Differential influence of proteolysis by calpain 2 and Lp82 on in vitro precipitation of mouse lens crystallins.
The purpose of the present study was to compare the susceptibility of crystallins proteolyzed by ubiquitous calpain 2 and by lens-specific calpain Lp82 to insolubilization. To test this, transgenic (TG) mice expressing a calpain 2, in which the active site cysteine 105 was mutated to alanine, were produced. Expression of mutated calpain 2 was driven in lens by coupling the mutated gene to the betaB1-crystallin promoter. Light scattering was measured in solutions of lens proteins after activation of endogenous calpain 2 and/or Lp82. Mass spectrometric analysis was performed to determine the cleavage sites and the calpain responsible for insolubilization of crystallins. Lens proteins from TG mice incubated in vitro with calcium showed higher light scattering compared to proteins from wild type (WT) mice. alphaA-crystallin from TG mice was proteolyzed by Lp82. In contrast, alphaA-crystallin in lenses from WT mice were proteolyzed by both calpain 2 and Lp82. These results suggested that Lp82-induced proteolysis of crystallins caused increased susceptibility of truncated crystallins to in vitro precipitation. Since Lp82 is highest in young animals, Lp82-induced proteolysis and precipitation may be one of the factors responsible for the cataract formation in young rodents.


Fine-tuning ADAS algorithm parameters for optimizing traffic safety and mobility in connected vehicle environment.
Under the Connected Vehicle environment where vehicles and road-side infrastructure can communicate wirelessly, the Advanced Driver Assistance Systems (ADAS) can be adopted as an actuator for achieving traffic safety and mobility optimization at highway facilities. In this regard, the traffic management centers need to identify the optimal ADAS algorithm parameter set that leads to the optimization of the traffic safety and mobility performance, and broadcast the optimal parameter set wirelessly to individual ADAS-equipped vehicles. Once the ADAS-equipped drivers implement the optimal parameter set, they become active agents that work cooperatively to prevent traffic conflicts, and suppress the development of traffic oscillations into heavy traffic jams. Measuring systematic effectiveness of this traffic management requires am analytic capability to capture the quantified impact of the ADAS on individual drivers' behaviors and the aggregated traffic safety and mobility improvement due to such an impact. To this end, this research proposes a synthetic methodology that incorporates the ADAS-affected driving behavior modeling and state-of-the-art microscopic traffic flow modeling into a virtually simulated environment. Building on such an environment, the optimal ADAS algorithm parameter set is identified through a multi-objective optimization approach that uses the Genetic Algorithm. The developed methodology is tested at a freeway facility under low, medium and high ADAS market penetration rate scenarios. The case study reveals that fine-tuning the ADAS algorithm parameter can significantly improve the throughput and reduce the traffic delay and conflicts at the study site in the medium and high penetration scenarios. In these scenarios, the ADAS algorithm parameter optimization is necessary. Otherwise the ADAS will intensify the behavior heterogeneity among drivers, resulting in little traffic safety improvement and negative mobility impact. In the high penetration rate scenario, the identified optimal ADAS algorithm parameter set can be used to support different control objectives (e.g., safety improvement has priority vs. mobility improvement has priority).


Leveraging the Code of Ethics to Practically Promote Ethics During COVID-19.
The COVID-19 pandemic has surfaced many ethical challenges for nurse leaders who need the courage, ability, and support to make the right decisions. This paper discusses 3 ethical challenges: workforce shortages, staff assignments, and moral distress. It also offers strategies to leverage our code of ethics to navigate these situations.


Highly branched dextrin prepared from high-amylose maize starch using waxy rice branching enzyme (WRBE).
Branching enzyme (BE, EC 188.8.131.52) was isolated from the developing waxy rice endosperm and used to prepare a highly branched dextrin based on high-amylose maize starch (HAMS) as a substrate. The molecular mass of the starch initially degraded quickly from 2.5 × 10(7) to 4.1 × 10(5)Da, and then stabilized, with a minimal increase during the BE treatment. The resultant branched dextrin had a narrow size distribution, with a mean molecular weight of 5.1 × 10(5)Da and a polydispersity index (PI) of 1.567. The results of high-performance anion exchange chromatography indicated that the degree of polymerization (DP) of the branched chains ranged from 3 to 27; approximately 75.26% of these chains were short (DP<10). These findings suggest that the isolated BE can cleave long chains into oligosaccharides, subsequently transferring oligosaccharides into highly branched dextrins with a narrow size distribution and short side chains.


Lactose intolerance associated with cataracts.
A 50-day-old boy with severe lactose intolerance is described. In addition to vomiting, failure to thrive, dehydration, metabolic acidosis and amino aciduria, bilateral cataracts were also found. At three months of age, a computerized axial tomography scan and an electroencephalogram were abnormal, and myoclonic spasms began at the age of seven months.


A correlational study between signature, writing abilities and decision-making capacity among people with initial cognitive impairment.
Some clinical conditions, including dementia, compromise cognitive functions involved in decision-making processes, with repercussions on the ability to subscribe a will. Because of the increasing number of aged people with cognitive impairment there is an acute and growing need for decision-making capacity evidence-based assessment. Our study investigates the relationship between writing abilities and cognitive integrity to see if it is possible to make inferences on decision-making capacity through handwriting analysis. We also investigated the relationship between signature ability and cognitive integrity. Thirty-six participants with diagnosis of MCI and 38 participants with diagnosis of initial dementia were recruited. For each subject we collected two samples of signature-an actual and a previous one-and an extract of spontaneous writing. Furthermore, we administered a neuropsychological battery to investigate cognitive functions involved in decision-making. We found significant correlations between spontaneous writing indexes and neuropsychological test results. Nonetheless, the index of signature deterioration does not correlate with the level of cognitive decline. Our results suggest that a careful analysis of spontaneous writing can be useful to make inferences on decision-making capacity, whereas great caution should be taken in attributing validity to handwritten signature of subjects with MCI or dementia. The analysis of spontaneous writing can be a reliable aid in cases of retrospective evaluation of cognitive integrity. On the other side, the ability to sign is not an index of cognitive integrity.


Mapping HDX-MS Data to Protein Conformations through Training Ensemble-Based Models.
An original approach that adopts machine learning inference to predict protein structural information using hydrogen-deuterium exchange mass spectrometry (HDX-MS) is described. The method exploits an in-house optimization program that increases the resolution of HDX-MS data from peptides to amino acids. A system is trained using Gradient Tree Boosting as a type of machine learning ensemble technique to assign a protein secondary structure. Using limited training data we generate a discriminative model that uses optimized HDX-MS data to predict protein secondary structure with an accuracy of 75%. This research could form the basis for new methods exploiting artificial intelligence to model protein conformations by HDX-MS.


Development, characterization, and testing of a personal passive sampler for measuring inhalation exposure to gaseous elemental mercury.
Inhalation of gaseous elemental mercury (GEM) is an occupational exposure concern for workers handling elemental mercury or mercury-containing waste. GEM is also often present near historically mercury-contaminated sites, potentially resulting in low-level, chronic exposure of the wider population. Here we introduce a passive sampler for personal GEM monitoring which combines a radial porous diffusive barrier with an activated carbon sorbent. A total mercury analyzer is used to quantify GEM sorbed to the carbon by thermal decomposition, amalgamation, and atomic absorption spectroscopy. A sampling rate of 0.070 m3/day was determined by calibrating the sampler at low and high concentrations. Deployments lasting 8 h result in limits of quantification well below 200 ng/m3. The sampler has a measurement range of at least four orders of magnitude. Derived air concentrations were not statistically significantly different from those obtained by active air sampling but were more precise than those obtained using a personal pump. If properly stored, the sampler maintains low blank levels in high GEM environments. Affordability, sturdiness, simplicity, and the wide availability of total mercury analyzers make this sampler highly suited for monitoring GEM inhalation exposure, including in developing countries.


Saliva contamination vs. efficacy of dentin-bonding agents.
The efficacy of two dentin-bonding agents (Gluma and Scotchbond Dual Cure) was investigated in vitro with or without saliva contamination of the dentin before or after application of the adhesive. The efficacy of the bonding agents was evaluated by a shear-bond strength test and a cavity test. When the dentin surface was contaminated, either before or after application of one of the bonding agents, the shear bond strength was reduced, but the difference between contaminated and non-contaminated specimens was not statistically significant. In the cavity test, the width and the extent of the marginal contraction gap were markedly increased when the dentin was contaminated with saliva before the bonding agent was applied. If the contamination happened after application of the adhesive, the efficacy of Gluma was further reduced, while that of Scotchbond was significantly improved. (This phenomenon has been investigated in detail in an accompanying paper.) The clinical consequence of saliva contamination seems to be that when Gluma is used as dentin-bonding agent, the contaminated area must be removed operatively, and then each of the various bonding procedures must be repeated.


Horizontal transport of macro- and microplastics on soil surface by rainfall induced surface runoff as affected by vegetations.
Surface runoff is considered as an important pathway that transport of plastic waste from terrestrial environment into the aquatic environment but the process is still poorly understood. In this work, runoff plot experiment was carried out to study the horizontal transport of macro- and microplastics between 50 mm and 0.25 mm in size on the soil surface by rain induced runoff. The influences of vegetation cover, characteristics of plastics, and rainfall scenarios were investigated. Results showed that the presence of vegetation significantly enhance the retention of plastics by about 20% under the experimental conditions. Lower density and smaller (<1 mm) plastics were found to have higher mobility. The herb plant (Photinia×fraseri Dress) showed a better interception efficiency on plastics than the shrub plant (Ophiopogon japonicus (Linn. f.) Ker-Gawl.) at the same planting density, while increasing plant density contributed litter to the interception of microplastics. Increase rainfall amount from 20 mm to 60 mm enhanced the transport of plastics while repeating 20 mm rainfall every 3 days did not affect the transport of plastics significantly. The same processes may involve in the transport of plastics and soil particles by rainfall induced surface runoff. Strategies controlling soil erosion could also be used to prevent plastics in soil from entering the aquatic environment. However, effects and risks of plastics retained in the soil are still unclear, which need to be investigated in future.


