third of the patients had resolution after the first THA, suggesting that contralateral hip OA continues to drive hip-driven spinopelvic motion. Acetabular component position targets based on functional pelvic position should incorporate these changes in spinopelvic motion with the understanding that resolution of hypermobility usually occurs after the second THA.


Short-term association between outdoor air pollution and osteoporotic hip fracture.
This study examines the association of the levels of different airborne pollutants on the incidence of osteoporotic hip fracture in a southern European region. Association was detected between SO2 and NO2 and hospital admissions due to hip fracture. To examine the short-term effects of outdoor air pollution on the incidence of osteoporotic hip fracture in a southern European region. This is an ecological retrospective cohort study based on data obtained from three databases. In a time-series analysis, we examined the association between hip fracture incidence and different outdoor air pollutants (sulfur dioxide (SO2), monoxide (NO), nitrogen dioxide (NO2), ozone (O3), and particulate matter in suspension < 2.5 (PM2.5) and < 10-μm (PM10) conditions by using general additive models (Poisson distribution). The incidence rate ratio (IRR), crude and adjusted by season and different weather conditions, was estimated for all parameters. Hip incidence was later analyzed by sex and age (under or over age 75) subgroups. The main outcome measure was daily hospital admissions due to fracture. Hip fracture incidence showed association with SO2 (IRR 1.11 (95% CI 1.04-1.18)), NO (IRR 1.01 (95% CI 1.01-1.02)), and NO2 (IRR 1.02 (95% CI 1.01-1.04)). For O3 levels, this association was negative (IRR 0.97 (95% CI 0.95-0.99)). The association persisted for SO2 and NO2 when the models were adjusted by season. After adjusting by season and weather conditions, the association persisted for NO2. When participants were stratified by age and sex, associations persisted only in women older than 75 years. A short-term association was observed with several indicators of air pollution on hip fracture incidence. This is the first study that shows these associations.


Factors influencing medication compliance among hypertensive older African American adults.
The purpose was to gain an indepth understanding of the factors influencing hypertension medication compliance among hypertensive older African Americans. Qualitative descriptive. In depth semistructured interviews were conducted with 28 patients. Interviews were recorded, transcribed, and analyzed by the Colaizzi-style method. Patients at a cardiovascular clinic in the Southeast. 28 African American males and females aged > or = 55 with controlled and uncontrolled hypertension were recruited and interviewed. Stroke Heart Attack and Prevention Program (SHAPP) patients reported self-efficacy, patient-provider communication, and social support contributed to their hypertension regimen compliance. Patients reported higher self-efficacy contributed to their hypertension control. Patients also reported that open communication with the SHAPP nurses and social support from their family, friends, and coworkers provided emotional support, information and guidance to assist them in being compliant with their hypertension management regimen. Our results can inform SHAPP providers and staff about patients' hypertension medication compliance, can improve patient-provider communication in other SHAPP clinics, and can aid in future patient hypertension management. Our results also suggest the importance of self-efficacy, patient-provider communication, and social support in hypertension regimen compliance.


Should healthy Medicare beneficiaries postpone enrollment in Part D?
(1) Total lifetime expected out-of-pocket costs are minimized if healthy 65-year-old Medicare beneficiaries enroll in Part D immediately upon eligibility rather than waiting until they contract a drug-intensive condition. (2) The savings from early enrollment are greater for females than for males. (3) The late enrollment penalty for Medicare Part D provides an important incentive for early enrollment, and eliminating the late enrollment penalty would create a significant cost advantage for postponed enrollment, especially for men.


