The performance of different classification criteria in paediatric Behçet's disease.
Behçet's disease (BD) is a variable vessel vasculitis. The most widely used classification criteria for adults is the International Behçet's Study Group (ISG) criteria. Recently, the paediatric BD (PEDBD) classification criteria has been developed for children. For disease activity, there are mainly two severity scores; the Iranian BD dynamic activity measure (IBDDAM) and BD current activity form (BDCAF). We tested the performances of PEDBD and ISG criteria and the correlation between severity scores and physician global assessment (PGA) in children with BD. Thirty BD patients from Hacettepe University, Ankara, Turkey; 24 from Erciyes University, Kayseri, Turkey; and 14 BD patients from Rambam Medical Centre, Haifa, Israel were included. As controls, children with systemic lupus erythematosus, polyarteritis nodosa, and Crohn disease from Turkey and Israel were included. The sensitivity and specificity of the PEDBD and ISG criteria were evaluated based on the features of the patients before or at 16 years of age. The gold standard for the diagnosis of BD was based on expert opinion at each centre. Expert PGA (visual analogue scale between 0-10; where 0 indicates no disease activity), IBDDAM, and BDCAF were evaluated at the time of diagnosis and at last follow-up in all patients. Sixty-eight BD (disease onset≤16 years; 44.1% male) and 90 control patients were included. The sensitivity and specificity of PEDBD/ISG criteria were 73.5%/52.9% and 97.7%/100%, respectively. Thirty-two (47%) patients with BD failed to fulfill ISG criteria while almost all met PEDBD criteria. The median (interquartile range; IQR) IBDDAM and BDCAF scores at diagnosis were 6(4)/4(2); significantly decreased to 1(2)/1(2), respectively at latest follow-up (p<0.001 for both). The median (IQR) PGA score at diagnosis was 5(2); significantly decreased to 1(2) at latest follow-up (p<0.001). IBDDAM positively correlated with BDCAF (r=0.637; p<0.001). PGA positively correlated with BDCAF and IBDDAM (r=0.502; p<0.001 and r=0.624;p<0.001, respectively). In our study, the PEDBD criteria showed better sensitivity than ISG criteria which is a big advantage for paediatric patients for early diagnosis. We also demonstrated that the severity scores were positively correlated with each other and PGA; thus may be used in clinical practice for paediatric BD patients.


Functional characterization of two chimeric proteins between a Petunia inflata S-locus F-box protein, PiSLF2, and a PiSLF-like protein, PiSLFLb-S2.
Self-incompatible solanaceous species possess the S-RNase and SLF (S-locus F-box) genes at the highly polymorphic S-locus, and their products mediate S-haplotype-specific rejection of pollen tubes in the style. After a pollen tube grows into the style, the S-RNases produced in the style are taken up; however, only self S-RNase (product of the matching S-haplotype) can inhibit the subsequent growth of the pollen tube. Based on the finding that non-self interactions between PiSLF (Petunia inflata SLF) and S-RNase are stronger than self-interactions, and based on the biochemical properties of PiSLF, we previously proposed that a PiSLF preferentially interacts with its non-self S-RNases to mediate their ubiquitination and degradation, thereby only allowing self S-RNase to exert its cytotoxic function. We further divided PiSLF into three potential Functional Domains (FDs), FD1-FD3, based on sequence comparison of PiSLF and PiSLF-like proteins, and based on S-RNase-binding properties of these proteins and various truncated forms of PiSLF(2) (S(2) allelic variant of PiSLF). In this work, we examined the in vivo function of FD2, which we proposed to be responsible for strong, general interactions between PiSLF and S-RNase. We swapped FD2 of PiSLF(2) with the corresponding region of PiSLFLb-S(2) (S(2) allelic variant of a PiSLF-like protein), and expressed GFP-fused chimeric proteins, named b-2-b and 2-b-2, in S(2) S(3) transgenic plants. We showed that neither chimeric protein retained the SI function of PiSLF(2), suggesting that FD2 is necessary, but not sufficient, for the function of PiSLF. Moreover, since we previously found that b-2-b and 2-b-2 only interacted with S(3)-RNase ~50 and ~30%, respectively, as strongly as did PiSLF(2) in vitro, their inability to function as PiSLF(2) is also consistent with our model predicating on strong interaction between a PiSLF and its non-self S-RNases as part of the biochemical basis for S-haplotype-specific rejection of pollen tubes.


Toxicokinetics of 8:2 fluorotelomer alcohol (8:2-FTOH) in male and female Hsd:Sprague Dawley SD rats after intravenous and gavage administration.
Fluorotelomer alcohols (FTOHs) are used in the production of persistent per- and polyfluorinated alkyl substances (PFAS). Rodents and humans metabolize FTOHs to perfluoralkyl carboxylic acids which have several associated toxicities. Thus, understanding the toxicokinetics of these FTOHs and their metabolites will be useful for interpreting their toxicity for humans. Here, male and female Hsd:Sprague-Dawley SD rats were administered a single dose of 8:2-FTOH via gavage (males: 12, 24, 48 mg/kg; females: 40, 80, 160 mg/kg) or IV (males: 12 mg/kg; females: 40 mg/kg). Toxicokinetics of 8:2-FTOH and two primary metabolites, perfluorooctanoic acid (PFOA) and 7:3-fluorotelomer acid (7:3-FTA) were determined in plasma. Concentrations (total) of these chemicals were determined in the liver, kidney, and brain. There was rapid absorption and distribution of 8:2-FTOH after gavage administration in male rats. The plasma elimination half-life ranged from 1.1 to 1.7 hours. Kinetic parameters of 8:2-FTOH in females were similar to that in males. Bioavailability of 8:2-FTOH ranged from 22 to 41% for both sexes with no dose-dependent trends. 8:2-FTOH metabolites, PFOA and 7:3-FTA were detected in plasma following administration of the parent FTOH. Consistent with existing literature, the plasma half-life of PFOA was longer in males than in females (198-353 hours and 4.47-6.9 hours, respectively). The plasma half-life of 7:3-FTA was around 2-3 days in both sexes. 8:2-FTOH and 7:3-FTA were detected in all tissues; PFOA was found in the liver and kidney but not the brain. Detectable concentrations of metabolites persisted longer than the parent FTOH. These data demonstrate that in rats given a single gavage dose, 8:2-FTOH is rapidly absorbed, metabolized to form PFOA and 7:3-FTA, distributed to tissues, and eliminated faster than its metabolites. Sex differences were observed in the tissue distribution and elimination of PFOA, but not 8:2-FTOH and 7:3-FTA.


Otolaryngology - Head and Neck Surgeon unemployment in Canada: a cross-sectional survey of graduating Otolaryngology - Head and Neck Surgery residents.
Recently graduated Otolaryngology - Head and Neck Surgeons (OTO-HNS) are facing an employment crisis. To date, there has been no systematic evaluation of the factors contributing to this situation, graduating OTO-HNS trainee employment rates, nor the employment concerns of these graduating residents. This investigation sought to empirically evaluate prospective OTO-HNS graduate employment, identify factors contributing to this situation, and provide suggestions going forward. A cross-sectional survey of the 2014 graduating cohort of OTO-HNS residents was conducted 6-months prior to graduation, and immediately following residency graduation. Surveyed items focused on the demographics of the graduating cohort, their future training and employment plans, and their concerns relative to the OTO-HNS employment situation. All twenty-nine Canadian medical school graduated OTO-HNS residents completed the initial survey, with 93% responding at the completion of residency. Only 6 (22%) indicated confirmed employment following residency training. 78% indicated that they were pursuing fellowship training. 90% identified the pursuit of fellowship training as a moderately influenced by limited job opportunities. The ability to find and secure full-time employment, losing technical skills if underemployed/unemployed, and being required to consider working in a less-desired city/province were most concerning. 34% of the residents felt that they were appropriately counseled during their residency training about employment. 90% felt that greater efforts should be made to proactively match residency-training positions to forecasted job opportunities. Canadian OTO-HN Surgeons lack confirmed employment, are choosing to pursue fellowship training to defer employment, and are facing startling levels of under- and unemployment. A multitude of factors have contributed to this situation and immediate action is required to rectify this slowly evolving catastrophe.


Genome evolution and plasticity of Serratia marcescens, an important multidrug-resistant nosocomial pathogen.
Serratia marcescens is an important nosocomial pathogen that can cause an array of infections, most notably of the urinary tract and bloodstream. Naturally, it is found in many environmental niches, and is capable of infecting plants and animals. The emergence and spread of multidrug-resistant strains producing extended-spectrum or metallo beta-lactamases now pose a threat to public health worldwide. Here we report the complete genome sequences of two carefully selected S. marcescens strains, a multidrug-resistant clinical isolate (strain SM39) and an insect isolate (strain Db11). Our comparative analyses reveal the core genome of S. marcescens and define the potential metabolic capacity, virulence, and multidrug resistance of this species. We show a remarkable intraspecies genetic diversity, both at the sequence level and with regards genome flexibility, which may reflect the diversity of niches inhabited by members of this species. A broader analysis with other Serratia species identifies a set of approximately 3,000 genes that characterize the genus. Within this apparent genetic diversity, we identified many genes implicated in the high virulence potential and antibiotic resistance of SM39, including the metallo beta-lactamase and multiple other drug resistance determinants carried on plasmid pSMC1. We further show that pSMC1 is most closely related to plasmids circulating in Pseudomonas species. Our data will provide a valuable basis for future studies on S. marcescens and new insights into the genetic mechanisms that underlie the emergence of pathogens highly resistant to multiple antimicrobial agents.


Collagenase and fibronectin in bronchoalveolar lavage fluid in patients with sarcoidosis.
Bronchoalveolar lavage fluid from 43 patients with biopsy proved sarcoidosis and 10 control subjects were assayed for fibronectin and collagenase activity. Fibronectin was significantly increased in the group with sarcoidosis and was found to be positively correlated with angiotensin converting enzyme activity, protein concentration, percentage of T cells and helper:suppressor ratios in the lavage fluid. Increased fibronectin in the bronchoalveolar lavage fluid was not related to functional or radiographic indices of interstitial disease and did not identify patients subsequently requiring treatment. Latent collagenase was present in bronchoalveolar lavage fluid from 16 patients with sarcoidosis but not in any control sample. There was no association between the collagenase activity and the cell profiles of the lavage fluid. Yet carbon monoxide transfer factor was decreased in patients with bronchoalveolar lavage fluid collagenase. Ten of 16 patients with bronchoalveolar lavage fluid collagenase had radiographic class III or IV disease and a disease duration of more than two years. On follow up 62% of patients with bronchoalveolar lavage fluid collagenase required subsequent treatment, compared with only 23% of patients without collagenase. These results indicate an association between bronchoalveolar lavage fluid collagenase and progressive, prolonged disease in sarcoidosis, whereas increased bronchoalveolar lavage fluid fibronectin is associated with indices of disease activity.


