Critical Care Organizations in Academic Medical Centers in North America: A Descriptive Report.
With the exception of a few single-center descriptive reports, data on critical care organizations are relatively sparse. The objectives of our study were to determine the structure, governance, and experience to date of established critical care organizations in North American academic medical centers. A 46-item survey questionnaire was electronically distributed using Survey Monkey to the leadership of 27 identified critical care organizations in the United States and Canada between September 2014 and February 2015. A critical care organization had to be headed by a physician and have primary governance over the majority, if not all, of the ICUs in the medical center. We received 24 responses (89%). The majority of the critical care organizations (83%) were called departments, centers, systems, or operations committees. Approximately two thirds of respondents were from larger (> 500 beds) urban institutions, and nearly 80% were primary university medical centers. On average, there were six ICUs per academic medical center with a mean of four ICUs under critical care organization governance. In these ICUs, intensivists were present in-house 24/7 in 49%; advanced practice providers in 63%; hospitalists in 21%; and telemedicine coverage in 14%. Nearly 60% of respondents indicated that they had a separate hospital budget to support data management and reporting, oversight of their ICUs, and rapid response teams. The transition from the traditional model of ICUs within departmentally controlled services or divisions to a critical care organization was described as gradual in 50% and complete in only 25%. Nearly 90% indicated that their critical care organization governance structure was either moderately or highly effective; a similar number suggested that their critical care organizations were evolving with increasing domain and financial control of the ICUs at their respective institutions. Our survey of the very few critical care organizations in North American academic medical centers showed that the governance models of critical care organizations vary and continue to evolve. Additional studies are warranted to improve our understanding of the factors that can foster the growth of critical care organizations and how they can be effective.


Investigation into the acceptability of door locking to staff, patients, and visitors on acute psychiatric wards.
There is disagreement among psychiatric professionals about whether the doors of acute psychiatric wards should be kept locked to prevent patients from leaving and harming themselves or others. This study explored patient, staff, and visitor perceptions about the acceptability of locking the ward door on acute psychiatric inpatient wards. Interviews were conducted with 14 registered nurses, 15 patients, and six visitors from three different acute wards. Findings revealed commonalities across all groups, with general agreement that locking the door reduced absconding. Staff expressed feelings of guilt, embarrassment, and fear of being blamed when a patient absconded. Staff also reported that open wards created anxious vigilance to prevent an abscond and increased workload in allocating staff to watch the door, whereas staff on partially-locked doors also perceived an increased workload in letting people in and out of the ward. Patients had mixed feelings about the status of the door, expressing depression, a sense of stigma, and low self-esteem when the door was locked. The issue of balancing safety and security on acute psychiatric wards against the autonomy of patients is not easily resolved, and requires focused research to develop innovative nursing practices.


A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells.
Recent findings on the inhibition of angiogenesis and vascular endothelial cell proliferation by anthracycline antibiotics, which contain a quinone moiety, make this type of compound a very promising lead in cancer research/therapy. We have reported that a new cannabinoid anticancer quinone, cannabidiol hydroxyquinone (HU-331), is highly effective against tumor xenografts in nude mice. For evaluation of the antiangiogenic action of cannabinoid quinones, collagen-embedded rat aortic ring assay was used. The ability of cannabinoids to cause endothelial cell apoptosis was assayed by TUNEL staining and flow cytometry analysis. To examine the genes and pathways targeted by HU-331 in vascular endothelial cells, human cDNA microarrays and polymerase chain reaction were used. Immunostaining with anti-CD31 of tumors grown in nude mice served to indicate inhibition of tumor angiogenesis. HU-331 was found to be strongly antiangiogenic, significantly inhibiting angiogenesis at concentrations as low as 300 nM. HU-331 inhibited angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro- and antiangiogenic cytokines and their receptors. A significant decrease in the total area occupied by vessels in HU-331-treated tumors was also observed. These data lead us to consider HU-331 to have high potential as a new antiangiogenic and anticancer drug.


Exercising on Different Unstable Surfaces Increases Core Abdominal Muscle Thickness: An Observational Study Using Real-Time Ultrasound.
The training of abdominal muscles has a positive impact on the functional capacity of healthy adults, being applied practically in fields of athletics and fitness through rehabilitation for lower back pain. The study compares abdominal muscle activity while performing graded isometric exercises on stable and unstable surfaces. The authors also examined perceived stability and comfort for the different surfaces. A total of 30 young, healthy adults performed 3 graded isometric exercises on a Pilates table, foam roller, and Oov (a newly developed tool). Ultrasound investigation measured transversus abdominis, internal oblique abdominis, and external oblique abdominis thickness during each task, comparing muscle thickness between conditions using general linear modeling. Core abdominal activation was greater on the foam roller than the Oov and Pilates table during crook lying (bilateral leg support). Both Oov and foam roller elicited greater contralateral transversus abdominis and internal oblique abdominis thickness than the Pilates table during tabletop and straight leg raises (unilateral leg exercises). For transversus abdominis only, the foam roller elicited more muscle thickness than the Oov during straight leg raises. The Oov was rated more comfortable than the foam roller. Exercises performed on the Oov and foam roller elicit core greater abdominal muscle thickness than those performed on a Pilates table. Unilateral leg exercises in a supine position elicit more contralateral muscle thickness than those with bilateral leg support. These results provide information to support choices in exercise progression from flat stable to more unstable surfaces and from those with bilateral foot support to unilateral foot support. The Oov was more comfortable that the foam roller, and this may help with exercise adherence.