bcl-2 Overexpression eliminates deprivation-induced cell death of brainstem auditory neurons.
Deprivation of afferent input in young animals results in transneuronal degeneration of postsynaptic sensory neurons in a variety of species and sensory pathways. Transneuronal degeneration is generally not seen in adult animals. The cellular and molecular basis for this dramatic developmental change in susceptibility is not understood. One possibility is that genes involved in the apoptotic process are involved in determining cell death or survival after afferent deprivation. To further investigate this possibility, we performed unilateral cochlear ablation on wild-type and bcl-2-overexpressing mice at a variety of ages. In postnatal day 5 (P5) or P8 wild-type mice, cochlea removal resulted in a 54% or 31% neuronal loss in the anteroventral cochlear nucleus (AVCN), respectively. When the same manipulation is performed on a P30 mouse, no loss of AVCN neurons occurs. This confirmed a rather abrupt change in the sensitivity to disruption of afferent input, a critical period. However, in littermates expressing bcl-2 under a neuron-specific enolase promoter, no significant loss of AVCN neurons was observed at any age after unilateral cochlear ablation. Furthermore, wild-type mice demonstrate rapid expression of activated caspase-3 in AVCN neurons within hours of deafferentation, whereas bcl-2-overexpressing mice do not. This suggests that bcl-2 can influence cell survival after removal of afferent input during the critical period and is consistent with the hypothesis that caspase-3 is one effector of cell death under these circumstances. These data are the first to indicate that known apoptotic mediators can play a role in central neuronal plasticity in models of afferent deprivation.


Photopolymer Electrolytes for Sustainable, Upscalable, Safe, and Ambient-Temperature Sodium-Ion Secondary Batteries.
The first example of a photopolymerized electrolyte for a sodium-ion battery is proposed herein. By means of a preparation process free of solvents, catalysts, purification steps, and separation steps, it is possible to obtain a three-dimensional polymeric network capable of efficient sodium-ion transport. The thermal properties of the resulting solid electrolyte separator, characterized by means of thermogravimetric and calorimetric techniques, are excellent for use in sustainable energy systems conceived for safe large-scale grid storage. The photopolymerized electrolyte shows a wide electrochemical stability window up to 4.8 V versus Na/Na(+) along with the highest ionic conductivity (5.1 mS cm(-1) at 20 °C) obtained in the field of Na-ion polymer batteries so far and stable long-term constant-current charge/discharge cycling. Moreover, the polymeric networks are also demonstrated for the in situ fabrication of electrode/electrolyte composites with excellent interfacial properties, which are ideal for all-solid-state, safe, and easily upscalable device assembly.


Molecular diagnosis of eosinophilic meningitis due to Angiostrongylus cantonensis (Nematoda: Metastrongyloidea) by polymerase chain reaction-DNA sequencing of cerebrospinal fluids of patients.
Cerebrospinal fluid (CSF) samples from clinically diagnosed patients with detectable Angiostrongylus cantonensis-specific antibodies (n = 10), patients with clinically suspected cases that tested negative for A. cantonensis-antibodies (n = 5) and patients with cerebral gnathostomiasis (n = 2) and neurocysticercosis (n = 2) were examined by a single-step polymerase chain reaction (PCR) method using the AC primers for the 66-kDa native protein gene. The PCR method detected A. cantonensis DNA in CSF samples from four of 10 serologically confirmed angiostrongyliasis cases. The PCR results were negative for the remaining CSF samples. The nucleotide sequences of three positive CSF-PCR samples shared 98.8-99.2% similarity with the reference sequence of A. cantonensis. These results indicate the potential application of this PCR assay with clinical CSF samples for additional support in the confirmation of eosinophilic meningitis due to A. cantonensis.


The Course of Hearing Loss in Patients With a Progressive Vestibular Schwannoma.
This study evaluates the natural course of hearing loss (HL) prior to treatment in patients with progressive tumors and an indication for active intervention. Evaluating this patient group specifically can put hearing outcomes after vestibular schwannoma therapy into an adequate context. Retrospective cohort study. Tertiary referral center. Inclusion criteria comprised unilateral vestibular schwannomas prior to active treatment, with ≥2 mm extracanalicular (EC) tumor growth and ≥2 audiograms. We performed a comprehensive assessment of hearing using multiple outcome parameters including (the annual decrease in) pure-tone averages (PTAs; an average of 0.5, 1, 2, and 3 kHz). Predictors for HL were evaluated (patient age, tumor size/progression, follow-up duration, baseline hearing). At presentation, 86% of patients suffered from sensorineural HL on the affected side (≥20 dB PTA) with a median of 39 dB (interquartile rate [IQR]: 27-51 dB). The median follow-up duration was 21 months (IQR: 13-34 months), after which 58% (187/322) of patients experienced progressive HL (≥10 dB), with a median increase of 6.4 dB/year. At the last follow-up, the median PTA was 56 dB (IQR: 37-73). Median speech discrimination scores deteriorated from 90% (IQR: 70%-100%) to 65% (IQR: 35%-100%). Tumor progression (maximal EC diameter) was significantly correlated to the progression of sensorineural HL, corrected for follow-up (F(2,228) = 10.4, p < .001, R2 = 8%). The majority of patients (58%) with radiologically confirmed progressive vestibular schwannomas experience progressive sensorineural HL during observation. Tumor progression rate, EC tumor extension, and longer follow-up are factors associated with more sensorineural HL.