Flexoskeleton Printing Enables Versatile Fabrication of Hybrid Soft and Rigid Robots.
One of the many secrets to the success and prevalence of insects is their versatile, robust, and complex exoskeleton morphology. A fundamental challenge in insect-inspired robotics has been the fabrication of robotic exoskeletons that can match the complexity of exoskeleton structural mechanics. Hybrid robots composed of rigid and soft elements have previously required access to expensive multi-material three-dimensional (3D) printers, multistep casting and machining processes, or limited material choice when using consumer-grade fabrication methods. In this study, we introduce a new design and fabrication process to rapidly construct flexible exoskeleton-inspired robots called "flexoskeleton printing." We modify a consumer-grade fused deposition modeling (FDM) 3D printer to deposit filament directly onto a heated thermoplastic base layer, which provides extremely strong bond strength between deposited material and the inextensible, flexible base layer. This process significantly improves the fatigue resistance of printed components and enables a new class of insect-inspired robot morphologies. We demonstrate these capabilities through design and testing of a wide library of canonical flexoskeleton elements; ultimately leading to the integration of elements into a flexoskeleton walking legged robot.


Workflow and Strategies for Recruitment and Retention in Longitudinal 3D Craniofacial Imaging Study.
Longitudinal epidemiological studies are considered the gold standard for understanding craniofacial morphologic development, but participant recruitment and retention can be challenging. This study describes strategies used to recruit and maintain a high level of participation in a longitudinal study involving annual three-dimensional (3D) craniofacial soft-tissue imaging from healthy Taiwanese Chinese elementary school students aged 6 to 12 years. The key aspects for project delineation, implementation, and the initial three-year practical experiment are portrayed in an integrated multistep workflow: ethics- and grant-related issues; contact, approval, and engagement from partners of the project (school stakeholders and parents); a didactic approach to recruit the students; research staff composition with task design; three station-based data collection days with two educative activities (oral hygiene and psychosocial interaction stations) and one 3D craniofacial imaging activity; and reinforcement tactics to sustain the longitudinal annual participation after the first enrollment. Randomly selected students and teachers answered an experience satisfaction questionnaire (five-point Likert scale ranging from one to five) designed to assist in understanding what they think about the data collection day. Measures of frequency (percentage) and central tendency (mean) were adopted for descriptive analysis. Six of seven contacted schools accepted participation in the project. All parents who attended the explanatory meetings agreed to join the project. A cohort of 676 students (336 girls) participated at baseline enrollment, with a follow-up rate of 96% in the second data collection. The average questionnaire-related scores were 4.2 ± 0.7 and 4.4 ± 0.6 for teachers and students, respectively. These 3D craniofacial norms will benefit multidisciplinary teams managing cleft-craniofacial deformities in the globally distributed ethnic Chinese population, particularly useful for phenotypic variation characterization, conducting quantitative morphologic comparisons, and therapeutic planning and outcome assessment. The described pathway model will assist other groups to establish their own age-, sex-, and ethnic-specific normative databases.


The deprofessionalization of Soviet physicians: a reconsideration.
Traditional explanations for the relatively low status of the Soviet medical profession credit the Bolshevik government in the 1920s with deprofessionalizing or "leveling" a once autonomous and powerful occupational group. This article presents new data which challenge that interpretation. The Russian medical profession was never autonomous and powerful. Many physicians cooperated with the Bolsheviks because of shared beliefs regarding the organization of medical care. By the late imperial period, many physicians advocated the inclusion of all medical workers in policy-making administrative organs. Focusing upon Russian psychiatrists, the author analyzes the events that prompted the profession to adopt this position. The finding of greater continuity between prerevolutionary Russian and Soviet physicians suggests that this presumably anomalous case has greater significance for theoretical models of professionalization and occupational prestige than previously supposed.


Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP.
The pharmacological phenotype of ATP-sensitive potassium (K(ATP)) channels is defined by their tissue-specific regulatory subunit, the sulfonylurea receptor (SUR), which associates with the pore-forming channel core, Kir6.2. The potassium channel opener diazoxide has hyperglycemic and hypotensive properties that stem from its ability to open K(ATP) channels in pancreas and smooth muscle. Diazoxide is believed not to have any significant action on cardiac sarcolemmal K(ATP) channels. Yet, diazoxide can be cardioprotective in ischemia and has been found to bind to the presumed cardiac sarcolemmal K(ATP) channel-regulatory subunit, SUR2A. Here, in excised patches, diazoxide (300 microM) activated pancreatic SUR1/Kir6.2 currents and had little effect on native or recombinant cardiac SUR2A/Kir6.2 currents. However, in the presence of cytoplasmic ADP (100 microM), SUR2A/Kir6.2 channels became as sensitive to diazoxide as SUR1/Kir6. 2 channels. This effect involved specific interactions between MgADP and SUR, as it required Mg(2+), but not ATP, and was abolished by point mutations in the second nucleotide-binding domain of SUR, which impaired channel activation by MgADP. At the whole-cell level, in cardiomyocytes treated with oligomycin to block mitochondrial function, diazoxide could also activate K(ATP) currents only after cytosolic ADP had been raised by a creatine kinase inhibitor. Thus, ADP serves as a cofactor to define the responsiveness of cardiac K(ATP) channels toward diazoxide. The present demonstration of a pharmacological plasticity of K(ATP) channels identifies a mechanism for the control of channel activity in cardiac cells depending on the cellular ADP levels, which are elevated under ischemia.


Leprosy trends in northern Thailand: 1951-1990.
Data of new, previously untreated leprosy patients from 6 northern provinces of Thailand, diagnosed at McKean Rehabilitation Center, Chiang Mai and associated clinics between 1951 and 1990 were analysed. The following trends were found: 1) Decreasing numbers of new, previously untreated patients. 2) Increasing average age of patients at onset and presentation of disease. 3) Decreasing duration between onset and presentation. 4) Increasing percentage of patients presenting within the first year of symptoms. 5) Increasing percentage of paucibacillary cases. 6) Decreasing percentage of patients presenting with deformity. These trends are a reflection of those seen for the whole of Thailand and indicate that leprosy control is being effective. Patients are presenting at an earlier stage than before, with consequent reduction in disability and infectivity. Better usage of chemotherapy since 1976 has helped to reduce the transmission of bacilli from person to person, combined with effective health education activities which have dispelled some wrong ideas about leprosy and encouraged patients to seek help early in the course of the disease. Additional factors related to public health and living standards have also contributed.


Impact of implant overloading on the peri-implant bone in inflamed and non-inflamed peri-implant mucosa.
To assess the impact of overloading on peri-implant bone level and the bone-to-implant contact (BIC) in the presence of healthy or inflamed peri-implant tissues. Four screw-shaped machined implants were placed bilaterally in the mandible of four beagle dogs and left submerged for 3 months. Prosthetic abutments were connected either in supra-occlusal contact with the opposite teeth (overloaded) or in infra-occlusal position (unloaded). In each dog, cotton floss ligatures were placed unilaterally around abutments to promote plaque accumulation; the contralateral side was brushed three times a week. There were four experimental sites, two implants in each: loaded uninflamed (LU), loaded inflamed (LI), unloaded uninflamed (UU), and unloaded inflamed (UI). Clinical and radiographic parameters were recorded at baseline and every 3 months throughout the observation period. At 12 months, the dogs were sacrificed and histomorphometric analysis was performed. Implants with ligature-induced peri-implantitis presented high inflammatory indices throughout the observation period. Clinical parameters did not change from baseline for both LU and UU. Loading significantly increased the percentage of BIC (BIC%) (P<0.05) and slightly increased crestal bone resorption, but not apical to the implant neck. Both LI and UI groups showed significant peri-implant bone loss (P<0.01), mostly horizontal on the buccal aspect and angular on the lingual aspect, which exposed implant threads. Loading significantly (P<0.05) increased implant thread exposure due to buccal and lingual vertical bone resorption. In the presence of uninflamed peri-implant mucosa, overloading of implants in the dog model increased BIC% and slightly reduced marginal bone level. However, resorption did not progress beyond the implant neck. Overloading aggravated the plaque-induced bone resorption when peri-implant inflammation was present.


The structural stability of the co-chaperonin GroES.
The structural stability of the co-chaperonin GroES has been studied by high sensitivity differential scanning calorimetry and circular dichroism under different solvent conditions. The thermal folding/unfolding of GroES is a spontaneous reversible process involving a highly cooperative transition between folded heptamers and unfolded monomers. During the denaturation process folded monomers are energetically unfavourable and consequently never become populated to an appreciable degree. Analysis of the high resolution structure indicates that isolated folded monomers of GroES bury a significantly smaller fraction of their total surface than typical globular proteins of similar molecular mass. For this reason the intramolecular interactions within each GroES monomer appear not to be sufficient for thermodynamic stabilization. The stabilization of the heptameric structure is due primarily to intersubunit interactions rather than intrasubunit interactions. These interactions favor oligomerization both enthalpically and entropically. Despite the high density of charged residues, the stability of GroES shows no measurable dependence on salt concentration at pH 7. On the other hand, millimolar concentrations of magnesium stabilize GroES, presumably by specific binding. The stabilization elicited by Mg2+ is consistent with a dissociation constant of the order of 0.5 mM and approximately three binding sites per heptamer. These results emphasize the role of quaternary structure in the stabilization of small oligomeric proteins.