Normal vitamin D and low free estradiol levels in women on enzyme-inducing antiepileptic drugs.
Relationships between reproductive hormone levels, bone turnover marker levels, bone mineral density, and rates of bone loss were evaluated in premenopausal women with epilepsy taking enzyme-inducing antiepileptic drugs (EIAEDs: phenytoin or carbamazepine) or lamotrigine. Calciotropic and reproductive hormone levels, bone turnover marker levels, and bone mineral density were measured at baseline and 1 year. Bone mineral density did not differ between groups. Serum calcium (P<0.001) and estrone (P<0.001) levels were lower in the EIAED group. Sex hormone-binding globulin levels were higher (P<0.001) and percentage free estradiol levels were lower (P<0.001) in the EIAED group. We detected no relationship between bone mineral density change and calciotropic hormone or bone turnover marker levels. Women with higher sex hormone-binding globulin and lower free estradiol levels sustained more bone loss at the total hip (P=0.04 and P=0.02) and a trend toward more bone loss at the lumbar spine (P=0.07 and P=0.08). These findings suggest that lower estrogen levels may contribute to bone loss in premenopausal women with epilepsy.


Nonlinear temporal diffraction and frequency shifts resulting from pulse shaping in chirped-pulse amplification systems.
We present experimental results of the amplification of strongly amplitude-modulated chirped pulses resulting from the coherent addition of two delayed short pulses. The nonlinearities in the amplifier chain induce a temporal diffraction resulting in prepulses and postpulses, in addition to the two main pulses when compressed. Simultaneously, temporal-resolved and spectral-resolved output pulses show that the prepulses and postpulses are blue shifted and red shifted, respectively, explaining the causality of the system.


QSARs for phenols and phenolates: oxidation potential as a predictor of reaction rate constants with photochemically produced oxidants.
Quantitative structure-activity relationships (QSARs) for prediction of the reaction rate constants of phenols and phenolates with three photochemically produced oxidants, singlet oxygen, carbonate radical, and triplet excited state sensitizers/organic matter, are developed. The predictive variable is the one-electron oxidation potential (E1), which is calculated for each species using density functional theory. The reaction rate constants are obtained from the literature, and for singlet oxygen, are augmented with new experimental data. Calculated E1 values have a mean unsigned error compared to literature values of 0.04-0.06 V. For singlet oxygen, a single linear QSAR that includes both phenols and phenolates is developed that predicts experimental rate constants, on average, to within a factor of three. Predictions for only 6 out of 87 compounds are off by more than a factor of 10. A more limited data set for carbonate radical reactions with phenols and phenolates also gives a single linear QSAR with prediction of rate constant being accurate to within a factor of three. The data for the reactions of phenols with triplet state sensitizers demonstrate that two sensitizers, 2-acetonaphthone and methylene blue, most closely predict the reactivity trend of triplet excited state organic matter with phenols. Using sensitizers with stronger reduction potentials could lead to overestimation of rate constants and thus underestimation of phenolic pollutant persistence.


Pan-cancer integrative histology-genomic analysis via multimodal deep learning.
The rapidly emerging field of computational pathology has demonstrated promise in developing objective prognostic models from histology images. However, most prognostic models are either based on histology or genomics alone and do not address how these data sources can be integrated to develop joint image-omic prognostic models. Additionally, identifying explainable morphological and molecular descriptors from these models that govern such prognosis is of interest. We use multimodal deep learning to jointly examine pathology whole-slide images and molecular profile data from 14 cancer types. Our weakly supervised, multimodal deep-learning algorithm is able to fuse these heterogeneous modalities to predict outcomes and discover prognostic features that correlate with poor and favorable outcomes. We present all analyses for morphological and molecular correlates of patient prognosis across the 14 cancer types at both a disease and a patient level in an interactive open-access database to allow for further exploration, biomarker discovery, and feature assessment.


Assessment of intramuscular administration of three doses of alfaxalone combined with hydromorphone and dexmedetomidine for endoscopic-guided orotracheal intubation in domestic rabbits (Oryctolagus cuniculus).
To determine the dose of alfaxalone for IM administration combined with dexmedetomidine and hydromorphone that would allow endoscopic-guided orotracheal intubation in rabbits without causing a decrease in respiratory rate or apnea. 15 sexually intact (9 females and 6 males) healthy Miniature Lop rabbits weighing a mean ± SD of 2.3 ± 0.3 kg and ranging in age from 4 to 9 months. In a randomized, controlled clinical trial, rabbits received 0.1 mg of hydro-morphone/kg and 0.005 mg of dexmedetomidine/kg, plus alfaxalone at either 2 mg/kg (5 rabbits), 5 mg/kg (5 rabbits), or 7 mg/kg (5 rabbits). Drugs were mixed in a single syringe and administered IM. Semiquantitative rating scales were used to evaluate quality of anesthesia and intubation. Orotracheal intubation was attempted with endoscopy and confirmed by capnography. The number of successful intubations was 0, 3, and 4 in rabbits receiving 2, 5, and 7 mg of alfaxalone/kg, respectively. Median (range) anesthesia quality scores (scale, 0 to 12; 12 = deepest anesthesia) were 3 (2 to 5), 6 (5 to 6), and 6 (4 to 9) for rabbits receiving 2, 5, and 7 mg of alfaxalone/kg, respectively. The median (range) intubation quality scores (scale, 0 to 3 [ie, intubation not possible to easiest intubation]) were 0 (0 to 0), 2 (0 to 3), and 2 (0 to 3) for rabbits receiving 2, 5, and 7 mg of alfaxalone/kg, respectively. None of the rabbits experienced a decrease in respiratory rate or apnea. Increasing doses of alfaxalone combined with hydromorphone and dexmedetomidine increased the success rate of endoscopic-guided orotracheal intubation. Increasing the dose of alfaxalone had no effect on respiratory rate.


Search for a new heavy gauge-boson resonance decaying into a lepton and missing transverse momentum in 36 fb - 1 of pp collisions at s = 13 TeV with the ATLAS experiment.
The results of a search for new heavy W ' bosons decaying to an electron or muon and a neutrino using proton-proton collision data at a centre-of-mass energy of s = 13 TeV are presented. The dataset was collected in 2015 and 2016 by the ATLAS experiment at the Large Hadron Collider and corresponds to an integrated luminosity of 36.1 fb - 1 . As no excess of events above the Standard Model prediction is observed, the results are used to set upper limits on the W ' boson cross-section times branching ratio to an electron or muon and a neutrino as a function of the W ' mass. Assuming a W ' boson with the same couplings as the Standard Model W boson, W ' masses below 5.1 TeV are excluded at the 95% confidence level.