Structure and function of the AAA+ ATPase p97/Cdc48p.
p97 (also known as valosin-containing protein (VCP) in mammals or Cdc48p in Saccharomyces cerevisiae) is an evolutionarily conserved ATPase present in all eukaryotes and archaebacteria. In conjunction with a collection of cofactors and adaptors, p97/Cdc48p performs an array of biological functions mostly through modulating the stability of 'client' proteins. Using energy from ATP hydrolysis, p97/Cdc48p segregates these molecules from immobile cellular structures such as protein assemblies, membrane organelles, and chromatin. Consequently, the released polypeptides can be efficiently degraded by the ubiquitin proteasome system or recycled. This review summarizes our current understanding of the structure and function of this essential cellular chaperoning system.


Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics.
The bioavailability of some dihydropyridine calcium antagonists can be markedly augmented by grapefruit juice and may involve the bioflavonoid naringin. The pharmacokinetics of nisoldipine coat-core tablet were studied in a Latin square-designed trial in which 12 healthy men were administered the drug with water, grapefruit juice, or encapsulated naringin powder at the same amount as that assayed in the juice. Compared with water, grapefruit juice increased the maximum concentration of nisoldipine to 406% +/- 73% (mean +/- SEM; range, 107% to 836%; p < 0.001), increased the area under the plasma concentration-time curve to 198% +/- 46% (range, 81% to 682%; p < 0.001), and reduced time to reach maximum nisoldipine concentration to 58% +/- 9% (range, 13% to 100%; p < 0.01), probably by inhibition of presystemic metabolism and possibly by enhancement of drug dissolution. The interaction could not be predicted from baseline pharmacokinetics with water and resulted in greater interindividual variability. The naringin capsule did not change nisoldipine pharmacokinetics. All treatments produced minor effects on supine blood pressure and heart rate, probably because subjects were normotensive. Current information supports the cautioning of patients about concomitant ingestion of grapefruit juice and nisoldipine.


Adiponectin downregulation is associated with volume overload-induced myocyte dysfunction in rats.
Adiponectin has been reported to exert protective effects during pathological ventricular remodeling, but the role of adiponectin in volume overload-induced heart failure remains unclear. In this study we investigated the effect of adiponectin on cardiac myocyte contractile dysfunction following volume overload in rats. Volume overload was surgically induced in rats by infrarenal aorta-vena cava fistula. The rats were intravenously administered adenoviral adiponectin at 2-, 6- and 9-weeks following fistula. The protein expression of adiponectin, adiponectin receptors (AdipoR1/R2 and T-cadherin) and AMPK activity were measured using Western blot analyses. Isolated ventricular myocytes were prepared at 12 weeks post-fistula to examine the contractile performance of myocytes and intracellular Ca(2+) transient. A-V fistula resulted in significant reductions in serum and myocardial adiponectin levels, myocardial adiponectin receptor (AdipoR1/R2 and T-cadherin) levels, as well as myocardial AMPK activity. Consistent with these changes, the isolated myocytes exhibited significant depression in cell shortening and intracellular Ca(2+) transient. Administration of adenoviral adiponectin significantly increased serum adiponectin levels and prevented myocyte contractile dysfunction in fistula rats. Furthermore, pretreatment of isolated myocytes with recombinant adiponectin (2.5 μg/mL) significantly improved their contractile performance in fistula rats, but had no effects in control or adenoviral adiponectin-administered rats. These results demonstrate a positive correlation between adiponectin downregulation and volume overload-induced ventricular remodeling. Adiponectin plays a protective role in volume overload-induced heart failure.


[Interventional endovascular therapy (stenting) for residual stenosis after lysis of the basilar artery].
Despite the introduction of local thrombolytic therapy, there is still a very high mortality rate in basilar thrombosis. We report three cases of successful intra-arterial thrombolysis of acute basilar artery occlusion and consecutive interventional endovascular therapy. In all cases, the acute thrombosis of the basilar artery probably developed from preexisting atherosclerotic stenoses. The clinical outcomes were excellent. We discuss early consecutive stenting as a possible therapeutic option in cases of residual stenosis after successful intra-arterial lysis of basilar artery occlusion.


Chordoid meningioma: a retrospective series of seven consecutive cases.
Chordoid meningioma is a rare variant of meningioma characterized by a more aggressive behavior. The present study documents the histological, radiological and clinical features of seven cases treated at the Policlinico Umberto I of Rome from 1999 to 2010. There were five males and two females. Most of the cases were located in the supratentorial space, especially the convexity. Surgical gross total resection was achieved in four cases. Of the remaining three cases, two relapsed and underwent further surgeries and adjuvant treatment. The MIB-1 index had a mean value of 7.5 (range 0.3-25.8). Tumors were composed of epithelioid cells or plump to spindle cells, forming cords, cribriforms or nests, in a mucoid matrix. All tumors showed diffuse positive immunoreactivity to vimentin and epithelial membrane antigen. Surgery is the first line of treatment for this kind of lesion. Gross total resection guaranteed a survival free from recurrences in our series. On the other hand, radiation therapy must be considered in patients submitted to a subtotal resection.


An alternative hypothesis for the evolution of same-sex sexual behaviour in animals.
Same-sex sexual behaviour (SSB) has been recorded in over 1,500 animal species with a widespread distribution across most major clades. Evolutionary biologists have long sought to uncover the adaptive origins of 'homosexual behaviour' in an attempt to resolve this apparent Darwinian paradox: how has SSB repeatedly evolved and persisted despite its presumed fitness costs? This question implicitly assumes that 'heterosexual' or exclusive different-sex sexual behaviour (DSB) is the baseline condition for animals, from which SSB has evolved. We question the idea that SSB necessarily presents an evolutionary conundrum, and suggest that the literature includes unchecked assumptions regarding the costs, benefits and origins of SSB. Instead, we offer an alternative null hypothesis for the evolutionary origin of SSB that, through a subtle shift in perspective, moves away from the expectation that the origin and maintenance of SSB is a problem in need of a solution. We argue that the frequently implicit assumption of DSB as ancestral has not been rigorously examined, and instead hypothesize an ancestral condition of indiscriminate sexual behaviours directed towards all sexes. By shifting the lens through which we study animal sexual behaviour, we can more fruitfully examine the evolutionary history of diverse sexual strategies.


Scintigraphic and radiological correlative and confirmative features obviating invasive biopsy in Caffey's disease.
Caffey's disease is not a common clinical occurrence; it often poses problems in diagnosis due to its close resemblance to osteomyelitis. Initial plain radiographic diagnosis is sometimes fraught with the limitation of not being able to differentiate it from chronic osteomyelitis. Skeletal scintigraphy is sensitive in localizing the disease activity to the radiological features of the affected regions and the characteristic location of the lesions helps make the diagnosis without resorting to biopsy and further workup.


Ceric ion initiated synthesis of polyacrylamide grafted oatmeal: Its application as flocculant for wastewater treatment.
Polyacrylamide grafted oatmeal (OAT-g-PAM) was synthesized by conventional method. The grafting of the PAM chains on the biomaterial backbone was confirmed through intrinsic viscosity study, FTIR spectroscopy, elemental analysis (C, H, N, S and O), SEM morphology and TGA study. The intrinsic viscosity of oatmeal appreciably improved on grafting of PAM chains, thus resulting grafted product with potential application as superior viscosifier. Further, flocculation efficacy of the graft copolymer was studied in coal fine suspension, kaolin suspension, iron-ore suspension and then in municipal wastewater through 'jar test' procedure.


Small Molecules against Metastatic Tumors: Concrete Perspectives and Shattered Dreams.
Metastasis is the main cause of anti-cancer therapy failure, leading to unfavorable prognosis for patients. The true challenge to increase cancer patient life expectancy by making cancer a chronic disease with periodic but manageable relapses relies on the development of efficient therapeutic strategies specifically directed against key targets in the metastatic process. Traditional chemotherapy with classical alkylating agents, microtubule inhibitors, and antimetabolites has demonstrated its limited efficacy against metastatic cells due to their capacity to select chemo-resistant cell populations that undergo epithelial-to-mesenchymal transition (EMT), thus promoting the colonization of distant sites that, in turn, sustain the initial metastatic process. This scenario has prompted efforts aimed at discovering a wide variety of small molecules and biologics as potential anti-metastatic drugs directed against more specific targets known to be involved in the various stages of metastasis. In this short review, we give an overview of the most recent advances related to important families of antimetastatic small molecules: intracellular tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, KRAS inhibitors, and integrin antagonists. Although the majority of these small molecules are not yet approved and not available in the drug market, any information related to their stage of development could represent a precious and valuable tool to identify new targets in the endless fight against metastasis.


Electrospun Aligned Coaxial Nanofibrous Scaffold for Cardiac Repair.
Cardiovascular diseases (CVDs) are one of the leading causes of mortality worldwide and a number one killer in the USA. Cell-based approaches to treat CVDs have only shown modest improvement due to poor survival, retention, and engraftment of the transplanted cells in the ischemic myocardium. Recently, tissue engineering and the use of 3D scaffolds for culturing and delivering stem cells for ischemic heart disease are gaining rapid potential. Here, we describe a protocol for the fabrication of aligned coaxial nanofibrous scaffold comprising of a polycaprolactone (PCL) core and gelatin shell. Furthermore, we describe a detailed protocol for the efficient seeding and maintenance of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) on these nanofibrous scaffolds, which could have a potential application in the generation of functional "cardiac patch" for myocardial repair applications as well as an in vitro 3D cardiac tissue model to evaluate the efficacy of cardiovascular drugs and cardiac toxicities.