Microtubular organization and its involvement in the biogenetic pathways of plasma membrane proteins in Caco-2 intestinal epithelial cells.
We characterized the three-dimensional organization of microtubules in the human intestinal epithelial cell line Caco-2 by laser scanning confocal microscopy. Microtubules formed a dense network approximately 4-microns thick parallel to the cell surface in the apical pole and a loose network 1-micron thick in the basal pole. Between the apical and the basal bundles, microtubules run parallel to the major cell axis, concentrated in the vicinity of the lateral membrane. Colchicine treatment for 4 h depolymerized 99.4% of microtubular tubulin. Metabolic pulse chase, in combination with domain-selective biotinylation, immune and streptavidin precipitation was used to study the role of microtubules in the sorting and targeting of four apical and one basolateral markers. Apical proteins have been recently shown to use both direct and transcytotic (via the basolateral membrane) routes to the apical surface of Caco-2 cells. Colchicine treatment slowed down the transport to the cell surface of apical and basolateral proteins, but the effect on the apical proteins was much more drastic and affected both direct and indirect pathways. The final effect of microtubular disruption on the distribution of apical proteins depended on the degree of steady-state polarization of the individual markers in control cells. Aminopeptidase N (APN) and sucrase-isomaltase (SI), which normally reach a highly polarized distribution (110 and 75 times higher on the apical than on the basolateral side) were still relatively polarized (9 times) after colchicine treatment. The decrease in the polarity of APN and SI was mostly due to an increase in the residual basolateral expression (10% of control total surface expression) since 80% of the newly synthesized APN was still transported, although at a slower rate, to the apical surface in the absence of microtubules. Alkaline phosphatase and dipeptidylpeptidase IV, which normally reach only low levels of apical polarity (four times and six times after 20 h chase, nine times and eight times at steady state) did not polarize at all in the presence of colchicine due to slower delivery to the apical surface and increased residence time in the basolateral surface. Colchicine-treated cells displayed an ectopic localization of microvilli or other apical markers in the basolateral surface and large intracellular vacuoles. Polarized secretion into apical and basolateral media was also affected by microtubular disruption. Thus, an intact microtubular network facilitates apical protein transport to the cell surface of Caco-2 cells via direct and indirect routes; this role appears to be crucial for the final polarity of some apical plasma membrane proteins but only an enhancement factor for others.


Interferon-alpha-associated bilateral simultaneous ischemic optic neuropathy.
The authors describe one patient with essential thrombocytosis and one with chronic hepatitis C infection who developed bilateral simultaneous anterior ischemic optic neuropathy within 3 months of starting treatment with interferon-alpha. One patient had several typical risk factors for conventional AION; the other did not. These cases are the fourth and fifth reported examples of this phenomenon. Interferon-alpha treatment may cause or aggravate the risk of developing anterior ischemic optic neuropathy. Vulnerable patients should be advised of this potential complication, assisted in reducing risk factors, and monitored for optic nerve and retinal vascular complications.


Ultrastructural changes in livers of young and aging rats exposed to methylated benzenes.
ULtrastructural examination was conducted on livers of young rats which were given (intraperitoneal injection) several methylated benzenes (73 mg/kg of body weight) for 3 consecutive days and on livers of aging rats (12 to 19 months old) which were fed methylated benzenes in the diet (200 mg/1,000 g of feed) for periods of 1, 2, 3, and 6 months. The young animals demonstrated white, raised, nodular lesions along the free margins of the liver. The lesions in young animals consisted of lipid droplets surrounded by macrophages and fibroblasts. Some fibroblasts in these lesions appeared to be active in collagen synthesis. Mast cells and eosinophils also occurred in the lesions. Hepatocytes in these young animals appeared morphologically normal. In contrast, hepatocytes in the aging rats developed 2 types of vacuoles. The 1st type of vacuole was bound by a double-unit membrane--the other unit membrane possibly derived from smooth endoplasmic reticulum; it contained a mottled, globular, electron-lucent material. The 2nd type of vacuole was peripherally located in hepatocytes, was single membrane-bound, and occasionally was observed opening into the space of Disse (spatium perisinusoideum). Our observations indicated that acute exposures (3 days) to at least some methylated benzenes does not cause ultrastructurally observable abnormalities in hepatocytes of young rats, but chronic oral ingestion of some can cause formation of vacuolar structures in aging rat hepatocytes.


Optimizing generalized motor program and parameter learning.
Two experiments examined generalized motor program (GMP) and parameter learning. Experiment 1 examined the effects of bandwidth knowledge of results (KR) about relative timing in constant and variable practice. The purpose was to determine if movement stability created by the bandwidth manipulation is associated with increased GMP learning and if bandwidth KR interacts with constant and variable practice. Participants were asked to depress four keys sequentially, using the same relative timing structure. Constant practice had one absolute timing requirement, whereas variable practice had three different absolute timing requirements. The results indicated that GMP learning was enhanced by constant practice (independent of the bandwidth KR condition) and by bandwidth KR, when variable practice was used. The findings suggest practice conditions (bandwidth KR, constant practice) that increase movement stability during practice enhance GMP learning. Parameter learning (during transfer), however, was enhanced by variable practice. Experiment 2 attempted to determine how constant and variable practice conditions could be combined to enhance both GMP and parameter learning. The results indicated that developing a stable GMP early in practice--by providing learners with constant practice early in practice--and refining parameter learning later in practice--by providing them with variable practice late in practice--were effective for both GMP and parameter learning. This suggests a hierarchy in the development of programmed actions with a stable GMP being a requisite for developing an effective and stable parameter rule.


Adjunctive Approaches to Aphasia Rehabilitation: A Review on Efficacy and Safety.
Aphasia is one of the most socially disabling post-stroke deficits. Although traditional therapies have been shown to induce adequate clinical improvement, aphasic symptoms often persist. Therefore, unconventional rehabilitation techniques which act as a substitute or as an adjunct to traditional approaches are urgently needed. The present review provides an overview of the efficacy and safety of the principal approaches which have been proposed over the last twenty years. First, we examined the effectiveness of the pharmacological approach, principally used as an adjunct to language therapy, reporting the mechanism of action of each single drug for the recovery of aphasia. Results are conflicting but promising. Secondly, we discussed the application of Virtual Reality (VR) which has been proven to be useful since it potentiates the ecological validity of the language therapy by using virtual contexts which simulate real-life everyday contexts. Finally, we focused on the use of Transcranial Direct Current Stimulation (tDCS), both discussing its applications at the cortical level and highlighting a new perspective, which considers the possibility to extend the use of tDCS over the motor regions. Although the review reveals an extraordinary variability among the different studies, substantial agreement has been reached on some general principles, such as the necessity to consider tDCS only as an adjunct to traditional language therapy.


Polypharmacy in nursing home residents with severe cognitive impairment: results from the SHELTER Study.
Pharmacological treatment of older adults with cognitive impairment represents a challenge for prescribing physicians, and polypharmacy is common in these complex patients. The aim of the current study is to assess prevalence and factors related to polypharmacy in a sample of nursing home (nursing home) residents with advanced cognitive impairment. We conducted a cross-sectional analysis of 1449 nursing home residents with advanced cognitive impairment participating to the Services and Health for Elderly in Long Term Care (SHELTER) project, a study collecting information on residents admitted to 57 nursing home in eight countries. Data were collected using the International Resident Assessment Instrument (InterRAI) for long-term care facilities. Polypharmacy status was categorized into three groups: nonpolypharmacy (zero to four drugs), polypharmacy (five to nine drugs), and excessive polypharmacy (≥10 drugs). Polypharmacy was observed in 735 residents (50.7%) and excessive polypharmacy was seen in 245 (16.9%). Compared with nonpolypharmacy, excessive polypharmacy was associated directly with ischemic heart disease (odds ratio [OR], 3.68; 95% confidence interval [CI], 2.01-6.74), diabetes mellitus (OR, 2.66; 95% CI; 1.46-4.84), Parkinson's disease (OR, 2.84; 95% CI, 1.36-5.85), gastrointestinal symptoms (OR, 1.20; 95% CI, 1.43-3.39), pain (OR, 3.12; 95% CI, 1.99-4.89), dyspnea (OR, 2.57; 95% CI, 1.31-5.07), and recent hospitalization (OR, 2.56; 95% CI, 1.36-5.85). An inverse relation with excessive polypharmacy was shown for age (OR, 0.74; 95% CI, 0.59-0.93), activities of daily living disability (OR, 0.79; 95% CI, 0.63-0.99) and presence of a geriatrician on the nursing home staff (OR, 0.36; 95% CI, 0.20-0.64). Polypharmacy and excessive polypharmacy are common among nursing home residents with advanced cognitive impairment. Determinants of polypharmacy status includes not only comorbidities, but also specific symptoms, age, and functional status. A geriatrician in the facility is associated with lower prevalence of excessive polypharmacy.


Vitamin D-resistant diseases.
Hereditary vitamin D receptor defects (HVDRDs) is a more appropriate and precise title for an inborn error of metabolism commonly known as pseudo-vitamin D deficiency or vitamin D dependency, type II. It is a rare autosomal recessive disorder, approximately 70 kindreds were described, but its main importance is elucidating the physiology of vitamin D and calcium homeostasis in humans. Patients usually develop the clinical and biochemical aberrations, identical to vitamin D deficiency, but with high serum levels of calcitriol, within the first year of life (i.e., muscle weakness, bone pain, deformities, and fractures). Defective calcium gut absorption leads to hypocalcemia, secondary hyperparathyroidism, hypophosphatemia, and defective mineralization of newly formed bone matrix. The disease is not cured by vitamin D replacement therapy, although some patients respond to very high doses of vitamin D or its metabolites. Cells derived from patients, mainly cultured skin fibroblasts, were used to assess steps in calcitriol action from cellular uptake to bioresponse and to elucidate the molecular aberrations in the vitamin D receptor (VDR). Point mutations in the VDR gene were identified in every patient examined, and the same defect was observed in the obligatory heterozygotes. The functional characterization of the patient's VDR reflected the localization of the mutation (18 different ones described to date), thus providing vital information about the structure-function relationship in the human VDR and the essentiality of the VDR as the mediator of vitamin D action.