Eating locally: Australasian gannets increase their foraging effort in a restricted range.
During the breeding season, seabirds adopt a central place foraging strategy and are restricted in their foraging range by the fasting ability of their partner/chick and the cost of commuting between the prey resources and the nest. Because of the spatial and temporal variability of marine ecosystems, individuals must adapt their behaviour to increase foraging success within these constraints. The at-sea movements, foraging behaviour and effort of the Australasian gannet (Morus serrator) was determined over three sequential breeding seasons of apparent differing prey abundance to investigate how the species adapts to inter-annual fluctuations in food availability. GPS and tri-axial accelerometer data loggers were used to compare the degree of annual variation within two stages of breeding (incubation and chick rearing) at a small gannet colony situated between two larger, nearby colonies. Interestingly, neither males nor females increased the total distance travelled or duration of foraging trip in any breeding stage (P>0.05 in all cases) despite apparent low prey availability. However, consistently within each breeding stage, mean vectorial dynamic body acceleration (an index of energy expenditure) was greater in years of poorer breeding success (increased by a factor of three to eight), suggesting birds were working harder within their range. Additionally, both males and females increased the proportion of a foraging trip spent foraging in a poorer year across both breeding stages. Individuals from this colony may be limited in their ability to extend their range in years of low prey availability due to competition from conspecifics in nearby colonies and, consequently, increase foraging effort within this restricted foraging area.


Multi-scale temporal patterns in fish presence in a high-velocity tidal channel.
The natural variation of fish presence in high-velocity tidal channels is not well understood. A better understanding of fish use of these areas would aid in predicting fish interactions with marine hydrokinetic (MHK) devices, the effects of which are uncertain but of high concern. To characterize the patterns in fish presence at a tidal energy site in Cobscook Bay, Maine, we examined two years of hydroacoustic data continuously collected at the proposed depth of an MHK turbine with a bottom-mounted, side-looking echosounder. The maximum number of fish counted per hour ranged from hundreds in the early spring to over 1,000 in the fall. Counts varied greatly with tidal and diel cycles in a seasonally changing relationship, likely linked to the seasonally changing fish community of the bay. In the winter and spring, higher hourly counts were generally confined to ebb tides and low slack tides near sunrise and sunset. In summer and fall of each year, the highest fish counts shifted to night and occurred during ebb, low slack, and flood tides. Fish counts were not linked to current speed, and did not decrease as current speed increased, contrary to observations at other tidal power sites. As fish counts may be proportional to the encounter rate of fish with an MHK turbine at the same depth, highly variable counts indicate that the risk to fish is similarly variable. The links between fish presence and environmental cycles at this site will likely be present at other locations with similar environmental forcing, making these observations useful in predicting potential fish interactions at tidal energy sites worldwide.


Surgical treatment of vertebral metastasis.
Fifty-seven patients with spinal metastases underwent 60 operations. 36 patients were operated on by anterior approach with decompressive coporectomy and stabilization by metal and methylmetacrylate and 24 patients by laminectomy and/or stabilization by osteosynthesis. Postoperative improvement of the pain syndrome was observed after 56 operations. Neurologic signs were present in 23 patients with paraplegia (5 patients) or paraparesis (18 patients); 15 of the latter patients improved and recovered walking capacity. Two types of metastasis were distinguished: corporal metastasis, in which vertebral wedging and posterior protrusion led to neural deficit, with a good prognosis if treated by anterior surgery, and pericordal metastasis in which the cord compression is due to metastatic proliferation into the spinal canal. Results after decompressive surgery, either by posterior or anterior approaches are more doubtful. Surgery is beneficial and should be preferred to radiation when there is medullary compression by corporal metastasis and also in the presence of intense pain or potential instability of the spine.


Development of in vitro parameters of cell-mediated immunity in the course of human cutaneous leishmaniasis infection.
The goal of the present study was to determine whether a correlation between the clinical stage of cutaneous leishmaniasis lesions and in vitro parameters of cell-mediated immunity could be established. For this purpose, we measured lymphocyte proliferation, using a total lymphocyte proliferation (TLP) blood assay, and leishmanicidal effector activity using peripheral blood mononuclear cells (PBMC) in a three-day assay. The parameters of leishmanicidal activity measured included percent infected monocytes and number of amastigotes per 100 infected monocytes 24 and 72 hr after infection. Three groups of people were studied: a group of patients in the course of the disease, a group of immune individuals, and unexposed controls. The results of the study suggested that the ability of PBMC to kill parasites increased in patients as the lesions cured, and was highest in immune individuals. In contrast, the TLP response once positive, did not increase after cure. In approximately 30% of the patients who were retested on several occasions during the course of the disease, a positive response reversed to negative both in the TLP and the effector assays while the lesions were still active. In approximately 50% of these cases, the response eventually became positive again. The data presented show that effector activity and proliferation correlate with immunity, and suggest that marked heterogeneity characterizes the immune response in the course of active disease.