Double-lung transplantation can be safely performed using donors with heavy smoking history.
Lung transplantation using grafts from donors with a history of heavy smoking (>20 pack-years) is thought to confer worse prognosis. We attempt to determine if adult, double-lung transplantation can be safely performed with lungs from heavy-smoking donors (HSD). The United Network for Organ Sharing (UNOS) database was examined for adult, double-lung transplants from 2005 to 2011. Of 5,900 double-lung transplants, 766 (13.0%) were from HSDs. The two groups were similar in recipient age (49.8 vs 50.5 years, p = 0.15), male sex (56.9% vs 56.5%, p = 0.87), and lung allocation score (45.8 vs 44.9, p = 0.18). Recipients of lungs from HSDs had lower forced expiratory volume in 1 second (FEV1; 34.3 vs 36.1% predicted, p = 0.04), longer ischemic time (5.75 vs 5.58 hours, p = 0.01), less human leukocyte antigen mismatch (4.51 vs 4.62, p = 0.01), and lower class I plasma reactive antigens (2.64 vs 3.69%, p = 0.001). HSDs were older (40.9 vs 32.6 years, p < 0.001) and less likely male (51.7 vs 59.7%, p < 0.001). Recipients of lungs from HSDs had longer median length of stay (18.0 vs 17.0 days, p < 0.001). Freedom from bronchiolitis obliterans syndrome (p = 0.09), decrement in FEV1 (p = 0.12), peak FEV1 (79.8% vs 79.0%, p = 0.51), and median survival (2,043 vs 1,928 days, p = 0.69) were not different. On multivariate analysis, HSD lungs were not associated with death (hazard ratio, 1.003; 95% confidence interval, 0.867 to 1.161, p = 0.96). Death was associated with donor age, ischemic time, race mismatch, mechanical ventilation, and extracorporeal membranous oxygenation before transplantation. Double-lung transplantation can be safely performed with lungs from donors with a heavy smoking history.


Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil and hydrochlorothiazide.
Most patients with hypertension require more than one agent to control blood pressure (BP). The purpose of this study was to assess the efficacy and safety of the angiotensin II receptor blocker olmesartan medoxomil in combination with hydrochlorothiazide (HCTZ). This was a randomized, double-blind, factorial design study. After a placebo run-in period, eligible patients (n = 502) with a baseline mean seated diastolic blood pressure (SeDBP) of 100 to 115 mm Hg were randomized to one of 12 groups: placebo, olmesartan medoxomil monotherapy (10, 20, or 40 mg/day, HCTZ monotherapy (12.5 or 25 mg/day), or one of six groups of olmesartan medoxomil/HCTZ combination therapy. The primary endpoint was the change in mean trough SeDBP from baseline at week 8. Statistical analyses were conducted to determine whether at least one combination produced a larger reduction in SeDBP at week 8 than the individual corresponding component doses, but did not compare BP reductions with different combination doses. Olmesartan medoxomil plus HCTZ produced greater reductions in both SeDBP and seated systolic blood pressure (SeSBP) at week 8 than did monotherapy with either component. All olmesartan medoxomil/HCTZ combinations significantly reduced SeDBP and SeSBP compared with placebo in a dose-dependent manner. Reductions from baseline in mean trough SeSBP/SeDBP were 3.3/8.2 mm Hg, 20.1/16.4 mm Hg, and 26.8/21.9 mm Hg with placebo, olmesartan medoxomil/HCTZ 20/12.5 mg, and olmesartan medoxomil/HCTZ 40/25 mg, respectively. All treatments were well tolerated. Olmesartan medoxomil/HCTZ combination therapy produced BP reductions of up to 26.8/21.9 mm Hg and was well tolerated.


MiniArc single-incision sling in the office setting.
To report MiniArc single-incision sling efficacy results in the office setting and the feasibility of performing the procedure in the office. Prospective, single-arm, nonrandomized, institutional review board-approved study (Canadian Task Force classification II-2). Three in-office clinical sites in the United States. Thirty-eight patients who underwent treatment of stress urinary incontinence using the MiniArc single-incision sling. A MiniArc single-incision sling was placed in 38 patients in an office-based setting under intravenous or oral sedation and/or local anesthesia. Thirty-eight implant recipients were evaluated for effectiveness and safety via qualitative (Urinary Distress Inventory-Short Form [UDI-6] and Incontinence Impact Questionnaire-Short Form [IIQ-7]) and quantitative (1-hour pad-weight test and cough stress test) measurements at 3 clinical sites. Secondary outcome measures included procedure time, estimated blood loss, length of stay, perioperative complications, Wong-Baker Faces Pain Scale, and adverse events. During the study, 38 women (mean [SD; 95% CI] age, 48.1 (8.4; 45.3-50.8 years)) received slings. Mean procedure time was 10.6 minutes, estimated blood loss was 23.2 mL, and length of stay was 1.3 hours. At discharge, the Wong-Baker pain score was 0.2 (0.0-2.0). At 2 years, 31 patients were available for follow-up. Of these, 93.5% had normal findings on the cough stress test, and 90.3% had pad weight <1 g; and 90.6% and 87.5%, respectively, using last failure carried forward analysis in 32 patients. The UDI-6 and IIQ-7 median scores showed a statistically significant decrease from baseline (p < .001). There were no reports of serious adverse events or of bowel, urethral, bladder, or major vessel perforation. The in-office experience suggests that implantation of a single-incision sling for treatment of stress urinary incontinence with the patient under intravenous or oral sedation and/or local anesthesia can be performed safely, with effective results. Thus, performing this procedure in an office setting is a viable option.


Localization of alkaline phosphatase in Streptomyces noursei.
Alkaline phosphatase activity appeared in Streptomyces noursei strain IMET 43,716 when cultures were shifted to phosphate limitation. By using p-nitrophenylphosphate as substrate, the activity detected at pH 9.4 was cell-bound, as long as young mycelia were studied. Supernatant fluids of the cultures were only active, if partial mycelial lysis had taken place after incubation for several days under the influence of shear forces. After cytochemical staining the phosphatase reaction products were microscopically visible as grains distributed rather homogeneously within the hyphal lumen. The frequency of grains was correlated to the rate of nourseothricin production. Electron microscopy of thin sections showed the phosphatase reaction products to be only present in the cytoplasm.


Analysis of MRE11 and Mortality Among Adults With Muscle-Invasive Bladder Cancer Managed With Trimodality Therapy.
Bladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches. To evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis. This prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020. Trimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy. MRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio. Of 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44). Higher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.


Quantitative determination of nebivolol from human plasma using liquid chromatography-tandem mass spectrometry.
In the present work, a rapid, sensitive, specific, precise and accurate liquid chromatography-tandem mass spectrometry method for determination of nebivolol in human plasma was developed and validated with a large calibration curve range (50-5000 pg/mL) which can be used for routine drug analysis and bioequivalence studies. Liquid-liquid extraction method was used to extract the analyte from the human plasma. The separation was achieved using Waters symmetry, C18, 4.6 × 150 mm, 5 μm column with formic acid in water, 0.01%, v/v: Acetonitrile (40:60) as a mobile phase. A flow rate of 0.8 mL/min, no splitting and run time 2.00 min was used for the chromatographic analysis of nebivolol. Sensitivity of this method was found to be 30 pg/mL. The analyte was analyzed by mass spectrometry in the multiple reaction monitoring mode. A Turbo-Ion spray source was interfaced between the HPLC and triple quadrupole mass spectrometer (MDS Sciex API 4000). The precursor-product ion m/z 406.00-151.00 for nebivolol and m/z 410.20-151.00 for nebivolol-D4 were used for quantification of an analyte and its IS. The method was validated in terms of accuracy, precision, selectivity, absolute recovery, freeze-thaw stability, bench-top stability, dry extract stability, short and long term stock solution stability, wet extract stability and re-injection reproducibility. The within- and between-batch accuracy was found to lie within the range of 87.00-100.40% and within- and between-batch precision was obtained within the range 0.33-8.67%. The mean recovery of all three concentration levels for drug was obtained 67.67% where as the mean recovery of IS was 68.74%. The %RSD value at higher concentration and lower concentration in all stability experiments was within 15%. This method is free from ion suppression, ion enhancement and any type of abnormal ionization.


Preoperative renal function affects outcomes of surgery for aortic arch aneurysm in the elderly.
This study aimed to determine the optimal surgical procedure for arch aneurysm in the elderly based on preoperative comorbidities, especially focusing on renal function. The medical records of 374 patients who experienced arch surgery between 2008 and 2019 were reviewed. Among the 374 patients, 92 who underwent total arch replacement (TAR) were assigned to the TAR group and the remaining 152 who underwent debranching thoracic endovascular aortic repair (DTEVAR) were assigned to the DTEVAR group. Chronic kidney disease (CKD) was an independent risk factor of mortality (hazard ratio, 2.85; p = 0.029) in the TAR group but not in the DTEVAR. In the Grade I/II category CKD (estimated glomerular filtration rate (eGFR) > 60 mL/min), freedom from all-cause mortality was significantly higher in the TAR group than in the DTEVAR group (p = 0.0155, log-rank). Freedom from all-cause mortality was comparable between the two groups in the Grade IIIa CKD (eGFR, 45-60) (p = 0.584, log-lank), Grade IIIb (eGFR, 30-45) (p = 0.822), and Grade IV/V (eGFR < 30) (p = 0.548). In elderly patients who underwent TAR, CKD was the independent risk factor of the mortality, but not in the patients who underwent debranching TEVAR. Conversion of surgical strategy from TAR to debranching TEVAR in the treatment of aortic arch aneurysms in the elderly with CKD below Grade IIIa is acceptable considering that less-invasiveness. While, in the elderly with Grade I/II CKD, TAR still remains as a primary choice for the arch repair for better mid-term survival.


[Accessory salivary tissue and deceptive ectopia].
Histopathologic diagnosis in three patients presenting with a cervicofacial salivary tumoral mass was respectively an inflamed accessory salivary glands, two small islets of ectopic salivary glands and an ectopic salivary duct.


UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.
p53 is the most intensively studied tumour suppressor1. The regulation of p53 homeostasis is essential for its tumour-suppressive function2,3. Although p53 is regulated by an array of post-translational modifications, both during normal homeostasis and in stress-induced responses2-4, how p53 maintains its homeostasis remains unclear. UFMylation is a recently identified ubiquitin-like modification with essential biological functions5-7. Deficiency in this modification leads to embryonic lethality in mice and disease in humans8-12. Here, we report that p53 can be covalently modified by UFM1 and that this modification stabilizes p53 by antagonizing its ubiquitination and proteasome degradation. Mechanistically, UFL1, the UFM1 ligase6, competes with MDM2 to bind to p53 for its stabilization. Depletion of UFL1 or DDRGK1, the critical regulator of UFMylation6,13, decreases p53 stability and in turn promotes cell growth and tumour formation in vivo. Clinically, UFL1 and DDRGK1 expression are downregulated and positively correlated with levels of p53 in a high percentage of renal cell carcinomas. Our results identify UFMylation as a crucial post-translational modification for maintenance of p53 stability and tumour-suppressive function, and point to UFMylation as a promising therapeutic target in cancer.


Holocene fire history in China: Responses to climate change and human activities.
Fire is an intrinsic feature of terrestrial ecosystems as well as a key Earth system process that significantly influences ecosystem patterns, the carbon cycle, and climate. Although local and regional paleofires across China have been investigated, the history of these phenomena at the national scale as well as possible drivers remain unknown. This study investigated spatiotemporal patterns in fire activity across China based on 107 individual site charcoal records. The aim of this work was to discuss the possible impact of climate and human activities on fire in China. Results showed that fire activities across China declined gradually overall between the early Holocene (12 ka BP) and the middle Holocene (7.3 ka BP) but then sharply increased in occurrence after 7.3 ka BP. Data showed that although regional fire activities did not vary synchronously, more events tended to occur in the late Holocene and there were relative less in the early-to-middle Holocene. These changes in Holocene fire activity closely mirrored millennial scale moisture variations across China. Intensified human activities over the last 3 ka might also be responsible for a sharp increase in fire activity. Variable trends in fire activities within regions might also be attributed to large-scale climatic controls modulated by local factors, which determined burn likelihood. This study enhances our insights into the fire history of China and may help to provide improved future projections for such phenomena given current climate change.


Comparative topo-optical investigation of cardiac glycoside localization.
The aldehyde-bisulfite-toluidine blue (ABT) reaction is a selective topo-optical test of vicinal-OH and amino-OH groups. The localization of cardiac glycoside was investigated morphologically. After digoxin the sarcolemma membranes, capillaries and sinus node showed strong basophilia and negative birefringence. The topo-optical reaction are useful for the histopathological examination. The new method gives the possibility to the digoxin intoxication with a high specificity.


DRB-induced premature termination of late adenovirus transcription.
Exposure of HeLa cells to 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazde (DRB) late in the course of adenovirus 2 infection results in the inhibition of virus-specific RNA synthesis from all parts of the previously identified, very long (approximately 28 kilobases) late transcriptional unit, except for the first approximately 400-800 nucleotides. It is suggested that DRB acts not as an inhibitor of RNA chain initiation, but rather causes "premature" chain termination close to the promoter. A practical aspect of these findings may be that RNA sequences near promoter sites that are responsible for mRNA formation can be isolated from DRB-treated cells.


Pathogenesis of optic disc edema in raised intracranial pressure.
Optic disc edema in raised intracranial pressure was first described in 1853. Ever since, there has been a plethora of controversial hypotheses to explain its pathogenesis. I have explored the subject comprehensively by doing basic, experimental and clinical studies. My objective was to investigate the fundamentals of the subject, to test the validity of the previous theories, and finally, based on all these studies, to find a logical explanation for the pathogenesis. My studies included the following issues pertinent to the pathogenesis of optic disc edema in raised intracranial pressure: the anatomy and blood supply of the optic nerve, the roles of the sheath of the optic nerve, of the centripetal flow of fluids along the optic nerve, of compression of the central retinal vein, and of acute intracranial hypertension and its associated effects. I found that, contrary to some previous claims, an acute rise of intracranial pressure was not quickly followed by production of optic disc edema. Then, in rhesus monkeys, I produced experimentally chronic intracranial hypertension by slowly increasing in size space-occupying lesions, in different parts of the brain. Those produced raised cerebrospinal fluid pressure (CSFP) and optic disc edema, identical to those seen in patients with elevated CSFP. Having achieved that, I investigated various aspects of optic disc edema by ophthalmoscopy, stereoscopic color fundus photography and fluorescein fundus angiography, and light microscopic, electron microscopic, horseradish peroxidase and axoplasmic transport studies, and evaluated the effect of opening the sheath of the optic nerve on the optic disc edema. This latter study showed that opening the sheath resulted in resolution of optic disc edema on the side of the sheath fenestration, in spite of high intracranial CSFP, proving that a rise of CSFP in the sheath was the essential pre-requisite for the development of optic disc edema. I also investigated optic disc edema with raised CSFP in patients, by evaluating optic disc and fundus changes by stereoscopic fundus photography and fluorescein fundus angiography. Based on the combined information from all the studies discussed above, it is clear that the pathogenesis of optic disc edema in raised intracranial pressure is a mechanical phenomenon. It is primarily due to a rise of CSFP in the optic nerve sheath, which produces axoplasmic flow stasis in the optic nerve fibers in the surface nerve fiber layer and prelaminar region of the optic nerve head. Axoplasmic flow stasis then results in swelling of the nerve fibers, and consequently of the optic disc. Swelling of the nerve fibers and of the optic disc secondarily compresses the fine, low-pressure venules in that region, resulting in venous stasis and fluid leakage; that leads to the accumulation of extracellular fluid. Contrary to the previous theories, the various vascular changes seen in optic disc edema are secondary and not primary. Thus, optic disc edema in raised CSFP is due to a combination of swollen nerve fibers and the accumulation of extracellular fluid. My studies also provided information about the pathogeneses of visual disturbances in raised intracranial pressure.


Association between blastocyst morphology and outcome of single-blastocyst transfer.
The aim of this study was to assess the ability of three individual blastocyst morphology parameters - expansion and hatching (EH) stage, inner cell mass (ICM) grade and trophectoderm grade - to predict outcome of a cycle with single-blastocyst transfer. The study was a secondary analysis of data prospectively collected in a large multicentre trial. A total of 618 intracytoplasmic sperm injection patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist cycle with compulsory single-blastocyst transfer on day 5 were included. In the simple logistic regression analysis, all three blastocyst morphology parameters were statistically significantly (P<0.005 for each) associated with positive human chorionic gonadotrophin, clinical and ongoing pregnancy rates and live birth rates, while only the ICM grade was significantly (P=0.033) associated with early pregnancy loss rate. Blastocyst EH stage was the only significant predictor of live birth (P=0.002) in the multiple logistic regression. In conclusion, although all three blastocyst morphology parameters were related to treatment outcome of fresh single-blastocyst cycles, selection of high-quality blastocysts for transfer should consider first the EH stage. Transfer of a blastocyst with ICM grade A may reduce the risk of early pregnancy loss. Choosing the embryo(s) with the best implantation potential is essential for securing each couple the highest chance of achieving pregnancy after assisted reproduction. The selection of embryo(s) for transfer at the blastocyst stage is based on morphology parameters of expansion and hatching stage, inner cell mass grade and trophectoderm grade. The aim of this study was to assess the relative impact of each parameter in predicting the probability of a successful outcome. The study was a secondary analysis of data prospectively collected in a large multicentre trial. A total of 618 patients who underwent single-blastocyst transfer on day 5 were included. Statistical analysis showed that all three blastocyst morphology parameters were significantly associated with positive human chorionic gonadotrophin (βHCG), clinical and ongoing pregnancy rates and live birth rates. Only the inner cell mass grade was significantly associated with early pregnancy loss between the positive βHCG test and confirmation of ongoing pregnancy 10-11weeks after transfer. The expansion and hatching stage was the only significant predictor of live birth in the multiple logistic regression analysis. In conclusion, although all three blastocyst morphology parameters were related to treatment outcome of fresh single-blastocyst cycles, selection of high-quality blastocysts for transfer should consider first the expansion and hatching stage. Transfer of a blastocyst with inner cell mass grade A may reduce the risk of early pregnancy loss.


Dehiscence with evisceration: a rare complication of diagnostic peritoneal lavage.
Diagnostic peritoneal lavage (DPL) is a well-established procedure for evaluating the patient suspected of having intraabdominal injury secondary to blunt abdominal trauma. Its accuracy and safety have been clearly documented; however, the procedure does have the potential for morbidity. This paper reports on the occurrence of a rare complication, dehiscence with evisceration, and reviews the literature regarding complications of DPL.


Making waves: Enhancing sustainability and resilience in coastal cities through the incorporation of seawater into urban metabolism.
Water and energy are critical components of urban metabolism. However, climate change-induced water scarcity and elevated temperatures pose a significant threat to the adequate supply of essential human services, including sanitation and space cooling, particularly in coastal cities where over 40% of the population resides. The water-energy nexus of sanitation and space cooling is crucial for promoting sustainability and resilience in coastal cities. For decades, Hong Kong has demonstrated the effectiveness of using seawater for toilet flushing and district cooling to save water and energy, which could serve as a potential solution for other coastal cities worldwide. Seawater is a superior alternative to other sources of toilet flushing water due to its abundant availability, easy detection of cross-contamination, and lower treatment costs. Furthermore, saline wastewater treatment requires fewer materials and energy inputs and produces less sludge. Using seawater for district cooling also saves energy without exacerbating water stress. However, there is a lack of comprehensive insights from Hong Kong on how seawater use can be adopted by other coastal cities to promote sustainable development. A successful introduction of seawater into coastal cities requires a holistic water-energy management framework that provides technical and policy-level guidance. We developed such a framework that follows four sustainability principles, namely customized solutions, efficient resource allocation, comprehensive evaluation, and optimized tradeoffs. These principles are designed into contextualized location analysis, urban spatial analysis, integrated sustainability assessment, and nexus analysis. The results of these analyses can aid decision-making regarding the technical and policy aspects of seawater uses in sanitation and space cooling to maximize the positive impacts on sustainable development. Breaking barriers between sectors and encouraging inter-municipal cooperation between sectors are critical to the successful use of seawater. By adopting this framework and promoting collaboration across different sectors, coastal cities can enhance their sustainability and resilience, providing a better quality of life for their citizens.