The role of triterpenoid on reactive oxygen scavenging system: approach from the new chemiluminescence system (XYZ system).
We propose that the reactive oxygen species/hydrogen donor/mediator system (XYZ system) is a new chemiluminescence system for the measurement of reactive oxygen scavenging activity. By using this method, we demonstrated the role of triterpenoid on a reactive oxygen scavenging system. DDMP (2,3-dihydro-2,5-dihydroxy-6-methyl-4H-pyran-4-one) conjugated saponin from soybean, produced a low level light emission in the presence of H202 (X) and gallic acid (Y). The soybean saponin acted as a mediator (Z) on the reactive oxygen scavenging system. When comparing the data of photon emission properties of saponin with that of cholic acids, it concludes that DDMP moiety of soybean saponin plays an important role rather than the aglycon moiety in the radical scavenging system.


The behaviour of ashes and heavy metals during the co-combustion of sewage sludges in a fluidised bed.
Co-combustion tests of dry sewage sludges with coal were performed in a pilot bubbling FBC aiming at the characterization of ashes and determining the behaviour of heavy metals in the process. The tests showed compliance with the regulatory levels as far as heavy metal emissions were concerned. The bottom ashes, which accounted for about 70% of the total ash production, were obtained in a granular form, with diameters ranging from 0.5 to 4 mm. The heavy metals were distributed in ashes obtained from different locations of the installation and their concentrations were found to vary depending on the location of capture. The increase in heavy metals content in bottom ashes was not found to lead to higher leachability and ecotoxicity compared to sewage sludges, suggesting that there could be opportunities for their further use. Mercury suffered vaporisation inside the reactor, thus leaving bottom ashes free of contamination by it. However, there was observed a strong retention of mercury in cyclone ashes due to the presence of unburned carbon which probably acted as an adsorbent. The effluent mercury was also found to be mostly associated with the particulate fraction, being less than 20% emitted in gaseous forms. The results suggested that the combustion of the sewage sludge could successfully be carried out and the amount of unburned carbon leaving the combustor but captured in cyclone was large enough to ensure substantial retention of mercury at low temperatures, hence could contribute to an improvement of the mercury release which still remains an issue of great concern to resolve during combustion of waste materials.


Visual localization in dyslexia.
Individuals with specific reading disability (SRD) may exhibit visual psychophysical abnormalities that include prolonged visual persistence, decreased luminance contrast sensitivity, lower flicker fusion thresholds, abnormal metacontrast masking, and lower motion detection sensitivity. These abnormalities could result from impairment of the magnocellular division of the visual afferent pathway to the cortex. The authors predicted that an impairment of this pathway would also cause abnormalities in ability to localize visual stimuli. This prediction was tested in 2 experiments. Results of both experiments showed that adults who reported a history of SRD and who currently had lower reading performance were less able than non-SRD participants to report the locations of small visual stimuli that were briefly flashed at positions similar to the ends of lines of text.


Relationship between EGFR mutations and clinicopathological features of lung adenocarcinomas diagnosed via small biopsies.
We performed this study to evaluate the frequency of epidermal growth factor receptor (EGFR) mutations and their association with the histological subtype of lung adenocarcinoma diagnosed via small biopsy specimens. Three hundred and fifty-nine lung adenocarcinoma specimens were tested for EGFR mutation by a direct sequencing method. In 135 patients, histological subtypes were classified according to the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. We compared the EGFR mutation frequency by clinicopathological characteristics. We detected 135 (37.6%) EGFR mutations and the incidence was highest in women who never smoked (54.6%). With regard to histological subtype, the highest prevalence of EGFR mutation was found in papillary (81.3%), followed by lepidic (70.4%), acinar (58.1%) and solid (28.3%) tumor types. In addition, the expression of thyroid transcription factor-1 was significantly higher in tumors with the EGFR mutation than in those without (p<0.001). The histological subtype of adenocarcinoma can be predictive of existing EGFR mutation, although the histology was confirmed using only small biopsies.


Chronic kidney disease predicts impaired membrane microviscosity of red blood cells in hypertensive and normotensive subjects.
Current evidence indicates that abnormalities in physical properties of the cell membranes may be strongly linked to hypertension and other circulatory disorders. Recent studies have shown that chronic kidney disease (CKD) might be a risk factor for cardiovascular and cerebrovascular outcomes. The purpose of the present study was to examine the possible relationship between kidney function and membrane fluidity (a reciprocal value of membrane microviscosity) of red blood cells (RBCs) in hypertensive and normotensive subjects using an electron spin resonance (ESR) and spin-labeling method. The order parameter (S) for the ESR spin-label agent (5-nitroxide stearate) in RBC membranes was significantly higher in hypertensive subjects than in normotensive subjects, indicating that membrane fluidity was decreased in hypertension. The order parameter (S) of RBCs was inversely correlated with estimated glomerular filtration rate (eGFR), suggesting that a decreased eGFR value might be associated with reduced membrane fluidity of RBCs. Multivariate regression analysis also demonstrated that, after adjustment for general risk factors, eGFR might be a significant predictor of membrane fluidity of RBCs. The reduced levels of both membrane fluidity of RBCs and eGFR were associated with increased plasma 8-iso-prostaglandin F2α (an index of oxidative stress) and decreased plasma nitric oxide (NO)-metabolites, suggesting that kidney function could be a determinant of membrane microviscosity of RBCs, at least in part, via oxidative stress- and NO-dependent mechanisms. The ESR study suggests that CKD might have a close correlation with impaired rheologic behavior of RBCs and microcirculatory disorders in hypertensive subjects.


Validating a Numerical Simulation of the ConsiGma(R) Coater.
Continuous manufacturing is increasingly used in the pharmaceutical industry, as it promises to deliver better product quality while simultaneously increasing production flexibility. GEA developed a semi-continuous tablet coater which can be integrated into a continuous tableting line, accelerating the switch from traditional batch production to the continuous mode of operation. The latter offers certain advantages over batch production, e.g., operational flexibility, increased process/product quality, and decreased cost. However, process understanding is the key element for process control. In this regard, computational tools can improve the fundamental understanding and process performance, especially those related to new processes, such as continuous tablet coating where process mechanics remain unclear. The discrete element method (DEM) and computational fluid dynamics (CFD) are two methods that allow transition from empirical process design to a mechanistic understanding of the individual process units. The developed coupling model allows to track the heat, mass, and momentum exchange between the tablet and fluid phase. The goal of this work was to develop and validate a high-fidelity CFD-DEM simulation model of the tablet coating process in the GEA ConsiGma® coater. After the model development, simulation results for the tablet movement, coating quality, and heat and mass transfer during the coating process were validated and compared to the experimental outcomes. The experimental and simulation results agreed well on all accounts measured, indicating that the model can be used in further studies to investigate the operating space of the continuous tablet coating process.


Rebound intragastric hyperacidity after abrupt withdrawal of histamine H2 receptor blockade.
In a series of 24 hour studies, intragastric acidity and plasma gastrin concentration were measured simultaneously in 46 healthy subjects before, during, and 24 to 48 hours after abrupt withdrawal of a histamine H2 receptor antagonist regimen. For 34 days subjects were given either cimetidine 800 mg at night (n = 8), ranitidine 150 mg twice daily (n = 10), ranitidine 300 mg at night (n = 12), nizatidine 300 mg at night (n = 8), or famotidine 40 mg at night (n = 8). All subjects responded to H2 blockade by a decrease in 24 hour intragastric acidity. Withdrawal of H2 blockade resulted in a significant rise in median nocturnal integrated intragastric acidity in 42 of 46 subjects (+36%; 95% CI +19, +55%) compared with prestudy values, but this rise was not associated with a significant change in the median integrated plasma gastrin concentration (+1%; 95% CI -12, +13%). A statistically significant rise in nocturnal acidity was observed after all regimens, except after dosing with famotidine. After stopping, median daytime integrated acidity and plasma gastrin concentrations in the whole group were raised, but not significantly: values were +15% (95% CI +4, +34%) and +5% (95% CI -2, +12%), respectively. A statistically significant increase in daytime acidity was observed only after dosing with ranitidine. In conclusion, intragastric hyperacidity occurs in most subjects after abrupt withdrawal of a histamine H2 receptor blocker, but this phenomenon is not associated with hypergastrinaemia.


Endoscopic endonasal access to the lateral recess of the sphenoid sinus.
The standard endoscopic endonasal approach gives access to the median sphenoid sinus, but not to its lateral part. We propose an endoscopic technique for lesions in the lateral sphenoid sinus. Based on our experience with 28 patients, we have developed a less invasive approach to the lateral recess of the sphenoid sinus, limiting the opening of the maxillary sinus while avoiding resection of the inferior turbinate and ethmoidal cells. The technique is described. The proposed endoscopic approach is reliable and safe to treat CSF leak or tumours located within the lateral recess of the sphenoid sinus.


Effect of Physician-Pharmacist Participation in the Management of Ambulatory Cancer Pain Through a Digital Health Platform: Randomized Controlled Trial.
Self-management of ambulatory cancer pain is full of challenges. Motivated by the need for better pain management, we developed a WeChat-supported platform, Medication Housekeeper (MediHK), to enhance communication, optimize outcomes, and promote self-management in the home setting. We conducted a randomized controlled trial to assess whether the joint physician-pharmacist team through MediHK would provide better self-management of ambulatory patients with cancer pain. Patients were randomly assigned to either an intervention group or control group. During the 4-week study period, the pharmacist would send 24-hour pain diaries daily, adverse drug reaction (ADR) forms every 3 days, and the Brief Pain Inventory form every 15 days to patients in the intervention group via MediHK. If a patient needed a change in drug/dosage or treatment of an ADR after the comprehensive review, the pharmacist would propose pharmacological interventions to the attending physician, who was then responsible for prescribing or adjusting pain medications. If no adjustments were needed, the pharmacist provided appropriate targeted education based on knowledge deficits. Patients in the control group received conventional care and did not receive reminders to fill out the forms. However, if the control group patients filled out a form via MediHK, the pain management team would review and respond in the same way as for the intervention group. The primary outcomes included pain intensity and pain interference in daily life. Secondary outcomes included patient-reported outcome measures, medication adherence, ADRs, and rehospitalization rates. A total of 100 patients were included, with 51 (51%) in the intervention group and 49 (49%) in the control group. The worst pain scores, least pain scores, and average pain scores in the intervention group and the control group were statistically different, with median values of 4 (IQR 3-7) vs 7 (IQR 6-8; P=.001), 1 (IQR 0-2) vs 2 (IQR 1-3; P=.02), and 2 (IQR 2-4) vs 4 (IQR 3-5; P=.001), respectively, at the end of the study. The pain interference on patients' general activity, mood, relationships with others, and interests was reduced, but the difference was not statistically significant compared with the control group (Ps=.10-.76). The medication adherence rate increased from 43% to 63% in the intervention group, compared with an increase of 33% to 51% in the control group (P<.001). The overall number of ADRs increased at 4 weeks, and more ADRs were monitored in the intervention group (P=.003). Rehospitalization rates were similar between the 2 groups. The joint physician-pharmacist team operating through MediHK improved pain management. This study supports the feasibility of integrating the internet into the self-management of cancer pain. Chinese Clinical Trial Registry ChiCTR1900023075; https://www.chictr.org.cn/showproj.aspx?proj=36901.