Is the current surge in political and financial attention to One Health solidifying or splintering the movement?
The global health field has witnessed the rise, short-term persistence and fall of several movements. One Health, which addresses links between human, animal and environmental health, is currently experiencing a surge in political and financial attention, but there are well-documented barriers to collaboration between stakeholders from different sectors. We examined how stakeholder dynamics and approaches to operationalising One Health have evolved further to recent political and financial support for One Health. We conducted a mixed methods study, first by qualitatively investigating views of 25 major policymakers and funders of One Health programmes about factors supporting or impeding systemic changes to strengthen the One Health movement. We then triangulated these findings with a quantitative analysis of the current operations of 100 global One Health Networks. We found that recent attention to One Health at high-level political fora has increased power struggles between dominant human and animal health stakeholders, in a context where investment in collaboration building skills is lacking. The injection of funding to support One Health initiatives has been accompanied by a rise in organisations conducting diverse activities under the One Health umbrella, with stakeholders shifting operationalisation in directions most aligned with their own interests, thereby splintering and weakening the movement. While international attention to antimicrobial resistance was identified as a unique opportunity to strengthen the One Health movement, there is a risk that this will further drive a siloed, disease-specific approach and that structural changes required for wider collaboration will be neglected. Our analysis indicated several opportunities to capitalise on the current growth in One Health initiatives and funding. In particular, evidence from better monitoring and evaluation of ongoing activities could support the case for future funding and allow development of more precise guidelines on best practices.


Pendellösung effect in photonic crystals.
At the exit surface of a photonic crystal, the intensity of the diffracted wave can be periodically modulated, showing a maximum in the "positive" (forward diffracted) or in the "negative" (diffracted) direction, depending on the slab thickness. This thickness dependence is a direct result of the so-called Pendell osung phenomenon, consisting of the periodic exchange inside the crystal of the energy between direct and diffracted beams. We report the experimental observation of this effect in the microwave region at about 14GHz by irradiating 2D photonic crystal slabs of different thickness and detecting the intensity distribution of the electromagnetic field at the exit surface and inside the crystal itself.


FAPI-74 PET/CT Using Either 18F-AlF or Cold-Kit 68Ga Labeling: Biodistribution, Radiation Dosimetry, and Tumor Delineation in Lung Cancer Patients.
68Ga-fibroblast activation protein inhibitors (FAPIs) 2, 4, and 46 have already been proposed as promising PET tracers. However, the short half-life of 68Ga (68 min) creates problems with manufacture and delivery. 18F (half-life, 110 min) labeling would result in a more practical large-scale production, and a cold-kit formulation would improve the spontaneous availability. The NOTA chelator ligand FAPI-74 can be labeled with both 18F-AlF and 68Ga. Here, we describe the in vivo evaluation of 18F-FAPI-74 and a proof of mechanism for 68Ga-FAPI-74 labeled at ambient temperature. Methods: In 10 patients with lung cancer, PET scans were acquired at 10 min, 1 h, and 3 h after administration of 259 ± 26 MBq of 18F-FAPI-74. Physiologic biodistribution and tumor uptake were semiquantitatively evaluated on the basis of SUV at each time point. Absorbed doses were evaluated using OLINDA/EXM, version 1.1, and QDOSE dosimetry software with the dose calculator IDAC-Dose, version 2.1. Identical methods were used to evaluate one examination after injection of 263 MBq of 68Ga-FAPI-74. Results: The highest contrast was achieved in primary tumors, lymph nodes, and distant metastases at 1 h after injection, with an SUVmax of more than 10. The effective dose per a 100-MBq administered activity of 18F-FAPI-74 was 1.4 ± 0.2 mSv, and for 68Ga-FAPI-74 it was 1.6 mSv. Thus, the radiation burden of a diagnostic 18F-FAPI-74 PET scan is even lower than that of PET scans with 18F-FDG and other 18F tracers; 68Ga-FAPI-74 is comparable to other 68Ga ligands. FAPI PET/CT supported target volume definition for guiding radiotherapy. Conclusion: The high contrast and low radiation burden of FAPI-74 PET/CT favor multiple clinical applications. Centralized large-scale production of 18F-FAPI-74 or decentralized cold-kit labeling of 68Ga-FAPI-74 allows flexible routine use.


Almost all infiltrating colloid carcinomas of the pancreas and periampullary region arise from in situ papillary neoplasms: a study of 39 cases.
Colloid carcinomas of organs such as the breast, colon, and prostate have been well characterized. However, up until now there have been only a few studies of colloid carcinomas of the pancreas and periampullary region, and the number of colloid carcinomas in these studies has been limited. A search of our files revealed 39 resections for pancreatic and periampullary carcinomas with colloid differentiation. All neoplasms were extensively sampled. "Carcinomas with colloid differentiation" were defined as tumors associated with abundant extracellular mucin containing free-floating mucinous epithelial cells. Cases with >50% colloid differentiation were classified as "colloid carcinomas," whereas those with less were termed "carcinomas with focal colloid features." Cases with no colloid differentiation at all were designated "carcinomas without colloid differentiation." Of the 39 carcinomas, 31 were colloid carcinomas, and eight were carcinomas with focal colloid features. Twenty-seven were centered in the pancreas, seven were in the duodenum, and five were in the ampulla of Vater. Remarkably, 38 of the 39 carcinomas (97%) arose in association with an intraductal papillary mucinous neoplasm or a tubular/tubulovillous adenoma. Of the patients with colloid carcinomas, the 2-and 5-year actuarial survival rates were 69% and 29%, respectively. There was no significant difference in survival rates between patients with colloid carcinomas and patients with adenocarcinomas without colloid differentiation, whether or not the latter arose in association with intraductal papillary mucinous neoplasms or tubular/tubulovillous adenomas. In a multivariate model colloid differentiation was not an independent predictor of patient survival, while other factors such as tumor location, perineural invasion, vascular invasion, and margin status after resection independently influenced patient survival. Most colloid carcinomas of the pancreas and periampullary region arise in association with a well-defined in situ papillary neoplasm. The diagnosis of a pancreatic or periampullary colloid carcinoma should encourage the pathologist to search for an associated low-grade in situ component. In addition, colloid carcinomas of the pancreas and periampullary region do not necessarily have a better prognosis than carcinomas without colloid differentiation. Instead, other factors such as tumor location, perineural invasion, vascular invasion, and margin status after resection are far more important.