Compartmentalization of 14C-DDT in an experimental old-field plot.
Of the 2.81 X 10(6) micrograms DDT applied to the plot in June 1976, 2.58 X 10(6) micrograms (91.8%) were accounted for as of June 1977. Silk screens, ethylene glycol air samples, and run-off contained 40.57 X 40(-3)%, 0.09 X 10(-3)%, and 1.18 X 10(-3)%, respectively of the DDT aplied. Soil was the major sink for DDT in this study, with 91.8% of the applied DDT located there. Most of the remaining 8.2% was probably lost during the formulation and application of the 14C-DDT granules, some was probably lost in organisms (mainly flying insects) leaving the plot, and some was accounted for by experimental error and error in the counting technique.


Neonatal splenic suppressor cells in the chicken. I. In vivo suppression of the immune response to bovine serum albumin by normal and tolerized neonatal spleen cells.
The presence of active splenic suppressor cells in neonatal chickens, either normal or tolerant to bovine serum albumin (BSA), was examined by assessment of their effect on both primary and adoptively transferred secondary responses to BSA or sheep red blood cells (SRC). Both normal and BSA tolerized spleen cells were shown to be highly suppressive of secondary anti-BSA responses generated by specifically primed adult spleen cells in inert recipients. Suppression of the secondary anti-BSA response by normal spleen cells was slightly less effective than that seen with BSA tolerant spleen cells. Transfer of BSA tolerant spleen cells into normal recipients, followed by BSA challenge, prevented any significant primary anti-BSA response. In contrast, transfer of normal spleen cells into normal recipients, followed by BSA challenge, failed to show any suppression of the resulting primary response. Neither normal nor BSA tolerant neonatal spleen cells were capable of suppressing either primary or secondary responses to SRC. Thus, chickens tolerized to BSA have suppressor cells specific for the tolerizing antigen. We present evidence that both the tolerance associated suppressors and the suppressors detected in normal neonatal chickens are T cells.


Staphylococcus intermedius: clinical presentation of a new human dog bite pathogen.
Staphylococcus intermedius is a Gram-positive, coagulase-positive coccus that can be distinguished from Staphylococcus aureus by routine microbiological testing. Whereas S intermedius is recognized as flora and pathogen of dogs, it has never been isolated from human infections. We hypothesized that S intermedius may cause human dog bite wound infections and that it has been previously misidentified as S aureus. Fourteen isolates from clinically infected dog bite wounds that were originally identified as S aureus were subjected to further testing; three (22%) were found to be S intermedius. The clinical and microbiological characteristics of these three S intermedius cases are described. All three patients were nonimmunocompromised persons seen within 24 hours for bites on the upper extremity. All patients developed cellulitis within one to three days. All S intermedius isolates were distinguished from S aureus by the lack of acetoin production and by the presence of beta-galactosidase activity. S intermedius was susceptible to a wide range of antibiotics; one isolate was resistant to penicillin. Two patients were treated with penicillin, one with amoxicillin-clavulanate, and all were clinically cured. These are the first three reported human infections involving S intermedius. Further study is necessary to define its clinical importance as a potential human pathogen.


beta-Oxidation in Candida tropicalis. Partial purification and biological function of an inducible 2,4-dienoyl coenzyme A reductase.
Evidence is presented that Candida tropicalis grown on oleic acid as sole carbon and energy source possesses the ability to degrade saturated as well as unsaturated fatty acids. Inducible activities of the four enzymes required for beta-oxidation of saturated fatty acids are demonstrated in this organism. Furthermore, it is shown that 2,3-enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase are induced simultaneously with the other beta-oxidation enzymes. A partial purification of 2,4-dienoyl-CoA reductase is described. This reductase has a specific requirement for NADPH, is unable to utilize NADH, and catalyzes the conversion of 2-trans, 4-cis-decadienoyl-CoA to 3-trans-decenoyl-CoA. It also reduces 2-trans, 4-trans-dienoyl-CoA esters. In vitro studies with extracts from oleate-grown cells of C. tropicalis containing the beta-oxidation enzymes showed that 4-cis-decenoyl-CoA, a metabolite of linoleic acid, was only degraded when the 2,4-dienoyl-CoA reductase step was not blocked by lack of NADPH. Based on the properties of the partially purified 2,4-dienoyl-CoA reductase and the results of the in vitro degradation studies, we conclude that in C. tropicalis the reductase together with the 2,3-dienoyl-CoA isomerase is necessary to link the degradation of unsaturated fatty acids to the beta-oxidation cycle. The implication of this conclusion for degradation of unsaturated fatty acids in general is discussed.


Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera.
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21OH) deficiency is an autosomal recessive inborn error of cortisol biosynthesis, with varying degrees of aldosterone production. There is a continuum of phenotypes which generally correlate with genotype and the expected residual 21OH activity of the less severely impaired allele. CYP21A1P/CYP21A2 chimeric genes caused by recombination between CYP21A2 and its highly homologous CYP21A1P pseudogene are common in CAH and typically associated with salt-wasting CAH, the most severe form. Nine chimeras have been described (CH-1 to CH-9). The aim of this study was to genetically evaluate two variant alleles carried by a 22-year-old female with the non-salt-wasting simple virilizing form of CAH and biallelic 30-kb deletions. The haplotypes of the CYP21A2 heterozygous variants, as well as the chimeric junction sites, were determined by Sanger sequencing TA clones of an allele-specific PCR product. Genetic testing revealed two rare CYP21A1P/CYP21A2 chimeras: allele 1 matches the previously described CAH CH-1 chimera but without the P30L variant, and allele 2, termed here as novel CAH CH-10, has a junction site between c.293-37 and c.29314, which is expected to retain partial 21OH activity. These two variant alleles further document the complex nature of RCCX modules and highlight that not all CYP21A1P/CYP21A2 chimera severely impair 21OH activity.


Early temporalis muscle transposition for the management of facial paralysis.
Temporalis muscle transposition is a reliable surgical technique for the reanimation of patients with long-standing facial paralysis. It is often employed when facial nerve reinnervation via crossover or cable grafting is not possible. Temporalis muscle transposition can also be used for the immediate treatment of complete facial paralysis due to insults leaving the facial nerve anatomically intact but requiring a prolonged recovery time (more than 1 year). Because temporalis muscle transposition does not interfere with neuronal regeneration, it may be employed early in the management of complete facial paralysis when recovery is predicted to be extended and incomplete. The authors report their experience with early temporalis muscle transposition in the management of facial paralysis in 56 patients with an anatomically intact facial nerve. More than 90% of these patients achieved improved symmetry at rest as well as purposeful movement at the corner of the mouth. In the last 30 patients, the temporoparietal fascial flap was simultaneously harvested and successfully used to obliterate the donor site defect. In conjunction with the immediate implantation of a gold weight in the ipsilateral upper eyelid, this approach to the early management of facial paralysis helps reduce the period of facial disability from years to weeks in a select group of patients.


Auto-assessment tools for mechanical computer aided design education.
Traditionally Computer Aided Design (CAD) courses have been carried out in computer classrooms requiring great amount of teaching personnel. Assessment of students' modeling exercises has been both time consuming and error prone. Utilization of the teaching resources could clearly benefit from online auto-assessment. The auto-assessment tools are widely in use in programming and language courses, but suitable tools for assessing 3D models used in CAD are lacking. This paper presents two new online auto-assessment tools to support the development of both command ("what steps are needed to create this shape?") and strategic ("how should I model this shape?") knowledge while learning CAD. The first tool is based on neutral file format (in this case STEP) and can recognize surface differences between student's model and reference model. This tool can assess student's skill to create certain predefined shape (i.e. command knowledge). The second auto-assessment tool utilizes commercial CAD software's API (Application Programming Interface) to test how student's model behaves when modeling parameters are changed. This tool assess student's capabilities to build and design a CAD model's design intent (i.e. strategic knowledge). Developed tools were tested on three mechanical engineering courses. This paper presents both the tools and the feedback received from the students and teachers. Overall, the auto-assessment tools functioned well and feedback from both students and teachers were positive. The most appreciated tool functionality was time and place independent submission and assessment of exercise works. These new tools able focusing teachers' workload from checking the basic exercises to guiding the learning process.


Infragluteal sulcus: a combined histologic and anatomic reappraisal.
The infragluteal fold is one of the major concerns in reshaping of the gluteal region. This study reevaluated the fold both histologically and anatomically. Five fixed cadavers were used. The infragluteal fold on the right side was explored by dissection, whereas the infragluteal fold of the contralateral side was removed en bloc. Tissue samples (6 cm long x 2 mm thick) were taken at three points from each fold bloc: the most medial point, the middle point, and the most lateral end of the sulcus. Anatomic dissections and histologic examinations showed that the infragluteal fold consists of strong fibrous bands extending from the dermis of the medial one-third of the fold to the ramus of the ischium and sacrum, forming the letter J. The infragluteal fold, which attaches to both the ischium and the sacrum in a continuous fashion, is an anatomic structure in its medial part and only a crease laterally.


Co-occurrence of sexual dysfunction within young married couple dyads living in rural China: a population-based study.
A total of 298 randomly selected married couple dyads in rural China were studied. Sexual dysfunction (SD) was reported by 84 (28.2%) of the husbands and 136 (45.6%) of the wives. Co-occurrence of SD was reported by 51 of the married couples; hence, SD co-occurred in the spouses of 60.7% of the husbands with SD and 37.5% of wives reporting SD. Pain during intercourse but not other SD of the wives was associated with SD of the husbands. Men's SD including inability to achieve orgasm, finding sex not pleasurable and lack of interest in sex, but not premature ejaculation or erectile dysfunction, were associated with the presence of SD among the wives. Decision-making control on sexual matters, communication between the spouses on sexual problems, the seeking of professional help, perceived adequacy of sexual knowledge as well as mental health and vitality quality of life indices were associated with co-occurrence of SD within the couple dyads.