An Innovation to Expand the Reach of Peer Support: A Feasibility and Acceptability Study.
Peer support is a well-established part of veteran care and a cost-effective way to support individuals pursuing health behavior change. Common models of peer support, peer coaching, and mutual peer support have limitations that could be minimized by building on the strengths of each to increase the overall reach and effectiveness. We conducted a 12-week, proof-of-concept study to test the acceptability and feasibility of a hybrid model of peer support which supplements dyadic mutual peer support with as-needed peer coaching. We tested our novel peer support model within the context of cardiovascular disease (CVD) risk reduction as a support mechanism for the promotion of heart-healthy diet and exercise behaviors. We recruited peer buddies (participants who would be matched with each other to provide mutual support) with at least one uncontrolled CVD risk factor (i.e., blood pressure, weight, or diabetes) and peer coaches (individuals who would provide additional, as-needed support for peer buddies) with a recent history of CVD health behavior improvement. We aimed for 50% of peer buddies to be women to assess for potential gender differences in intervention engagement. Participants received didactic instruction during three group sessions, and peer dyads were instructed to communicate weekly with their peer buddy to problem-solve around action plans and behavioral goals. We tracked frequency of dyadic communication and conducted semi-structured interviews at the intervention's end to assess acceptability. We recruited three peer coaches and 12 peer buddies. Ten buddies (five dyads) met at the first group session, and all were still in weekly contact with each other at week 12. Peer buddies had a mean of 8.75 out of 12 possible weekly peer buddy communications (range 6-15 in total). Peer coaches provided additional support to four participants over 12 weeks. Participants reported liking the intervention, including mixed-gender groups. Clarity and expectation setting around the role of peer coaches were important. The supplementation of mutual peer support with as-needed peer coaching is an acceptable and feasible way to expand the potential reach and effectiveness of peer support for behavior change among veterans.


Regional scalp block for postcraniotomy analgesia: a systematic review and meta-analysis.
Up to two-thirds of patients report moderate to severe surgical site pain after craniotomy procedures, and there is understandable reluctance to manage these symptoms with systemic opioids that may impair neurological assessment. Furthermore, there is a lack of consensus and evidence concerning alternative analgesia strategies for cranial neurosurgery. Regional scalp block (RSB) is an established technique that involves infiltration of local anesthetic (LA) at well-defined anatomical sites targeting the major sensory innervation of the scalp. However, the efficacy of RSB in reducing postoperative pain remains unclear. In this study, we sought to systematically identify and review randomized controlled trials (RCTs) of RSB and synthesize an overall estimate of efficacy in a quantitative meta-analysis. Medline, EMBASE, and the Cochrane Central Register of Controlled Trials databases were searched for all RCTs evaluating the effect of RSB on postoperative pain after craniotomy. Titles, abstracts, and papers were reviewed independently by 2 authors against predefined inclusion criteria. Two authors independently assessed the quality of included studies and extracted data on patient-reported pain scores, other analgesia requirements, and complications of RSB. Pain scores were scaled to a common 0 to 10 interval with higher scores indicating more severe pain. Meta-analysis of the pooled treatment effect was performed with a random-effects inverse-variance weighted model; heterogeneity was quantified with the I(2) statistic. The literature search identified 138 unique citations, from which 7 RCTs with a total recruitment of 320 patients met the inclusion criteria. All studies used standard LA drugs (lidocaine, bupivacaine, or ropivacaine); in 3 studies, LA was combined with epinephrine. In 3 studies, RSB was performed preoperatively; in the other 4 studies, it was administered postoperatively after wound closure. No complications attributable to RSB were reported. Meta-analysis found a pooled reduction in pain score at 1 hour postoperatively (N = 5 studies; mean difference, -1.61; 95% confidence interval, -2.06 to -1.15; P < 0.001; I(2) = 0%). Subgroup analysis of preoperative RSB showed significant reduction in pain scores at 2, 4, and 6 to 8 hours after surgery whereas postoperative RSB was associated with significant reduction in pain scores at 2, 4, 6 to 8 and 12 hours assessments. There was also an overall reduction in the opioid requirements over the first 24 hours postoperatively, although with significant heterogeneity among the studies (N = 6 studies; standardized mean difference, -0.79; 95% confidence interval, -1.55 to -0.03; P = 0.04; I(2) = 86%). Published RCTs of RSB are small and of limited methodological quality but meta-analysis shows a consistent finding of reduced postoperative pain. This evidence supports the use of RSB for patients undergoing craniotomy.


Neural correlates of binaural masking level difference in the inferior colliculus of the barn owl (Tyto alba).
Humans and animals are able to detect signals in noisy environments. Detection improves when the noise and the signal have different interaural phase relationships. The resulting improvement in detection threshold is called the binaural masking level difference. We investigated neural mechanisms underlying the release from masking in the inferior colliculus of barn owls in low-frequency and high-frequency neurons. A tone (signal) was presented either with the same interaural time difference as the noise (masker) or at a 180 degrees phase shift as compared with the interaural time difference of the noise. The changes in firing rates induced by the addition of a signal of increasing level while masker level was kept constant was well predicted by the relative responses to the masker and signal alone. In many cases, the response at the highest signal levels was dominated by the response to the signal alone, in spite of a significant response to the masker at low signal levels, suggesting the presence of occlusion. Detection thresholds and binaural masking level differences were widely distributed. The amount of release from masking increased with increasing masker level. Narrowly tuned neurons in the central nucleus of the inferior colliculus had detection thresholds that were lower than or similar to those of broadly tuned neurons in the external nucleus of the inferior colliculus. Broadly tuned neurons exhibited higher masking level differences than narrowband neurons. These data suggest that detection has different spectral requirements from localization.


Acute abducens nerve palsy as a presenting feature in carotid-cavernous fistula in a 6-year-old girl.
Carotid-cavernous fistulas (CCF) are abnormal communications between the internal carotid artery and the cavernous sinus. Traumatic carotid-cavernous fistulae are rare potential complications of craniofacial trauma. Typical findings of CCF are proptosis, chemosis, headache, oculomotor or abducens nerve palsy, trigeminal pain and pulsating bruit over the temporal skull and the bulb. CCF are reported very rarely in childhood. This report describes the clinical and radiological findings of a pediatric patient presented with CCF.


Traversing the fungal terpenome.
Fungi (Ascomycota and Basidiomycota) are prolific producers of structurally diverse terpenoid compounds. Classes of terpenoids identified in fungi include the sesqui-, di- and triterpenoids. Biosynthetic pathways and enzymes to terpenoids from each of these classes have been described. These typically involve the scaffold generating terpene synthases and cyclases, and scaffold tailoring enzymes such as e.g. cytochrome P450 monoxygenases, NAD(P)+ and flavin dependent oxidoreductases, and various group transferases that generate the final bioactive structures. The biosynthesis of several sesquiterpenoid mycotoxins and bioactive diterpenoids has been well-studied in Ascomycota (e.g. filamentous fungi). Little is known about the terpenoid biosynthetic pathways in Basidiomycota (e.g. mushroom forming fungi), although they produce a huge diversity of terpenoid natural products. Specifically, many trans-humulyl cation derived sesquiterpenoid natural products with potent bioactivities have been isolated. Biosynthetic gene clusters responsible for the production of trans-humulyl cation derived protoilludanes, and other sesquiterpenoids, can be rapidly identified by genome sequencing and bioinformatic methods. Genome mining combined with heterologous biosynthetic pathway refactoring has the potential to facilitate discovery and production of pharmaceutically relevant fungal terpenoids.


Caries inhibition with a CO2 9.3 μm laser: An in vitro study.
The caries preventive effects of different laser wavelengths have been studied in the laboratory as well as in pilot clinical trials. The objective of this in vitro study was to evaluate whether irradiation with a new 9.3 μm microsecond short-pulsed CO2 -laser could enhance enamel caries resistance with and without additional fluoride applications. One hundred and one human tooth enamel samples were divided into seven groups. Each group was treated with different laser parameters (CO2 -laser, wavelength 9.3 μm, 43 Hz pulse-repetition rate, pulse duration between 3 µs at 1.5 mJ/pulse to 7 µs at 2.9 mJ/pulse). A laboratory pH-cycling model followed by cross-sectional microhardness testing determined the mean relative mineral loss delta Z (ΔZ) for each group to assess caries inhibition in tooth enamel by the CO2 9.3 µm short-pulsed laser irradiation. The pH-cycling was performed with or without additional fluoride. The non-laser control groups with additional fluoride had a relative mineral loss (ΔZ, vol% × µm) that ranged between 646 ± 215 and 773 ± 223 (mean ± SD). The laser irradiated and fluoride treated samples had a mean ΔZ ranging between 209 ± 133 and 403 ± 245 for an average 55% ± 9% reduction in mineral loss (ANOVA test, P < 0.0001). Increased mean mineral loss (ΔZ between 1166 ± 571 and 1339 ± 347) was found for the non-laser treated controls without additional fluoride. In contrast, the laser treated groups without additional fluoride showed a ΔZ between 470 ± 240 and 669 ± 209 (ANOVA test, P < 0.0001) representing an average 53% ± 11% reduction in mineral loss. Scanning electron microscopical assessment revealed that 3 µs pulses did not markedly change the enamel surface, while 7 µs pulses caused some enamel ablation. The CO2 9.3 µm short-pulsed laser energy renders enamel caries resistant with and without additional fluoride use. The observed enhanced acid resistance occurred with the laser irradiation parameters used without obvious melting of the enamel surface as well as after irradiation with energies causing cutting of the enamel. Lasers Surg. Med. 48:546-554, 2016. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.