The psychology of good judgment: frequency formats and simple algorithms.
Mind and environment evolve in tandem--almost a platitude. Much of judgment and decision making research, however, has compared cognition to standard statistical models, rather than to how well it is adapted to its environment. The author argues two points. First, cognitive algorithms are tuned to certain information formats, most likely to those that humans have encountered during their evolutionary history. In particular, Bayesian computations are simpler when the information is in a frequency format than when it is in a probability format. The author investigates whether frequency formats can make physicians reason more often the Bayesian way. Second cognitive algorithms need to operate under constraints of limited time, knowledge, and computational power, and they need to exploit the structures of their environments. The author describes a fast and frugal algorithm. Take The Best, that violates standard principles of rational inference but can be as accurate as sophisticated "optimal" models for diagnostic inference.


Predisposition to and effects of methamphetamine use on the adolescent brain.
Adolescence is a period of heightened vulnerability both to addictive behaviors and drug-induced brain damage. Yet, only limited information exists on the brain mechanisms underlying these adolescent-specific characteristics. Moreover, distinctions in brain correlates between predisposition to drug use and effects of drugs in adolescents are unclear. Using cortical thickness and diffusion tensor image analyses, we found greater and more widespread gray and white matter alterations, particularly affecting the frontostriatal system, in adolescent methamphetamine (MA) users compared with adult users. Among adolescent-specific gray matter alterations related to MA use, smaller cortical thickness in the orbitofrontal cortex was associated with family history of drug use. Our findings highlight that the adolescent brain, which undergoes active myelination and maturation, is more vulnerable to MA-related alterations than the adult brain. Furthermore, MA-use-related executive dysfunction was greater in adolescent MA users than in adult users. These findings may provide explanation for the severe behavioral complications and relapses that are common in adolescent-onset drug addiction. Additionally, these results may provide insights into distinguishing the neural mechanisms that underlie the predisposition to drug addiction from effects of drugs in adolescents.


A retrospective analysis of the costs and consequences of a tobacco-cessation program for active duty service members.
Health system records of 126 active-duty (AD) service members who were participants in the Davis-Monthan AFB "Quitters are Winners" tobacco cessation program (QAWP) between June 1993 and May 1994 were reviewed retrospectively during the fall of 1994. Participants received an average of 2.84 (+/- 1.46) prescriptions for transdermal nicotine replacement therapy representing 6 weeks duration. Tobacco abstinence, determined by 6-month point prevalence abstinence (PPA), was 19.05 and 15.08% for 6-month continuous abstinence (CA). PPA and CA rates were significantly higher than expected (z = 3.94, p < 0.002; z = 2.38, p < 0.02). Average operational cost per successful outcome at 6 months after entry into the QAWP were $778.93 using PPA and $983.92 using CA. Additional analyses revealed corresponding increases between average cost per successful outcome and duration of TNRT. This research provides an initial analysis of the efficiency of the QAWP for AD participants and a model for subsequent evaluations within military medical treatment facilities.


Management of chronic expanding haematoma using triamcinolone after latissimus dorsi flap harvesting.
Chronic expanding haematoma (CEH) is a rare type of haematoma that enlarges slowly and continuously without coagulation. It can occur following surgery because of shear stress-induced bleeding in the scar tissue between the subcutaneous fat and fascia. We present three cases of large chronic CEH that were successfully treated with triamcinolone injections. Three female patients developed large chronic CEH at 9 months, 5 years, and 6 years, respectively, after latissimus dorsi flap harvesting for breast reconstruction. Although the condition did not improve after multiple sessions of haematoma aspiration in the first two patients, it resolved following a single 40-mg triamcinolone injection along with appropriate compression dressing for several weeks. In the third patient, triamcinolone was injected immediately after the initial aspiration of the haematoma, and the condition improved considerably. There were no side effects in any of the patients. To the best of our knowledge, this is the first report of successful treatment of large CEH using triamcinolone. Therefore, we suggest that triamcinolone injections be considered for the treatment of CEH.


Predictors of Time to Metastasis in Castration-resistant Prostate Cancer.
To investigate predictors of time to metastasis among men treated with androgen deprivation therapy for nonmetastatic prostate cancer who developed castration-resistant prostate cancer (CRPC) within the Shared Equal Access Regional Cancer Hospital cohort. This is a retrospective analysis of 458 nonmetastatic CRPC men. Metastases were detected in routine bone scans or other imaging tests. Predictors of time to metastasis were analyzed using proportional hazards model with CRPC as time zero. A total of 256 (56%) men were diagnosed with metastatic disease over a median follow-up of 36 months. Metastasis-free survival was 79%, 65%, 52%, 47%, and 41% at 1, 2, 3, 4, and 5 years after CRPC, respectively. In multivariable analysis, Gleason score 8-10 (hazard ratio [HR] = 1.61; P = .026), receiving primary localized treatment (HR = 1.38; P = .028), higher prostate-specific antigen (PSA) levels at CRPC diagnosis (logPSA HR = 1.64; P < .001), and PSA doubling time ≤6 months (HR = 1.42; P = .040) were independently associated with shorter time to metastasis. Race, year of CRPC, age, and time from androgen deprivation therapy to CRPC were not associated with metastasis. Among nonmetastatic CRPC men, nearly 60% developed metastatic disease during the first 5 years, with most of the metastasis occurring within the first 3 years. Higher Gleason score, receiving primary treatment, higher PSA, and shorter PSA doubling time were independently associated with shorter time to metastasis. Therefore, these variables can be used to stratify patients according to metastasis risk.