Antiproliferative activity of 2,3-disubstituted indoles toward apoptosis-resistant cancers cells.
Many types of cancer, including glioma, melanoma, NSCLC, among others, are resistant to apoptosis induction and poorly responsive to current therapies with propaptotic agents. We describe a series of 2,3-disubstituted indoles, which display cytostatic rather than cytotoxic effects in cancer cells, and serve as a new chemical scaffold to develop anticancer agents capable of combating apoptosis-resistant cancers associated with dismal prognoses.


Adverse reactions and interactions of cyclosporin.
Cyclosporin is a potent, widely used specific immunosuppressive agent which affects T-helper cells, and has little myelotoxicity. Its pharmacokinetics are complex and many of its actions remain poorly understood. Numerous side effects have been reported, affecting most organs. Most troublesome have been renal injury, systemic hypertension and vascular changes. Oral use is more effective than intramuscular and safer than the intravenous route. Interactions with other drugs include those which affect hepatic metabolism and those which reduce clearance. Aminoglycosides, macrolide antibiotics, imidazole derivatives, calcium channel blockers, sulphonamides and steroids are included in such interactions. Other metabolic effects of cyclosporin are more subtle and include hyperchloraemic alkalosis, changes in serum potassium and magnesium and effects on testosterone and prolactin levels. Acute poisoning with cyclosporin has been reported, again without myelosuppression. Cyclosporin is an important agent with multisystem toxicity, which requires precise monitoring of drug concentrations, liver and renal function, haemoglobin levels and plasma electrolytes. Cyclosporin pharmacodynamics and interactions with other drugs need to be carefully considered if lower rates of toxicity are to be achieved.


Effect of cognitive-behavioral group therapy for panic disorder in changing coping strategies.
Cognitive-behavioral group therapy (CBGT) is an efficient treatment for panic disorder (PD). However, the role of CBGT in enhancing strategies to cope with stressful events has not been established. To evaluate the effect of CBGT on the choice of coping strategy by PD patients compared to a group of individuals without mental disorders. Forty-eight PD patients who completed a 12-session CBGT protocol were compared to 75 individuals without mental disorders regarding coping strategies as evaluated by the Coping Strategies Inventory (CSI). The severity of PD was assessed at baseline and after CBGT through the Clinical Global Impression (CGI) scale, the Hamilton Anxiety Scale (HAM-A), and the Panic Inventory (PI). Treatment was effective in reducing PD severity in all outcome measures. Patients used significantly fewer confrontation, escape and avoidance strategies after CBGT. The use of more adaptive coping strategies was related to a decrease in panic attacks and anticipatory anxiety. Application of the CSI showed that the use of strategies was also significantly different in patients as compared to the control group, except for escape and avoidance, which became similar after the CBGT protocol. Despite the changes observed after the CBGT protocol, the choice of coping strategy was still different in patients vs. controls. The current CBGT protocol was used specifically to assess PD symptoms. Other cognitive tools should be included to address maladaptive coping strategies.


Case studies of fulvestrant ("Faslodex") in postmenopausal women with advanced breast cancer.
Fulvestrant is a new oestrogen receptor (ER) antagonist that is licensed for the treatment of postmenopausal women with advanced breast cancer progressing following antioestrogen treatment and may also be effective in those progressing after non-steroidal aromatase inhibitors. The use of fulvestrant in a Compassionate Use Programme (CUP) in a "real-life" setting has permitted its activity and tolerability profile in patients with different disease characteristics to be observed. Here, we present five case reports of fulvestrant use in postmenopausal women with advanced breast cancer progressing after prior endocrine therapy. Clinical experience from the CUP supports the published clinical trial data and suggests that fulvestrant is a valuable new treatment for postmenopausal women with advanced breast cancer, including those with visceral metastases and human epidermal growth factor receptor 2-positive disease.


Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation.
Binding abilities of current inhibitors to MDMX are weaker than to MDM2. Polarizable molecular dynamics simulations (MD) followed by Quantum mechanics/molecular mechanics generalized Born surface area (QM//MM-GBSA) calculations were performed to investigate the binding difference of inhibitors to MDM2 and MDMX. The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX. The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98. The calculated results using the residue-based free energy decomposition method further prove that the interaction strength of inhibitors with M53, V92, P95 and L98 from MDMX are obviously reduced compared to MDM2. We expect that this study can provide significant theoretical guidance for designs of potent dual inhibitors to block the p53-MDM2/MDMX interactions.


From microbiology to cell biology: when an intracellular bacterium becomes part of its host cell.
Mitochondria and chloroplasts are now called organelles, but they used to be bacteria. As they transitioned from endosymbionts to organelles, they became more and more integrated into the biochemistry and cell biology of their hosts. Work over the last 15 years has shown that other symbioses show striking similarities to mitochondria and chloroplasts. In particular, many sap-feeding insects house intracellular bacteria that have genomes that overlap mitochondria and chloroplasts in terms of size and coding capacity. The massive levels of gene loss in some of these bacteria suggest that they, too, are becoming highly integrated with their host cells. Understanding these bacteria will require inspiration from eukaryotic cell biology, because a traditional microbiological framework is insufficient for understanding how they work.


Structural requirements of anticoagulant protein S for its binding to the complement regulator C4b-binding protein.
The vitamin K-dependent anticoagulant protein S binds with high affinity to C4b-binding protein (C4BP), a regulator of complement. Despite the physiological importance of the complex, we have only a patchy view of the C4BP-binding site in protein S. Based on phage display experiments, protein S residues 447-460 were suggested to form part of the binding site. Several experimental approaches were now used to further elucidate the structural requirements for protein S binding to C4BP. Peptides comprising residues 447-460, 451-460, or 453-460 of protein S were found to inhibit the protein S-C4BP interaction, whereas deletion of residues 459-460 from the peptide caused complete loss of inhibition. In recombinant protein S, each of residues 447-460 was mutated to Ala, and the protein S variants were tested for binding to C4BP. The Y456A mutation reduced binding to C4BP approximately 10-fold, and a peptide corresponding to residues 447-460 of this mutant was less inhibitory than the parent peptide. A further decrease in binding was observed using a recombinant variant in which a site for N-linked glycosylation was moved from position 458 to 456 (Y456N/N458T). A monoclonal antibody (HPSf) selective for free protein S reacted poorly with the Y456A variant but reacted efficiently with the other variants. A second antibody, HPS 34, which partially inhibited the protein S-C4BP interaction, reacted poorly with several of the Ala mutants, suggesting that its epitope was located in the 451-460 region. Phage display analysis of the HPS 34 antibody further identified this region as its epitope. Taken together, our results suggest that residues 453-460 of protein S form part of a more complex binding site for C4BP. A recently developed three-dimensional model of the sex hormone-binding globulin-like region of protein S was used to analyze available experimental data.


The pre-hospital epidemiology and management of spinal cord injuries in New South Wales: 2004-2008.
Patients who have sustained a traumatic spinal cord injury require appropriate management in the immediate post-injury period for both survival and to reduce the chances of costly and disabling permanent neurological deficits. Emerging time-critical neuroprotective therapies require the prompt recognition and transfer of patients to a specialised centre for early intervention. The Ambulance Research Institute, with the New South Wales State Spinal Cord Injury Service retrospectively linked prehospital data to spinal cord injury unit (SCIU) outcome data for all 324 patients transported by ambulance and subsequently admitted to a SCIU with a persisting traumatic spinal cord injury (SCI) between January 2004 and June 2008, with the aim of identifying factors that impact on the provision of timely and appropriate care. Paramedics appropriately managed 88% of SCI patients. Only 4.9% of patients had initial vital signs potentially indicative of neurological injury. The median time to a SCIU was 12h, with 60% of patients undergoing multiple transfers. The odds of reaching a SCIU in over 24h were 1.71 times greater for patients injured in a major city (95% CI 1.00-2.90) in comparison to other areas of NSW. More SCI patients with multiple trauma experienced delays in reaching a SCIU (59%), compared to patients with isolated SCI (40%; p=0.039). Patients initially transported to a designated major trauma centre were more likely to be delayed in reaching a SCIU, regardless of whether their injury was an isolated SCI or associated with multiple trauma, compared with other patients. Patients who took greater than 24h to reach a SCIU were 2.5 times more likely to develop a secondary complication (95% CI 1.51-4.17, p=0.0004). Patients who sustained their SCI as a result of a low fall were older and less likely to have their SCI identified and treated early, with less than half of this group reaching a SCIU within 24h compared with other SCI patients (OR 0.42, 95% CI 0.19-0.93, p=0.004). Early recognition, appropriate prehospital management, triage, timely and appropriate interfacility transfers of all SCI patients are critical for access to specialised care and reducing preventable complications. Elderly fallers present particular challenges to early identification.


Epilepsia arithmetices revisited.
Three patients whose epileptic seizures are precipitated by arithmetic calculations are reported and their clinical and EEG features analysed along with those of 7 previous cases. The seizure disorder, in general, was characterised by an onset, in adolescence, of myoclonic jerks with or without tonic-clonic seizures and generalised bisynchronous 2-5 Hz spike-and-wave discharges in the EEG. Problems involving processing of spatial information were among the tasks which induced the dysrhythmia. The specificity and the consistency of the seizure-provoking stimuli suggest that in these patients the cortical areas responsible for calculations and related functions are abnormally hyperexcitable and the repeated stimulation during cognitive activities triggers seizure discharges. Two or our patients responded well to clobazam during a follow-up period of 6 months.