Immunoprecipitation of herpes simplex virus polypeptides with human sera is related to their ELISA titre.
Out of 485 human sera tested by neutralization and enzyme immunoassay 13 were negative in both tests, while a positive correlation was found in 457 samples (94.3%). The rest of sera (3.2%) showed discordant results. Selected sera were examined, in addition, by Western blot and immunoprecipitation assays with the aim to analyse the precipitation profile of discordant sera and correlate the ELISA titre with the precipitation profiles. High titre sera precipitated the main glycoproteins (gC, gB, gE, gD), the capsid polypeptides (VP 5, VP 19, VP 21, VP 22) and several other structural and nonstructural proteins. The ability of sera to precipitate viral structural proteins was related to their ELISA titre rather than to their neutralizing activity.


Management of a malignant case of solid pseudopapillary tumor of pancreas: a case report and literature review.
Solid pseudopapillary tumor of the pancreas is a rare neoplasm with low malignant potential, which affects predominantly young females. Only approximately 10% to 15% cases of solid pseudopapillary tumors (SPTs) are malignant. We present the case of a 57-year-old woman who developed malignant SPT of the pancreas. Meanwhile, a literature review was carried out. Some clinicopathological features and strategies of management of malignant SPT are presented. In general, surgical removal of the tumor even in case of metastases or recurrence offers an excellent prognosis. Chemotherapy and radiotherapy should be taken into consideration in patients with unresectable tumor.


Shear at twin domain boundaries in YBa2Cu3O7-x.
The microstructure and strain state of twin domains in YBa2Cu3O7-x are discussed based upon synchrotron white-beam x-ray microdiffraction measurements. Intensity variations of the fourfold twin splitting of Laue diffraction peaks are used to determine the twin domain structure. Strain analysis shows that interfaces between neighboring twin domains are strained in shear, whereas the interior of these domains are regions of low strain. These measurements are consistent with the orientation relationships of twin boundaries within and across domains and show that basal plane shear stresses can exceed 100 MPa where twin domains meet. Our results support stress field pinning of magnetic flux vortices by twin domain boundaries.


Expression of human factor VIII by splicing between dimerized AAV vectors.
Adeno-associated virus (AAV) is a useful vector for hemophilia gene therapy, but the limited effective packaging capacity of AAV (5 kb) appears to be incompatible with factor VIII (gene symbol F8) cDNA (7 kb). Although we previously demonstrated efficient packaging and expression of B-domain-deleted human F8 (BDD-F8) using a single AAV vector, the packaging limit still excludes the use of large/strong regulatory elements. Here we exploited the split AAV vector technology that expands the packaging capacity of AAV through head-to-tail dimerization. To test the feasibility of AAV heterodimerization for F8 expression, we generated a 5' vector that includes a large enhancer/promoter cassette linked with exons 1-12 of the F8 cDNA and a half-intron-carrying splice donor site. A complementing 3' vector contains another half-intron-carrying splice acceptor site linked with the remaining F8 cDNA and a polyadenylation signal. Following coinfection of 293 and HepG2 cells, the 5' and 3' vectors together produced functional human factor VIII protein at a level of 120 mU/ml (24 ng/ml). No factor VIII protein was detected if only one of the vectors was used. Correct head-to-tail vector dimerization as well as spliced BDD-F8 mRNA was detected by DNA PCR and RT-PCR, respectively. Furthermore, intraportal injection of two rAAV/F8 vectors in immunodeficient mice produced 2% of the normal level of factor VIII for four months. Our results demonstrate the potential use of AAV dimerization for F8 expression.