Ultra-processed food intake and eating disorders: Cross-sectional associations among French adults.
Data regarding the association between ultra-processed food (UPF) consumption and eating disorders (ED) are scarce. Our aim was to investigate whether UPF intake was associated with different ED types in a large population-based study. 43,993 participants (mean age = 51.0 years; 76.1% women) of the French NutriNet-Santé web-cohort who were screened for ED in 2014 via the Sick-Control-One stone-Fat-Food (SCOFF) questionnaire, were included in the analysis. The clinical algorithm Expali TM tool was used to identify four ED types: restrictive, bulimic, binge eating, and other (not otherwise specified). Mean dietary intake was evaluated from at least 2 self-administered 24-h dietary records (2013-2015); categorization of food as ultra-processed or not relied on the NOVA classification. The associations between UPF intake (as percent and reflecting mean daily UPF quantity (g/d) within the dietary intake, %UPF) and ED types were evaluated using polytomous logistic regression models. 5,967 participants (13.6%) were categorized as likely ED (restrictive n = 444; bulimic n = 1,575; binge eating n = 3,124; other ED n = 824). The fully-adjusted analyses revealed a positive association between UPF intake and bulimic, binge eating, and other ED: ED risk (odds ratio, OR) for an absolute 10-percentage point incremental increase in %UPF intake were 1.08 (1.01-1.14; P = 0.02), 1.21 (1.16-1.26; P < 0.0001), and 1.11 (1.02-1.20; P = 0.02), respectively. No significant association was detected for restrictive ED. This study revealed an association of UPF intake with different ED types among French adults. Future research is needed to elucidate the direction of the observed associations.


Rodent models of AKI-CKD transition.
Acute kidney injury (AKI) is a contributing factor in the development and progression of chronic kidney disease (CKD). Despite rapid progresses, the mechanism underlying AKI-CKD transition remains largely unclear. Animal models recapitulating this process are crucial to the research of the pathophysiology of AKI-CKD transition and the development of effective therapeutics. In this review, we present the commonly used rodent models of AKI-CKD transition, including bilateral ischemia-reperfusion injury (IRI), unilateral IRI, unilateral IRI with contralateral nephrectomy, multiple episodes of IRI, and repeated treatment of low-dose cisplatin, diphtheria toxin, aristolochic acid, or folic acid. The main merits and pitfalls of these models are also discussed. This review provides helpful information for establishing reliable and clinically relevant models for studying post-AKI development of chronic renal pathologies and the progression to CKD.


Clinical Surveillance After Macroscopically Complete Surgery for Low-Grade Appendiceal Mucinous Neoplasms (LAMN) with or Without Limited Peritoneal Spread: Long-Term Results in a Prospective Series.
Low-grade appendiceal mucinous neoplasm (LAMN) is the most common primary lesion of pseudomyxoma peritonei, a disease whose standard treatment is cytoreduction and hyperthermic intraperitoneal chemotherapy. The optimal management of LAMN is not well defined. This study prospectively assessed a clinical surveillance strategy for LAMN with or without limited peritoneal spread. During 2003-2017, the study prospectively enrolled 41 patients treated by macroscopically complete surgery for LAMN with or without limited peritoneal spread (pelvis and right lower quadrant). Follow-up assessment included thoracic-abdomino-pelvic computed tomography scan and serum tumor markers scheduled after surgery, then every 6 months for 5 years, and yearly thereafter. All specimens were reviewed by a dedicated pathologist. Appendectomy and five right colectomies were performed for 36 patients. Nine patients also underwent macroscopically complete cytoreduction of mucinous peritoneal disease, and four patients had hysterectomy plus bilateral salphingo-oophorectomy. Appendiceal rupture was evaluable in 38 of the 41 patients, being present in 21 patients (51.2%). Mucin, cells, or both outside the appendix were observed in 24 patients (58.5%). The median follow-up period was 58 months (range 9.3-162 months). The 5-year recurrence-free survival rate was 95.1%. Only two patients experienced peritoneal recurrences (4.9%), respectively 18 and 22 months after appendectomy. Their primary lesions were LAMNs with and without appendix wall rupture or extra-appendiceal mucin, respectively. No death occurred. These findings strongly suggest that radically resected LAMN, even with limited peritoneal spread, carries a low recurrence risk. Furthermore, appendix wall perforation and the presence of mucin, cells, or both outside the appendix were not associated with a higher risk of metachronous peritoneal dissemination. In this setting, clinical and radiologic surveillance is a viable choice.


Streptococcus pneumoniae NanC: STRUCTURAL INSIGHTS INTO THE SPECIFICITY AND MECHANISM OF A SIALIDASE THAT PRODUCES A SIALIDASE INHIBITOR.
Streptococcus pneumoniae is an important human pathogen that causes a range of disease states. Sialidases are important bacterial virulence factors. There are three pneumococcal sialidases: NanA, NanB, and NanC. NanC is an unusual sialidase in that its primary reaction product is 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en, also known as DANA), a nonspecific hydrolytic sialidase inhibitor. The production of Neu5Ac2en from α2-3-linked sialosides by the catalytic domain is confirmed within a crystal structure. A covalent complex with 3-fluoro-β-N-acetylneuraminic acid is also presented, suggesting a common mechanism with other sialidases up to the final step of product formation. A conformation change in an active site hydrophobic loop on ligand binding constricts the entrance to the active site. In addition, the distance between the catalytic acid/base (Asp-315) and the ligand anomeric carbon is unusually short. These features facilitate a novel sialidase reaction in which the final step of product formation is direct abstraction of the C3 proton by the active site aspartic acid, forming Neu5Ac2en. NanC also possesses a carbohydrate-binding module, which is shown to bind α2-3- and α2-6-linked sialosides, as well as N-acetylneuraminic acid, which is captured in the crystal structure following hydration of Neu5Ac2en by NanC. Overall, the pneumococcal sialidases show remarkable mechanistic diversity while maintaining a common structural scaffold.