Involvement of the aphthovirus RNA region located between the two functional AUGs in start codon selection.
Initiation of translation in picornavirus RNAs occurs internally, mediated by an element termed internal ribosome entry site (IRES). In the aphthovirus RNA, the IRES element directs translation initiation at two in-frame AUGs separated by 84 nucleotides. We have found that bicistronic constructs that contained the IRES element followed by the fragment including the aphthovirus start codons in front of the second gene mimicked the translation initiation pattern of viral RNA observed in infected cells. In those constructs, the frequency of initiation at the first AUG was increased by a sequence context that resembled the favorable consensus for cap-dependent translation, although initiation at the second site was always preferred. In addition, we have found that initiation at the second start codon was not diminished under conditions in which the first initiation codon was blocked by antisense oligonucleotide interference. Interestingly, mutations that positioned the second AUG out-of-frame with the first AUG did not interfere with the frequency of initiation at the second one. On the contrary, IRES-dependent translation initiation in bicistronic constructs lacking the sequences present between functional AUGs in the viral RNA was sensitive to the presence of out-of-frame initiator codons and hairpins in the spacer region. This remarkable difference in start codon recognition was due to the nucleotide composition of the RNA that separated the IRES from the initiator codon. Thus our results indicate that the region located in the aphthovirus RNA between functional AUGs is involved in start codon recognition, strongly favoring selection of the second start AUG as the main initiator codon.


Porcine oocyte activation induced by a cytosolic sperm factor.
It is not known how the fertilizing sperm elicits the release of Ca(2+) from the oocyte's intracellular stores. We investigated whether a crude extract isolated from boar sperm could induce the Ca(2+) release and trigger subsequent early and late activation events upon injection into matured porcine oocytes. The sperm extract induced an immediate rise in the intracellular free Ca(2+) concentration in all oocytes tested, which was followed by repetitive Ca(2+) transients in 11 out of 14 oocytes. Heat or trypsin treatment of the extract totally abolished the Ca(2+) releasing activity of the sperm factor. The injected oocytes showed cortical granule exocytosis, they resumed meiosis and entered first interphase: pronuclei were formed in 89.2% (132/148) of the cases. Pronuclear formation was accompanied by the appearance of a new 22 kDa protein as normally seen at fertilization. Of the successfully injected oocytes 51.7% (105/203) cleaved and 2.0% (4/203) developed to the blastocyst stage after being cultured for 7 days in NCSU 23 medium. Injection of the carrier medium could not trigger these changes. The results indicate that the sperm might activate porcine oocytes by introducing a soluble factor into the oocyte's cytoplasm after gamete fusion.


Evolving Approaches to Meet Clinical Hours for Undergraduate Nursing Students during COVID-19.
The COVID-19 pandemic challenged all healthcare professionals to re-think how patient care is provided. Faculty in nursing schools faced similar challenges in offering adequate clinical hours to nursing students, because of the limited availability of clinical placements. A faculty in one school of nursing introduced virtual simulation resources to supplement in-person clinical hours. The faculty developed a revised clinical curriculum for students that included weekly objectives and deliverables for virtual simulations. The Simulation Effectiveness Tool-Modified (SET-M) was utilized to evaluate the effectiveness of the virtual simulations. 130 students (88.4%) completed the post-implementation survey. After using the virtual simulations, 50% of the students reported feeling confident in providing interventions that foster patient safety. Furthermore, students reported a sound understanding of disease pathophysiology (60%) and medications (53.8%). The qualitative data indicated that students found the virtual simulations beneficial and a safe learning environment. Pre-pandemic virtual simulations were not used by this school of nursing to replace the traditional in-person clinical experiences. However, the pandemic demonstrated that the utilization of innovative virtual simulations are effective methods for student learning to augment traditional clinical experiences.


NO from smooth muscle cells decreases NOS expression in endothelial cells: role of TNF-alpha.
Despite the evidence that cytokines stimulate nitric oxide (NO) production by inducible nitric oxide synthase (iNOS), several reports recently demonstrated that the hypotensive response related to endothelial nitric oxide synthase (eNOS) activity could be inhibited by the same cytokines. The aim of the present work was to analyze whether NO generated by vascular smooth muscle cells (VSMC) could modify eNOS protein expression in endothelial cells. Bovine aortic endothelial cells (BAEC) and bovine VSMC (BVSMC) in coculture were used for the study. Interleukin-1beta (IL-1beta, 10 ng/ml)-treated BVSMC, which expressed iNOS protein, decreased eNOS protein expression in BAEC. The presence of NO antagonists N(omega)-nitro-L-arginine methyl ester (10(-3) mol/l) or N(G)-monomethyl-L-arginine (10(-3) mol/l) prevented the decrease in eNOS protein expression induced by IL-1beta-treated BVSMC. Surprisingly, two different NO donors, 3-morpholinosydnonimine (10(-4) mol/l) and S-nitroso-N-acetyl-D,L-penicillamine (10(-4) mol/l), failed to modify eNOS expression in BAEC, suggesting the existence of a diffusible mediator released from IL-1beta-treated BVSMC that acts on endothelial cells by reducing eNOS expression. The presence of NO antagonists reduced tumor necrosis factor-alpha (TNF-alpha) production by IL-1beta-stimulated BVSMC. This effect was also produced in the presence of a protein kinase G inhibitor, guanosine-5'-O-(2-thiodiphosphate) trilithium salt. A polyclonal antibody against TNF-alpha prevented eNOS expression in the BAEC-BVSMC coculture. In conclusion, NO by itself failed to modify eNOS protein expression in endothelial cells but increased TNF-alpha generation by IL-1beta-stimulated BVSMC and, in this way, reduced eNOS expression in the endothelium.


Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity.
Increased susceptibility to 5-fluorouracil (5-FU)/capecitabine can lead to rapidly occurring toxicity caused by impaired clearance, dihydropyrimidine dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5-FU. Life-threatening 5-FU overdoses occur because of infusion pump errors, dosage miscalculations, and accidental or suicidal ingestion of capecitabine. Uridine triacetate (Vistogard) was approved in 2015 for adult and pediatric patients who exhibit early-onset severe or life-threatening 5-FU/capecitabine toxicities or present with an overdose. Uridine triacetate delivers high concentrations of uridine, which competes with toxic 5-FU metabolites. In 2 open-label clinical studies, patients who presented with a 5-FU/capecitabine overdose or an early onset of severe toxicities were treated. Patients received uridine triacetate as soon as possible (most within the first 96 hours after 5-FU/capecitabine). Outcomes included survival, resumption of chemotherapy, and safety. Their survival was compared with the survival of a historical cohort of overdose patients who received only supportive care. A total of 137 of 142 overdose patients (96%) treated with uridine triacetate survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity; in addition, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical cohort, 21 of 25 patients (84%) died. Among the 141 uridine triacetate-treated overdose patients with a diagnosis of cancer (the noncancer patients included 6 intentional or accidental pediatric overdoses), 53 resumed chemotherapy in < 30 days (median time after 5-FU, 19.6 days), and this indicated a rapid recovery from toxicity. Adverse reactions in patients receiving uridine triacetate included vomiting (8.1%), nausea (4.6%), and diarrhea (3.5%). In these studies, uridine triacetate was a safe and effective lifesaving antidote for capecitabine and 5-FU overexposure, and it facilitated the rapid resumption of chemotherapy. Cancer 2017;123:345-356. © 2016 American Cancer Society.


Highly efficient phosphor-converted white organic light-emitting diodes with moderate microcavity and light-recycling filters.
We demonstrate the combined effects of a microcavity structure and light-recycling filters (LRFs) on the forward electrical efficiency of phosphor-converted white organic light-emitting diodes (pc-WOLEDs). The introduction of a single pair of low- and high-index layers (SiO(2)/TiO(2)) improves the blue emission from blue OLED and the insertion of blue-passing and yellow-reflecting LRFs enhances the forward yellow emission from the YAG:Ce(3+) phosphors layers. The enhancement of the luminous efficacy of the forward white emission is 1.92 times that of a conventional pc-WOLED with color coordinates of (0.34, 0.34) and a correlated color temperature of about 4800 K.


6-Bromoindirubin-3'-oxime inhibits JAK/STAT3 signaling and induces apoptosis of human melanoma cells.
STAT3 is persistently activated and contributes to malignant progression in various cancers. Janus activated kinases (JAK) phosphorylate STAT3 in response to stimulation by cytokines or growth factors. The STAT3 signaling pathway has been validated as a promising target for development of anticancer therapeutics. Small-molecule inhibitors of JAK/STAT3 signaling represent potential molecular-targeted cancer therapeutic agents. In this study, we investigated the role of JAK/STAT3 signaling in 6-bromoindirubin-3'-oxime (6BIO)-mediated growth inhibition of human melanoma cells and assessed 6BIO as a potential anticancer drug candidate. We found that 6BIO is a pan-JAK inhibitor that induces apoptosis of human melanoma cells. 6BIO directly inhibited JAK-family kinase activity, both in vitro and in cancer cells. Apoptosis of human melanoma cells induced by 6BIO was associated with reduced phosphorylation of JAKs and STAT3 in both dose- and time-dependent manners. Consistent with inhibition of STAT3 signaling, expression of the antiapoptotic protein Mcl-1 was downregulated. In contrast to the decreased levels of phosphorylation of JAKs and STAT3, phosphorylation levels of the Akt and mitogen-activated protein kinase (MAPK) signaling proteins were not inhibited in cells treated with 6BIO. Importantly, 6BIO suppressed tumor growth in vivo with low toxicity in a mouse xenograft model of melanoma. Taken together, these results show that 6BIO is a novel pan-JAK inhibitor that can selectively inhibit STAT3 signaling and induces tumor cell apoptosis. Our findings support further development of 6BIO as a potential anticancer therapeutic agent that targets JAK/STAT3 signaling in tumor cells.