A quality improvement project to assess the use of visual aids to improve understanding and motivation in periodontal patients.
A quality improvement project was carried out in a General Dental Practice in London. The aim was to improve understanding and motivation in periodontal patients. Research into interventions in the medical field to improve understanding and motivation amongst patients, lead to the idea of using visual aids to help motivate periodontal patients and to improve their understanding of the disease. The results from the first Plan-Do-Study-Act cycle using visual aids are presented. After the use of visual aids, patients felt more motivated in maintaining good oral hygiene, felt the visual aids improved their understanding of gum disease and how to take care of their gums and teeth. One hundred percent of patients preferred their diagnosis to be explained to them with visual aids. The project supported the increase in motivation and understanding in periodontal patients. However further data is required to learn more about how visual aids influence patient behaviour, how effective they are in improving patients' understanding and motivation, and other factors which play a role in this. The results of this quality improvement project are promising; it has highlighted that visual aids can have a place in the management of periodontitis in general practice.


Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea-pig.
Procainamide is class Ia Na(+) channel blocker that may prolong ventricular repolarization secondary to inhibition of IK r , the rapid component of the delayed rectifier K(+) current. In contrast to selective IN a blockers such as lidocaine, procainamide was shown to produce arrhythmogenic effects in the clinical setting. This study examined whether pro-arrhythmic responses to procainamide may be accounted for by drug-induced repolarization abnormalities including impaired electrical restitution kinetics, spatial gradients in action potential duration (APD), and activation-to-repolarization coupling. In perfused guinea-pig hearts, procainamide was found to prolong the QT interval on ECG and left ventricular (LV) epicardial monophasic APD, increased the maximum slope of electrical restitution, enhanced transepicardial APD variability, and eliminated the inverse correlation between the local APD and activation time values determined at distinct epicardial recording sites prior to drug infusion. In contrast, lidocaine had no effect on electrical restitution, the degree of transepicardial repolarization heterogeneities, and activation-to-repolarization coupling. Spontaneous episodes of monomorphic ventricular tachycardia were observed in 57% of procainamide-treated heart preparations. No arrhythmia was induced by lidocaine. In summary, this study suggests that abnormal changes in repolarization may contribute to pro-arrhythmic effects of procainamide.


Influence of photoactivation method on conversion, mechanical properties, degradation in ethanol and contraction stress of resin-based materials.
To investigate the influence of photoactivation method on degree of conversion (DC), flexural strength (FS), flexural modulus (FM) and Knoop hardness (KHN) of a composite and an unfilled resin (Filtek Z250 and Scotchbond multi-purpose plus, 3M ESPE) after storage in water or ethanol, and on composite contraction stress (CS). Specimens 1x2x10 mm were prepared for FS test, photoactivated by 600 mW/cm2 x 40 s (A), 200 mW/cm2 x 120 s (B), or 600 mW/cm2 x1 s +3 min delay +600 mW/cm2 x 39 s (C), and tested after 24 h in water or ethanol. Load and displacement values were used to calculate FM. Specimen fragments were used to measure KHN. DC was determined by FT-Raman spectroscopy. CS was determined by mechanical testing. Data were submitted to ANOVA/Tukey's test (alpha=0.05). Composite DC was not affected by photoactivation (A: 65+/-1.8%; B: 66+/-3.4%; C: 65+/-2.9%). Unfilled resin DC was statistically higher using method A (79+/-0.3%) than B (74+/-1.0%) and C (73+/-0.9%). Photoactivation did not influence composite properties, regardless of the storage medium (p>0.05). After ethanol storage, FS of the unfilled resin was lower for specimens irradiated by method B (p<0.001). Pulse-delay curing (C) significantly reduced CS (7.7+/-1.3 MPa), compared to A (10.7+/-1.2 MPa) and B (10.1+/-1.3 MPa). Photoactivation method did not affect composite properties or susceptibility to ethanol degradation. For the unfilled resin, DC was lower with the use of low intensity and pulse-curing, while FS after ethanol storage was reduced by low intensity curing. Pulse-delay curing significantly reduced CS.


Characterization of the Relationship of Inotuzumab Ozogamicin Exposure With Efficacy and Safety End Points in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia.
Inotuzumab ozogamicin (InO), an anti-CD22 monoclonal antibody conjugated to calicheamicin, is approved in Europe and the United States for treatment of adults with relapsed or refractory acute lymphoblastic leukemia (ALL). Population analyses were performed to evaluate the relationship between InO exposure and efficacy and safety end points in patients with ALL. The probability of achieving complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD)-negativity for InO relative to chemotherapy was also investigated. Data from study 1010 (NCT01363297) and INO-VATE (NCT01564784) were pooled for exposure-response (InO, n = 234) and treatment-response (InO, n = 234; chemotherapy, n = 143) analyses. The analyses demonstrated that InO exposure was significantly correlated with achieving CR/CRi and MRD-negativity, as well as with hepatic event adjudication board-reported veno-occlusive disease/sinusoidal obstruction. Patients with ALL treated with InO had significantly greater odds of achieving CR/CRi (7-times higher) and MRD-negativity (13-times higher) than those receiving chemotherapy.


Measure of synchronisation of right atrial depolarisation wavefronts during atrial fibrillation.
A new index of synchronisation (IS) between the electrical activity of pairs of close atrial sites during atrial fibrillation (AF) is introduced. The index assesses the probability of finding synchronous activations in intra-atrial bipolar electrograms and is based on the assumption that two activations closely spaced in time are likely to belong to the same depolarisation wavefront. A dedicated statistical treatment to test this hypothesis is also illustrated. Experimental data were obtained using a multipolar basket catheter in the right atrium in 20 patients during normal sinus rhythm (NSR), atrial flutter (AFL, one patient), high-frequency pacing (HFP, two patients) and chronic AF (17 patients), and 30 segments were obtained from each. From the 24 pairs of bipoles, a single averaged IS and its standard deviation were extracted. The IS was 1 in NSR and HFP and 0.95 +/- 0.02 during AFL. During AF, the IS provided a quantitative measure of the degree of coupling of various atrial sites. The IS varied significantly among the recording sites (range 0.38-0.96), showing a patient-dependent pattern, and decreased as the arrhythmia complexity increases. No temporal trends were observed for the IS values in any chronic AF patient. On average, in each site, the dispersion of the IS over time was lower than 32% of the mean, for all patients. Additional relevant features of the proposed index are its high temporal resolution (2s) and robustness to activation time estimation error, to missing or false detections and to the ever-changing pattern of propagation. The index of synchronisation is a descriptor of the electrophysiological properties of atrial tissues.


Recognition of cell-specific binding of phage display derived peptides using an acoustic wave sensor.
ASSLNIA, a peptide selected for murine myofibers using phage display technology, was immobilized onto an acoustic wave sensor. The sensor responded to murine and feline muscle homogenates indicating crosspieces interactions. Kidney, liver, and brain preparations produced insignificant responses.


Effects of synaptic noise on a neuronal pool model with strong excitatory drive and recurrent inhibition.
A model originally proposed by Akazawa and Kato (1990) for the spinal cord was adopted as prototypical of a neuronal pool with strong excitatory drive and strong recurrent inhibition. Our simulations of the model have shown that a strong synchronization occurs between the spike trains in the neuronal pool. This happens because the proposed model has a single and strong excitatory drive on the neuronal pool. However, usually a multitude of other randomly occurring synaptic inputs impinge on the neuronal pool and therefore a new investigation was carried out to study the effects of synaptic noise on the network behavior. The synaptic noise decreased the degree of synchronization of the neuronal spike trains but on the other hand caused an unexpected decrease in the mean firing rate of the neuronal pool. A detailed analysis indicated that this phenomenon is due to a combination of two mechanisms: a saturation of the feedback inhibition and a decrease of the synchronization in the neuronal pool with synaptic noise. The synaptic noise caused a more frequent activation of the saturated recurrent inhibitory feedback loop along time, thereby increasing the inhibitory effect on the neuronal pool.


Comparative studies of two types of "spontaneous" malignant alteration of ST/A mouse lung fibroblasts propagated in vitro.
Two types of apparently spontaneous malignant alterations of fibroblastlike ST/a mouse lung cells (ST-L cells) grown in vitro are described. One type is characterized by a high tumorigenic potential of the altered cells in nonconditioned syngeneic recipients, a fibroblastlike morphology with cell surface showing very few microvilli by scanning electron-microscopy (SEM), and a growth pattern typical of nontransformed cells. These cells were described as R- cells. The other type is characterized bya low tumorigenic potential in non-conditioned, immunocompetent syngeneic recipients, rounding up of the cells which by SEM showed numerous microvilli on the surface, and a growth pattern typical of transformed cells. These cells were described as round cells or R+ cells. In immunoincompetent mice, R+ cells readily produced sarcomas, which grew faster than those produced by R- cells. Both types of ST-L cells expressed murine leukemia virus (MuLV) when tested in a peroxidase anti-p30 plaque test. The concentration of murine leukemia virus envelope glycoprotein (gp70) has previously (5) been shown to be threefold higher in R+ cells compared to R- cells. Furthermore, round-cell transformation was accompanied by the development of crossreacting rejection antigens protective against a secondary shallenge with Ehrlich ascites tumor and with syngeneic dimethylbenzanthracene induced ST/a mouse leukemia (STABAL). A similar protection was obtained by preimmunization with a cloned embryonic feral mouse cell line (SC-1) infected with ST-L virus as well as with virus-free SC-1 cells, suggesting the presence of rejection antigens both of viral (gp70) and nonviral origin.