When does mother to child transmission of hepatitis C virus occur?
To investigate when hepatitis C virus (HCV) infection from mother to child occurs, and evaluate possible associated factors. Prospective cohort study. Fifty four HCV infected children tested within three days of birth and their mothers. HCV RNA polymerase chain reaction (PCR) results. Seventeen of the children (31%, 95% confidence interval 19% to 46%) were positive in the first 3 days of life and could be assumed to have acquired infection in utero. Testing PCR positive was not associated with sex (53% v 49% boys; p=0.77) or mode of delivery (29% elective caesarean section in both groups; p=0.98). Children with evidence of intrauterine infection were significantly more likely to be of lower birth weight and infected with genotype 1 (58% v 12%, p=0.01). Although a higher proportion of infants born to HCV/HIV co-infected women were PCR positive in the first 3 days of life, this difference did not reach statistical significance; excluding infants born to co-infected women did not affect the results. Thirty seven of the children (68%) were negative in the first 3 days of life, 27 of whom were positive when tested again at 3 months, and nine were first PCR positive after 3 months (one child had no further tests). These results suggest that at least one third and up to a half of infected children acquired infection in utero. Although postpartum transmission cannot be excluded, these data suggest that it is rare. The role of HCV genotypes in the timing and mechanism of infection should be explored further.


[Cognitive therapy and interpersonal psychotherapy for major depressive disorder: how do they work, how long, and for whom?]
Although the effectiveness of cognitive therapy (ct) and interpersonal psychotherapy (ipt) for depression has been well established, little is known about how, how long and for whom they work.
 AIM: To summarize findings from a large rct to the (differential) effects and mechanisms of change of ct/ipt for depression.
 METHOD: 182 adult depressed outpatients were randomized to ct (n = 76), ipt (n = 75), or a two-month wait-list-control condition (n = 31). Primary outcome was depression severity (bdi-ii). Other outcomes were quality of life, social and general psychological functioning and various potential process measures. Interventions were compared at the end of treatment, and up to 17 months follow-up.
 RESULTS: Overall, ct and ipt were both superior to the wait-list, but did not differ significantly from one another. However, the pathway through which therapeutic change occurred appeared to be different for ct and ipt, and many patients were predicted to have a clinically meaningful advantage in one of the two interventions. We did not find empirical support for the theoretical models of change.
 CONCLUSION: (Long-term) outcomes of ct and ipt appear to not differ significantly. The field would benefit from further refinement of research methods to disentangle mechanisms of change, and from advances in the field of personalized medicine.


Automated Affect Detection in Deep Brain Stimulation for Obsessive-Compulsive Disorder: A Pilot Study.
Automated measurement of affective behavior in psychopathology has been limited primarily to screening and diagnosis. While useful, clinicians more often are concerned with whether patients are improving in response to treatment. Are symptoms abating, is affect becoming more positive, are unanticipated side effects emerging? When treatment includes neural implants, need for objective, repeatable biometrics tied to neurophysiology becomes especially pressing. We used automated face analysis to assess treatment response to deep brain stimulation (DBS) in two patients with intractable obsessive-compulsive disorder (OCD). One was assessed intraoperatively following implantation and activation of the DBS device. The other was assessed three months post-implantation. Both were assessed during DBS on and o conditions. Positive and negative valence were quantified using a CNN trained on normative data of 160 non-OCD participants. Thus, a secondary goal was domain transfer of the classifiers. In both contexts, DBS-on resulted in marked positive affect. In response to DBS-off, affect flattened in both contexts and alternated with increased negative affect in the outpatient setting. Mean AUC for domain transfer was 0.87. These findings suggest that parametric variation of DBS is strongly related to affective behavior and may introduce vulnerability for negative affect in the event that DBS is discontinued.


Fluid mechanical and physicochemical modeling interprets hypertension to be capable of inducing secondary complications.
The relationship of hypertensives and many pathological syndromes still remains unclear. A mathematical model in terms of the fluid mechanics and physicochemical analyses is established to correlate the plasma viscosity, the shear stress and the rate of shear in blood stream with the ligand-receptor dissociation constant. This model has arrived at the conclusive results that high viscosity, high rate of shear created in the blood streams, and the peripheral resistance may act as important preceding factors to induce a serial subsequent pathological clinical manifestations. High viscosity may interfere with the ligand-receptor combination, in contrast, high rate of shear may knock the ligand (s) off the existing ligand-receptor complex, while elevation of peripheral resistance may slow down the blood flow rate, resulting in a diminished dissociation of ligand-receptor complex. This model has successfully interpreted the possible cause of some post-hypertensive abnormal outcome manifestations involving obstructive and degenerative stenosis (such as renal artery stenosis), growth retardation, blood vessel detriment, coarctation of aorta, coronary thrombotics, atherosclerosis, hyperinsulinemia, diabetes, obesity, hypothyroidism, infertility, and at the worst, carcinoma, etc.


Effects of oat β-glucan consumption at breakfast on ad libitum eating, appetite, glycemia, insulinemia and GLP-1 concentrations in healthy subjects.
There is evidence that oat β-glucan lowers appetite and ad libitum eating; however, not all studies are consistent, and the underpinning mechanisms are not entirely understood. We investigated the effects of 4 g high molecular weight (MW) oat β-glucan on ad libitum eating, subjective appetite, glycemia, insulinemia and plasma GLP-1 responses in 33 normal-weight subjects (22 female/11 male, mean age (y): 26.9 ± 1.0, BMI (kg/m2): 23.5 ± 0.4). The study followed a randomised double-blind, cross-over design with subjects fed two test breakfasts with and without oat β-glucan followed by an ad libitum test meal on two different days. Blood samples and ratings for subjective appetite were collected postprandially at regular time intervals. Oat β-glucan increased feelings of fullness (p = 0.048) and satiety (p = 0.034), but did not affect energy and amount eaten at the ad libitum test meal. There was a treatment by time interaction for plasma GLP-1, plasma insulin and blood glucose. GLP-1 was significantly reduced at 90 min (p = 0.021), blood glucose at 30 min (p = 0.008) and plasma insulin at 30 and 60 min (p = 0.002 and 0.017, respectively) following the oat β-glucan breakfast when compared with the control breakfast. Four grams of high MW oat β-glucan lowers appetite but not ad libitum eating and beneficially modulates postprandial glycaemia, it does however, not increase plasma GLP-1 secretion.