Variation in intravenous iron use internationally and over time: the Dialysis Outcomes and Practice Patterns Study (DOPPS).
To examine patterns of intravenous (IV) iron use across 12 countries from 1999 to 2011. Trends in iron use are described among 32 192 hemodialysis (HD) patients in the Dialysis Outcomes and Practice Patterns Study. Adjusted associations of IV iron dose with serum ferritin and transferrin saturation (TSAT) values were also studied. IV iron was administered to 50% of patients over 4 months in 1999, increasing to 71% during 2009-11, with increasing use in most countries. Among patients receiving IV iron, the mean monthly dose increased from 232 ± 167 to 281 ± 211 mg. Most countries used 3 to 4 doses/month, but Canada used about 2 doses/month, Italy increased from 3 to almost 6 doses/month and Germany used 5 to 6 doses/month. The USA and most European countries predominantly used iron sucrose and sodium ferric gluconate. A significant use of iron dextran was limited to Canada and France; iron polymaltose was used in Australia and New Zealand; and Japan used ferric oxide saccharate, chondroitin polysulfate iron complex and cideferron. Ferritin values rose in most countries: 22% of patients had ≥ 800 ng/mL in the recent years of study. TSAT levels increased to a lesser degree over time. Japan had much lower IV iron dosing and ferritin levels, but similar TSAT levels. In adjusted analyses, serum ferritin and TSAT levels increased signifcantly by 14 ng/mL and 0.16%, respectively, for every 100 mg/month higher mean monthly iron dose. IV iron prescription patterns varied between countries and changed over time from 1999 to 2011. IV iron use and dose increased in most countries, with notable increases in ferritin but not TSAT levels. With rising cumulative IV iron doses, studies of the effects of changing IV iron dosing and other anemia management practices on clinical outcomes should be a high priority.


Gold nanoparticle based fluorescent oligonucleotide probes for imaging and therapy in living systems.
Gold nanoparticles (AuNPs) with unique physical and chemical properties have become an integral part of research in nanoscience. In particular, the development of AuNP-based fluorescent oligonucleotide (AuFO) probes targeted at living systems through fluorescence are drawing increasing attention and have become a current hot topic in biomedical research. This review describes recent advances and developments in the use of AuFO probes from their preparation and features that allow the desired intracellular delivery to their applications in cellular imaging and drug delivery in living systems.


Measurement of aortic augmentation index in pregnant women with raised blood pressure and subsequent outcomes: a preliminary prospective cohort study.
Preeclampsia is associated with arterial dysfunction and augmentation index (AIX%) is an established indicator of arterial dysfunction. Our aim was to investigate the relationship of AIX% with time-to-delivery and other outcomes in women admitted to an antenatal triage unit. We recruited 28 women with singleton pregnancies attending antenatal triage ward for assessment of hypertension. After 10 min rest, seated brachial blood pressure (Omron HEM-757) and AIX% (SphygmoCor applanation tonometry pulse wave analysis, PWA) were measured by a single investigator; other clinicians remained blinded to PWA results. Routine assessment included cardiotocography, urine analysis and blood tests. Subsequent outcomes were extracted from the obstetric records. Mean AIX% was 19.7% (SD 11.5; range -4% to +36%), maternal age 31 years, gestation 37 weeks, brachial BP 145/95, proteinuria 39%. Nine women had preeclampsia at assessment and six subsequently developed preeclampsia. Median time-to-delivery was 10 d (IQR 1.6-25 d) and was shorter for AIX% ≥ 20% (median 8.9 versus 19.8 d). AIX% was higher with preeclampsia (24.0%; SD 9.5) versus gestational hypertension (15.2%; SD 12.4); absolute difference 8.8% (95%CI 0.1-17.5; p = 0.05). A one-point higher AIX% (adjusted for age, urate and gestation) was associated with 0.3 d (95%CI -0.5 to 0.0; p = 0.06) reduced time-to-delivery. A higher AIX% was also associated with induction for preeclampsia, severe preeclampsia, peripartum-anti-hypertensives and discharge-on-anti-hypertensives. Area under the curve (AUC) for AIX% predicting preeclampsia was 0.80 (95%CI 0.59-1.00; p = 0.04). AIX% is associated with time-to-delivery and other outcomes in pregnancy.


Genetic analysis of insect bite hypersensitivity (summer eczema) in Icelandic horses.
There is a lack of knowledge about the genetic background of eczema due to insect bite hypersensitivity, also called summer eczema, in horses. The condition is known in several horse breeds and countries and it causes reduced welfare of the horse and economic losses to the owner. The aim of this study was to estimate genetic parameters for summer eczema in Swedish-born Icelandic horses. A questionnaire was sent to owners of horses sired by stallions with more than 50 offspring born in Sweden between 1991 and 2001. Variance components of summer eczema classified as healthy, mild, moderate or severe were estimated using the threshold methodology with sire models. In addition, summer eczema was analysed as a binary trait (healthy v. affected). The analyses included 1250 horses sired by 33 stallions. The prevalence of summer eczema was 8%, with a range of 0% to 30% in different paternal half-sib groups. Offspring of dams suffering from eczema had a higher risk of developing eczema. The heritability for severity of summer eczema was estimated at 0.3 (s.d. < 0.2) with a threshold sire model. In contrast to the age of the horse, different geographic areas and gender were significantly associated with severity of the eczema. We conclude that genetic selection could decrease the prevalence of summer eczema among Swedish-born Icelandic horses. The amount and quality of data are, however, crucial for the possibility to introduce a genetic evaluation of summer eczema. The symptoms should be classified in several classes according to severity, and this classification could be made by the horse owner.


Chromone and donepezil hybrids as new multipotent cholinesterase and monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease.
A series of chromone and donepezil hybrids were designed, synthesized, and evaluated as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential therapy of Alzheimer's disease (AD). In vitro studies showed that the great majority of these compounds exhibited potent inhibitory activity toward BuChE and AChE and clearly selective inhibition for hMAO-B. In particular, compound 5c presented the most balanced potential for ChE inhibition (BuChE: IC50 = 5.24 μM; AChE: IC50 = 0.37 μM) and hMAO-B selectivity (IC50 = 0.272 μM, SI = 247). Molecular modeling and kinetic studies suggested that 5c was a mixed-type inhibitor, binding simultaneously to peripheral and active sites of AChE. It was also a competitive inhibitor, which occupied the substrate and entrance cavities of MAO-B. Moreover, compound 5c could penetrate the blood-brain barrier (BBB) and showed low toxicity to rat pheochromocytoma (PC12) cells. Altogether, these results indicated that compound 5c might be a hopeful multitarget drug candidate with possible impact on Alzheimer's disease therapy.


Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position.
We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. We discovered classes of DNA-binding factors that strictly avoided, could tolerate or tended to overlap with nucleosomes. Using ATAC-seq maps of human CD4(+) T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual's epigenome on a timescale compatible with clinical decision-making.


[Study on treatment of infectious shock with recipe of liqi huoxue and kaibi gutuo].
Based on the pathogenesis of infectious shock which were stagnation of Qi, blood stasis, impairment of body resistance and trends to collapse, a series of new preparations of traditional Chinese Medicine was developed, Injection Kangjue Tongmai, Injection Yiqi Jiuyin and Injection Yiqi Huiyang, which could Liqi Huoxue and Kaibi Gutuo (regulate the flow of Qi, promote blood circulation, strengthen the body resistance and remit collapse), the result of 183 cases of infectious shock treated with them showed that the mortality was 4.37%, significantly lower than that of control group (23.0%). All three injections could rapidly elevate blood pressure and stabilize it for prolonged time, increase renal blood flow and lower blood viscosity. In animal experiment, the injections reduced lipid peroxide of vital organs, stabilized bio-membrane, protected the cell structure and maintained their normal functions.


Functional Annotation of MicroRNAs Using Existing Resources.
MicroRNAs (miRNAs) are endogenous small noncoding RNAs that are involved in most biological signaling pathways, including the cell cycle, apoptosis, proliferation, immune response, metabolism as well as in biological processes including organ development and in human diseases like cancers. During the past two decades, high-throughput transcriptomic profiling using next generation sequencing and microarrays have been extensively utilized to identify differentially expressed miRNAs across different conditions and diseases. A natural extension of miRNA identification is to the process of functionally annotating known or predicted gene targets of those miRNAs and, by inference, revealing their potential influences on diverse biological pathways and functions. In this chapter, we provide a stepwise guideline on how to perform functional enrichment analyses on miRNAs of interest using publicly available resources such as miRWalk2.0.


Lung cancer and type 2 diabetes experience in Dolj County (southwest region of Romania) - a clinical, bioclinical and pathological study.
Type 2 diabetes (T2D) and cancer, the most important public health problems nowadays, and the mechanisms between the presence of diabetes and the development of malignancies remain unclear. The leading cause of cancer death in 2020 is attributed to lung cancer. This study aimed to highlight the impact of the association of these two diseases and the predominant histopathological type of lung cancer in the selected group, glycemic imbalance, and information about the course and outlook for these patients. The authors proposed a case-control 10-year period study, between 2007 and 2017, of two groups of patients diagnosed with T2D and lung cancer who underwent hospitalization at the Clinic of Medical Oncology, Emergency County Hospital, Craiova, Romania. Our study showed a higher incidence of lung adenocarcinoma in patients diagnosed with T2D. The inflammatory syndrome is more pronounced in the diabetic group, which is supported by correlations between lactate dehydrogenase (LDH), albumin, and hemoglobin levels. The duration of cancer treatment in lung cancer and the survival rate is strongly influenced by the presence of diabetes as a concomitant disease.


Development of Phodopus sungorus brown preadipocytes in primary cell culture: effect of an atypical beta-adrenergic agonist, insulin, and triiodothyronine on differentiation, mitochondrial development, and expression of the uncoupling protein UCP.
A new cellular model for the study of brown adipocyte development and differentiation in vitro is presented. Preadipocytes isolated from brown adipose tissue (BAT) of the djungarian dwarf hamster Phodopus sungorus are able to proliferate and differentiate in vitro into true brown adipocytes able to express the BAT marker protein the uncoupling protein (UCP). Whereas basal UCP expression is very low, its mRNA levels as well as the UCP detected by immunoblotting are highly increased by beta-adrenergic stimulation. The novel, atypical beta-adrenergic compound D7114 (ICI Pharmaceuticals, Macclesfield, Cheshire, England) was found to increase the number of adipocytes as well as UCP mRNA and UCP content of mitochondria, indicating the involvement of an atypical or beta 3 receptor. Insulin was found to play an important role in brown adipocyte differentiation and mitochondrial development, whereas T3 seemed to be implicated more directly in UCP expression. In a defined, serum-free medium a synergistic stimulatory action of insulin and T3 on UCP expression was found, which seems to involve a pathway different from that of beta-adrenergic UCP stimulation.