A two-compartment modification of the silicone chamber model for nerve regeneration.
In the nerve regeneration silicone chamber model, the regenerate which forms across a 10-mm gap between proximal and distal nerve stumps is a monofascicular structure with an outer perineurial-like cell sheath. Recent work has provided indications that the geometry of the regenerate within a silicone chamber can be altered by experimental modifications of the chamber matrix. In the present study we modified the standard silicone chamber into a two-compartment chamber by inserting a 6- or 10-mm-long siliconized nitrocellulose strip in order to obtain two separate regenerates. Light microscopy 16 days after implantation revealed that two separate nerve structures had formed, one on each side of the nitrocellulose partition and adjacent to it, and each with its own perineurial-like cell sheath. In chambers with 6-mm-long strips a monofascicular regenerate started from the proximal stump and divided into two separate structures as it approached the proximal end of the strip: the two fascicles joined again into a monofascicular structure in the distal portion of the chambers. The new two-compartment silicone chamber model appears suitable for future examinations of experimental fasciculation. In addition, the nitrocellulose partition should allow one to study specific effects of growth factors on axonal regeneration in vivo, as growth factors bind strongly to untreated nitrocellulose while retaining their biological activity.


Changes in cerebral autoregulation, stroke-related blood biomarkers, and autonomic regulation after patent foramen ovale closure in severe migraine patients.
This study aimed to investigate changes in dynamic cerebral autoregulation (dCA), 20 stroke-related blood biomarkers, and autonomic regulation after patent foramen ovale (PFO) closure in severe migraine patients. Patent foramen ovale severe migraine patients, matched non-PFO severe migraine patients, and healthy controls were included. dCA and autonomic regulation were evaluated in each participant at baseline, and within 48-h and 30 days after closure in PFO migraineurs. A panel of stroke-related blood biomarkers was detected pre-surgically in arterial-and venous blood, and post-surgically in the arterial blood in PFO migraineurs. Forty-five PFO severe migraine patients, 50 non-PFO severe migraine patients, and 50 controls were enrolled. The baseline dCA function of PFO migraineurs was significantly lower than that of non-PFO migraineurs and controls but was rapidly improved with PFO closure, remaining stable at 1-month follow-up. Arterial blood platelet-derived growth factor-BB (PDGF-BB) levels were higher in PFO migraineurs than in controls, which was immediately and significantly reduced after closure. No differences in autonomic regulation were observed among the three groups. Patent foramen ovale closure can improve dCA and alter elevated arterial PDGF-BB levels in migraine patients with PFO, both of which may be related to the preventive effect of PFO closure on stroke occurrence/recurrence.


Developmental toxicity: web resources for evaluating risk in humans.
This review presents a brief overview of Internet resources that provides information on developmental toxicity. The advantages and limitations of these resources for evaluating human risk and where each one is useful for informing various stages of the risk assessment process (i.e. hazard characterization, dose-response assessment, exposure assessment and risk characterization) are reviewed. How these Internet resources can be utilized to obtain information on and evaluate the developmental risk associated with exposures during pregnancy will be illustrated using toluene. Translating information derived from laboratory and human population studies into clinical management prescriptions for individual patients is difficult. With the increasing availability of Internet resources that provide information relevant for developmental risk assessments, health care professionals will be better equipped to make more accurate estimations of potential risk for their patients.


Multi-functional pH-sensitive active and intelligent packaging based on highly cross-linked zein for the monitoring of pork freshness.
Intelligent packaging not only protects food from environmental hazards but intuitively monitors the changes of food quality and safety. A novel intelligent packaging film with pH sensitivity and antibacterial and antioxidant effects was developed based on the highly cross-linked zein. The composite film with 0.05 g/g crosslinking agent had the best mechanical properties. The tensile strength (TS) and elongation-at-break (EBA) were 2.42 and 1.53 times of that of zein film, respectively. Moreover, the intelligent packaging showed longstanding antimicrobial and antioxidant effects because of the addition of the tea tree essential oil (TTEO)-loaded mesoporous silica nanoparticles (MSNs). The blueberry anthocyanin as colorimetric indicator was added in the packaging film to monitor the safety of meat products using a mobile phone. The color of the composite film as the packaging of the pork products changed from colorless to brown after 9-day storage to show the spoilage of the pork. To the best of our knowledge, this is the first-time report of 1) the application of TTEO-loaded MSNs for food packing, 2) the addition of TTEO as the antimicrobial agent for zein film, and 3) using the applications of mobile phone to measure the RBG value of the zein-based film. This study offers an example of the highly promising biodegradable intelligent packaging with multi-functions for the enhancement of food safety.


Diagnostic, expanatory, and detection models of Munchausen by proxy: extrapolations from malingering and deception.
The overriding objective is a critical examination of Munchausen syndrome by proxy (MSBP) and its closely-related alternative, factitious disorder by proxy (FDBP). Beyond issues of diagnostic validity, assessment methods and potential detection strategies are explored. A painstaking analysis was conducted of the MSBP and FDBP literature as it relates diagnostic and assessment issues. Given the limitations of this literature, extrapolations were provided from the extensive theory and research on malingering as a related response style. Diagnostic formulations for both MSBP and FDBP de-emphasize the clinical characteristics of the perpetrator. In the case of FDBP, inferential judgments about motivation (e.g., adoption of a sick role) are challenging on conceptual and clinical grounds. When explanatory models from malingering are applied, most research has focused pathogenic models, often allied with psychodynamic thought. Finally, clinical methods for the assessment of MSBP and FDBP are not well developed. Refinements in the conceptualization of MSBP and FDBP can be provided through prototypical analysis. Drawing from malingering research, explanatory models should be expanded to include adaptational and criminological models. Finally, detection strategies for MSBP and FDBP must be formally operationalized and rigorously validated.


Endocrine diagnosis by ultrasound. I. The thyroid, parathyroid and adrenal glands.
The value of ultrasounds in diagnosis endocrine disorders and especially in localizing the tumors of the endocrine glands such as the thyroid, parathyroid, ovary and adrenal has been proved. Ultrasounds are also useful in following up the structural changes occurring in these glands after drug or radioisotopic therapy.


Current Status and Future Prospects of Inflammatory Bowel Disease Genetics.
The genetic background of inflammatory bowel diseases (IBDs) has been explored using genetic analysis techniques, such as genome-wide association studies for the population and whole-exome sequencing analyses of family lineages in cases of very early onset. The results of genetic analysis for IBD indicated the involvement of innate and adaptive immune system variations and epithelial abnormalities in the pathogenesis of IBD. Several associated genes were also reported, indicating that IBD occurs in a heterogeneous population with an extremely diverse background. The genetic background of IBDs is currently being studied to understand not only its onset but also its prognosis, response to treatment, and adverse effects. In the future, it will be possible to use an individual's genetic information for determining appropriate treatment. In Japan, the NUDT15 polymorphism test is performed before administering thiopurine preparations. However, because of racial differences in genetic analysis, biased analysis toward some racial groups may result in overlooking important genetic backgrounds of IBD. Studies of IBDs in a more diverse range of races are expected to elucidate genetic factors through a transethnic analysis, thereby aiding the development of novel treatments and precision medicine for IBDs.


Iris melanoma: features and prognosis in 317 children and adults.
To evaluate iris melanoma in children versus adults. Retrospective, nonrandomized clinical case series including all patients with a clinical diagnosis of iris melanoma managed at the Ocular Oncology Service at Wills Eye Institute over 40 years. Patients were divided into three age categories based on age at presentation: children (≤ 20 years), mid-adults (21-60 years), and older adults (>60 years). The clinical features, treatments, and outcomes were statistically analyzed based on patient age at presentation. The main outcome measures were melanoma features and related metastasis and death. Of 8,101 eyes with uveal melanoma, there were 317 (4%) with iris melanoma, including 24 (8%) children (≤ 20 years), 187 (59%) mid-adults (21-60 years), and 106 (33%) older adults (>60 years). There was no age-related difference in race, sex, tumor quadrant, thickness, pigmentation, associated corectopia, ectropion uveae, hyphema, or extraocular extension. Significant age-related differences were found with mean tumor basal diameter, tapioca appearance, mean intraocular pressure, secondary glaucoma, tumor seeding in angle, and mean number of clock hours of angle seeding. Multivariate analysis of factors predictive of metastasis included extraocular extension and high intraocular pressure. Factors predictive of death included increased tumor thickness and high intraocular pressure. There was no difference in metastasis or death by age group. Iris melanoma shows significant clinical differences in children versus adults, with smaller tumor size, less tumor seeding in angle, and lower incidence of secondary glaucoma. There was no significant difference in metastasis or death by age group.


Genome-wide identification and analysis of a cotton secretome reveals its role in resistance against Verticillium dahliae.
The extracellular space between the cell wall and plasma membrane is a battlefield in plant-pathogen interactions. Within this space, the pathogen employs its secretome to attack the host in a variety of ways, including immunity manipulation. However, the role of the plant secretome is rarely studied for its role in disease resistance. Here, we examined the secretome of Verticillium wilt-resistant Gossypium hirsutum cultivar Zhongzhimian No.2 (ZZM2, encoding 95,327 predicted coding sequences) to determine its role in disease resistance against the wilt causal agent, Verticillium dahliae. Bioinformatics-driven analyses showed that the ZZM2 genome encodes 2085 secreted proteins and that these display disequilibrium in their distribution among the chromosomes. The cotton secretome displayed differences in the abundance of certain amino acid residues as compared to the remaining encoded proteins due to the localization of these putative proteins in the extracellular space. The secretome analysis revealed conservation for an allotetraploid genome, which nevertheless exhibited variation among orthologs and comparable unique genes between the two sub-genomes. Secretome annotation strongly suggested its involvement in extracellular stress responses (hydrolase activity, oxidoreductase activity, and extracellular region, etc.), thus contributing to resistance against the V. dahliae infection. Furthermore, the defense response genes (immunity marker NbHIN1, salicylic acid marker NbPR1, and jasmonic acid marker NbLOX4) were activated to varying degrees when Nicotina benthamiana leaves were agro-infiltrated with 28 randomly selected members, suggesting that the secretome plays an important role in the immunity response. Finally, gene silencing assays of 11 members from 13 selected candidates in ZZM2 displayed higher susceptibility to V. dahliae, suggesting that the secretome members confer the Verticillium wilt resistance in cotton. Our data demonstrate that the cotton secretome plays an important role in Verticillium wilt resistance, facilitating the development of the resistance gene markers and increasing the understanding of the mechanisms regulating disease resistance.