Two novel ubiquitin-fold modifier 1 (Ufm1)-specific proteases, UfSP1 and UfSP2.
Ubiquitin-fold modifier 1 (Ufm1) is a recently identified new ubiquitin-like protein, whose tertiary structure displays a striking resemblance to ubiquitin. Similar to ubiquitin, it has a Gly residue conserved across species at the C-terminal region with extensions of various amino acid sequences that need to be processed in vivo prior to conjugation to target proteins. Here we report the isolation, cloning, and characterization of two novel mouse Ufm1-specific proteases, named UfSP1 and UfSP2. UfSP1 and UfSP2 are composed of 217 and 461 amino acids, respectively, and they have no sequence homology with previously known proteases. UfSP2 is present in most, if not all, of multicellular organisms including plant, nematode, fly, and mammal, whereas UfSP1 could not be found in plant and nematode upon data base search. UfSP1 and UfSP2 cleaved the C-terminal extension of Ufm1 but not that of ubiquitin or other ubiquitin-like proteins, such as SUMO-1 and ISG15. Both were also capable of releasing Ufm1 from Ufm1-conjugated cellular proteins. They were sensitive to inhibition by sulfhydryl-blocking agents, such as N-ethylmaleimide, and their active site Cys could be labeled with Ufm1-vinylmethylester. Moreover, replacement of the conserved Cys residue by Ser resulted in a complete loss of the UfSP1 and UfSP2 activities. These results indicate that UfSP1 and UfSP2 are novel thiol proteases that specifically process the C terminus of Ufm1.


Effect of thermocycling on the flexural strength of porcelain laminate veneers.
The aim of this study was to examine the impact of thermocycling on the flexural strength and development of surface flaws on the glazed surface of porcelain laminate veneer restorations with and without resin luting cement. 80 Vitadur alpha dentin porcelain discs (10 mm diameter, 0.9 mm thickness) were glazed on one side and divided into two groups: A (porcelain laminate veneer only without resin luting cement) and B (porcelain laminate veneer luted with resin cement), each containing 40 discs. The discs in groups A and B were then thermocycled at different temperatures and were subjected to SEM analysis to evaluate the effect of thermocycling on crack propagation. Mean flexural strength was determined by using the ball-on-ring test. Student's t -test was used to find out the difference between strength values of the thermocycled porcelain discs and discs luted with resin cement. SEM analysis revealed crack propagation in the subgroups subjected to extremes of temperature, i.e., 4 +/- 1 degrees C, 37 +/- 1 degrees C and 4 +/- 1 degrees C, 65 +/- 1 degrees C in the porcelain laminate veneers luted with resin cement. Flexural strength analysis revealed superior flexural strength for porcelain laminate veneers: 88.58 +/- 6.94 MPa when compared to porcelain laminate veneers luted with resin cement: 8.42 +/- 2.60 MPa. Results were tabulated and statistically analyzed using Student's t -test. Laminate veneer specimens exhibited greater flexural strength than those which were luted with resin cements. Laminate veneer specimens luted with resin cement and subjected to extremes of temperature, 4 +/- 1 degrees C and 37 +/- 1 degrees C and 4 +/- 1 degrees C and 65 +/- 1 degrees C, showed a marked decrease in flexural strength. After thermocycling at extremes of temperature, laminate veneer specimens luted with resin cement showed crack propagation. Fit of laminate veneers cannot / should not be compensated by the thickness of luting agent.


Corrosion and creep of dental amalgam.
The influence of stress on corrosion was investigated by a potentiostatic technique. Amalgrams with low creep, both with and without gamma2-phase, revealed small increases in current with stress application while alloys with high creep exhibited large increases in current. Rupture of protective oxide due to increased strain for high creep alloys may explain the phenomenon.