Economic and environmental effects of the manure policy in The Netherlands: synthesis of integrated ex-post and ex-ante evaluation.
This paper summarises the results of both an ex-post evaluation of the Dutch Mineral Accounting System (MINAS) and an ex-ante evaluation of the effect of different levy-free surplus values. The MINAS system has been introduced in 1998 in order to reduce nitrate and phosphate leaching from agricultural soils. MINAS resulted in a reduction of the N surplus on dairy farms of approximately 50 kg ha(-1) to limited or no costs to the farms involved. MINAS resulted in higher costs for manure removal for intensive livestock farmers. Though emissions of N and P have decreased significantly during the last five years effects of this reduction in environmental quality cannot be observed, except for a small decrease in nitrate concentration of the upper groundwater. The ex-ante evaluation of different variants for possible future levy-free surplus levels indicated that under the lowest variant, the nitrate concentration in groundwater will exceed 50 mg per litre on 14% of the area. The environmental effect of the different variants for P were not distinguished. The lowering of the levy-free surplus for P will have a drastic effect on the intensive livestock farms. The incorporation of fertiliser P under the MINAS system would be a cheap option to reduce the P surplus.


Heteroleptic strontium complexes stabilized by donor-functionalized alkoxide and β-diketonate ligands.
Heteroleptic complexes of strontium () were prepared by employing β-diketonates and donor-functionalized alkoxides as coordinating ligands. The results illustrate the effect of alkoxide substituent groups on the overall structures of the complexes. The presence of a terminal methoxy group in the alkoxide ligands leads to the formation of trimeric complexes , whereas the substituents on the amine nitrogen prove to have less influence in determining the structure. The attempts to increase steric bulkiness of the aminoalkoxide ligands by introducing ethyl groups on the amine nitrogen and to the alkoxy carbon did not lead to a structural change from the dimeric form in but resulted in structurally interesting strontium complexes. In trimeric complexes , the three strontium atoms were held together by two μ3-O bonds using alkoxide oxygen atoms and two μ2-O bonds using a combination of alkoxide and β-diketonate ligand oxygens. The strontium metal centers in these complexes exhibit seven-coordination states in and , whereas exhibits one six-coordinated and two seven-coordinated strontium metals in its structure. All of the complexes were characterized using FT-NMR, FT-IR, elemental analyses, and thermogravimetric (TG) analyses.


Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events?
Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions. To explore whether the association between funding and conclusions in randomized drug trials reflects treatment effects or adverse events. Observational study of 370 randomized drug trials included in meta-analyses from Cochrane reviews selected from the Cochrane Library, May 2001. From a random sample of 167 Cochrane reviews, 25 contained eligible meta-analyses (assessed a binary outcome; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment). The primary binary outcome from each meta-analysis was considered the primary outcome for all trials included in each meta-analysis. The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect, adverse events, and additional confounding factors (methodological quality, control intervention, sample size, publication year, and place of publication). Conclusions in trials, classified into whether the experimental drug was recommended as the treatment of choice or not. The experimental drug was recommended as treatment of choice in 16% of trials funded by nonprofit organizations, 30% of trials not reporting funding, 35% of trials funded by both nonprofit and for-profit organizations, and 51% of trials funded by for-profit organizations (P<.001; chi2 test). Logistic regression analyses indicated that funding, treatment effect, and double blinding were the only significant predictors of conclusions. Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice (odds ratio, 5.3; 95% confidence interval, 2.0-14.4) compared with trials funded by nonprofit organizations. This association did not appear to reflect treatment effect or adverse events. Conclusions in trials funded by for-profit organizations may be more positive due to biased interpretation of trial results. Readers should carefully evaluate whether conclusions in randomized trials are supported by data.


Chronic alcoholism enhances hepatocarcinogenicity of diethylnitrosamine in rats fed a marginally methyl-deficient diet.
To determine whether the chronic consumption of ethanol was capable of enhancing the hepatocarcinogenic activity of diethylnitrosamine per se, or through the accentuation of a methyl deficiency, two groups (A and B) of Sprague-Dawley female rats were fed for 10 months either a 20% casein basal diet marginally deficient in methyl, or the same diet supplemented with choline (1 gm per 100 gm) and folic acid (0.54 mg per 100 gm). Both groups were offered a drinking ethanol solution, while two other nonalcohol control groups (C and D) were isocalorically pair-fed to Groups A and B, and received diets in which the alcohol consumed by the corresponding groups was replaced by isocaloric amounts of sucrose. A baseline nonalcohol Group E, isocalorically pair-fed to Group A, received the intact basal diet of Group A and water. One day before the initiation of the experiment, and again 2 months later, all rats from the five groups were injected with a single i.p. dose of diethylnitrosamine (100 mg per kg). The growth attained by all groups was statistically similar. Hepatic triglycerides in Group A were significantly higher than in all the other groups. While in Group A primary hepatocellular carcinomas and renal tumors were encountered at the end of the experiment in 3 of 6 and in 2 of 6 rats, respectively, no malignancies were observed in any of the other groups. These results indicate that chronic ethanol consumption enhances the hepatocarcinogenic and renal tumorigenic activity of diethylnitrosamine, and strongly suggest that this action is mediated through the accentuation of methyl deficiency.


[Effect of pituitary adenyl cyclase activating polypeptide on the cells of anterior pituitary cells].
Pituitary adenylate cyclase activating polypeptide was first isolated from sheep hypothalamus by its potent activity in stimulating cyclic adenosine monophosphate production in anterior pituitary cells. The present review deals with the actions of this polypeptide on anterior pituitary cell types and with the putative role of the polypeptide as a hypophysiotropic factor regulating anterior pituitary cell activity. The evidence to date is strongly suggestive that pituitary adenylate cyclase activating polypeptide may act not as a "classic" hypophysiotropic factor stimulating or modifying anterior pituitary hormone release in vivo, since it does not appear in vitro to be a particularly potent stimulator of hormone release. The polypeptide rather may modulate the responses to factors such as gonadotrop hormone releasing hormone or have more general actions by regulating hormone synthesis or cell differentiation. Pituitary adenylate cyclase activating polypeptide also has indirect actions on anterior pituitary cell activity by stimulating the release of the paracrine factor interleukin-6. Its receptors appear to be present on most of the anterior pituitary cell types and unlike many other hypophysiotropic factors, pituitary adenylate cyclase activating polypeptide interacts with most, if not all, of the anterior pituitary cell types. Its exact effects and mechanisms of action in the anterior pituitary gland are still poorly understood.


Clinical trials and clinical practice: do doctors use the same criteria to judge outcome?
The results of clinical trials often seem to have little influence on the practice of individual doctors. This could be because trial information is presented in the style of a scientific experiment which cannot often be clearly related to the context of everyday patient care. We tested the hypothesis that such framing effects would cause doctors to assess the clinical significance of treatment outcomes differently when presented as clinical trial results rather than as individual patient data. Fourteen rheumatologists independently reviewed the same 50 sets of data obtained from patients with rheumatoid arthritis. The data consisted of 10 commonly used clinical and laboratory variables measured before and after a period of treatment. The same data were presented in two formats on two separate occasions. The patient data format was a collection of typed sheets attributing each set of results to an individual patient. The clinical trial format was a professionally printed and bound booklet in which each set of results was laid out as summary results of a small uncontrolled clinical trial. Doctors judged the degree of improvement or deterioration and its clinical importance for each data set for both formats. These changes were converted into units of 'Clinical Importance'. Although some statistically significant differences emerged in the individual doctors' judgements between the formats none of these was of a clinically important size. The median of the mean trial--patient difference between the formats for all 14 doctors was 0.035 units of clinical importance [95% CI -0.244 to 0.074]. This evidence does not support the hypothesis that framing effects are a major cause of the failure of clinical trials to influence clinical practice.


Loss of ACOT7 potentiates seizures and metabolic dysfunction.
Neurons uniquely antagonize fatty acid utilization by hydrolyzing the activated form of fatty acids, long chain acyl-CoAs, via the enzyme acyl-CoA thioesterase 7, Acot7. The loss of Acot7 results in increased fatty acid utilization in neurons and exaggerated stimulus-evoked behavior such as an increased startle response. To understand the contribution of Acot7 to seizure susceptibility, we generated Acot7 knockout (KO) mice and assayed their response to kainate-induced seizures. Acot7 KO mice exhibited potentiated behavioral and molecular indices of seizure severity following kainic acid administration, suggesting that fatty acid metabolism in neurons can be a critical regulator of neuronal activity. These data are consistent with the presentation of seizures in a human with genomic deletion of ACOT7 demonstrating the conservation of function across species. To further understand the metabolic complications arising from a deletion in Acot7, we subjected Acot7 KO mice to a high-fat diet. While the loss of Acot7 did not result in metabolic complications following a normal chow diet, a high-fat diet induced greater body weight gain, adiposity, and glucose intolerance in Acot7 KO mice. These data demonstrate that Acot7, a fatty acid metabolic enzyme highly enriched in neurons, regulates both brain-specific metabolic processes related to seizure susceptibility and the whole body response to dietary lipid.


Viewers extract the mean from images of the same person: A route to face learning.
Research on ensemble encoding has found that viewers extract summary information from sets of similar items. When shown a set of four faces of different people, viewers merge identity information from the exemplars into a representation of the set average. Here, we presented sets containing unconstrained images of the same identity. In response to a subsequent probe, viewers recognized the exemplars accurately. However, they also reported having seen a merged average of these images. Importantly, viewers reported seeing the matching average of the set (the average of the four presented images) more often than a nonmatching average (an average of four other images of the same identity). These results were consistent for both simultaneous and sequential presentation of the sets. Our findings support previous research suggesting that viewers form representations of both the exemplars and the set average. Given the unconstrained nature of the photographs, we also provide further evidence that the average representation is invariant to several high-level characteristics.