Effects of the decellularization method on the local stiffness of acellular lungs.
Lung bioengineering, a novel approach to obtain organs potentially available for transplantation, is based on decellularizing donor lungs and seeding natural scaffolds with stem cells. Various physicochemical protocols have been used to decellularize lungs, and their performance has been evaluated in terms of efficient decellularization and matrix preservation. No data are available, however, on the effect of different decellularization procedures on the local stiffness of the acellular lung. This information is important since stem cells directly sense the rigidity of the local site they are engrafting to during recellularization, and it has been shown that substrate stiffness modulates cell fate into different phenotypes. The aim of this study was to assess the effects of the decellularization procedure on the inhomogeneous local stiffness of the acellular lung on five different sites: alveolar septa, alveolar junctions, pleura, and vessels' tunica intima and tunica adventitia. Local matrix stiffness was measured by computing Young's modulus with atomic force microscopy after decellularizing the lungs of 36 healthy rats (Sprague-Dawley, male, 250-300 g) with four different protocols with/without perfusion through the lung circulatory system and using two different detergents (sodium dodecyl sulfate [SDS] and 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate [CHAPS]). The local stiffness of the acellular lung matrix significantly depended on the site within the matrix (p<0.001), ranging from ∼ 15 kPa at the alveolar septum to ∼ 60 kPa at the tunica intima. Acellular lung stiffness (p=0.003) depended significantly, albeit modestly, on the decellularization process. Whereas perfusion did not induce any significant differences in stiffness, the use of CHAPS resulted in a ∼ 35% reduction compared with SDS, the influence of the detergent being more important in the tunica intima. In conclusion, lung matrix stiffness is considerably inhomogeneous, and conventional decellularization procedures do not result in substantially different local stiffness in the acellular lung.


Solitary Recurrence of IgG4-related Giant Coronary Aneurysm: Case Report and Review of the Literature Focusing on Treatment Strategies and Complications.
Coronary periarteritis is a dangerous manifestation of IgG4-related disease because it forms coronary artery aneurysms, which may cause sudden cardiac death. We report the case of a 78-year-old woman with IgG4-related coronary periarteritis and a coronary aneurysm which showed progressive enlargement despite maintenance therapy for type 1 autoimmune pancreatitis. This case was unique in that coronary periarteritis was the only active lesion that recurred. Low-dose glucocorticoids suppressed the progression of periarterial lesions but led to rapid thinning of the aneurysmal wall and an increase in the size of mural thrombi, which poses a risk of myocardial infarction. Our systematic literature review including 98 cases of 86 articles was performed to examine its treatment strategies and complications. Among the cases in which the effect of immunosuppressive therapy could be followed radiologically, 33 of 37 (89.1%) cases showed improvement in wall thickening/periarterial soft tissue, while six of 13 (46.2%) showed worsening increase in the outer diameter of the coronary aneurysms. We propose a draft treatment algorithm and suggest that immunosuppressive therapy for IgG4-related coronary periarteritis with coronary aneurysms should be conducted only after the therapeutic benefit has been determined to outweigh the risks. Because coronary periarteritis can occur without other organ involvement, as in our case, all cases of IgG4-related disease require careful monitoring for coronary artery lesions.


Longitudinal study of disease severity and external factors in cognitive failure after COVID-19 among Indonesian population.
The COVID-19 infection is assumed to induce cognitive failure. Identifying the relationship between COVID-19, the effect of vaccination and medication, and accommodating non-COVID-19 factors to cognitive failure is essential. This study was conducted in Indonesia from September 2021 to January 2023. Demographic information, clinical data, comorbidities, vaccination, and medication during COVID-19 were obtained, as well as a 6-month cognitive assessment with Cognitive Failures Questionnaire/CFQ, Fatigue Severity Score, and Generalized Anxiety Disorder (GAD-7). A Structural Equation Model explains the relationship between potential predictors and cognitive failure. The average score of CFQ after 6 months was 45.6 ± 23.1 out of 100. The severity of the disease, which was associated with vaccination status, age, previous infection, and unit of treatment (p < 0.05), was not related to cognitive failure (p = 0.519), although there is a significant direct impact of worst vaccination status to cognitive failure(p < 0.001). However, age, fatigue, and current anxiety were associated with higher cognitive failure (p < 0.001), although comorbidities and recent headaches were not significant in other models (p > 0.05). This study concludes that cognitive failure after COVID-19 is a multifactorial event and does not solely depend on COVID-19 severity. It is crucial to re-address the factors related to the long-term efficacy of vaccination and medication and focus on non-health factors affecting cognitive failure.Trial Registration: NCT05060562.


The transmission dynamics of the aetiological agent of scrapie in a sheep flock.
We formulate and investigate the properties of a model framework to mimic the transmission dynamics of the aetiological agent of scrapie in a sheep flock. We derive expressions for summary parameters that characterize transmission scenarios, notably the basic reproduction number R(0) and the mean generation time T(g). The timescale of epidemic outbreaks is expressed in terms of R(0) and cumulants of the generation time distribution. We discuss the relative contributions to the overall rate of transmission of horizontal and vertical routes during invasion and in endemicity. Simplified models are used to obtain analytical insight into the characteristics of the endemic state.


Treatment of Class II open bite in the mixed dentition with a removable functional appliance and headgear.
Early diagnosis of patients exhibiting open bites that are complicated by skeletal Class II and vertical growth problems can facilitate subsequent treatment. Eight patients with Class II skeletal open bite were treated with the high-pull activator appliance and compared to reasonably matched controls to determine the effects of the appliance. The high-pull activator was found to reduce forward growth of the maxilla and increase mandibular alveolar height, transforming the Class II molar relationship into a Class I molar relationship. The overjet and open bite were decreased, and, in addition, the appliance reduced the amount of forward and downward movement of the maxillary molars, providing vertical control of the maxilla during Class II orthopedic correction. These results demonstrated that open bite complicated by a Class II vertical growth pattern can be treated during the mixed dentition with favorable results by a combination of a removable functional appliance and high-pull headgear.


CyberKnife Frameless Radiosurgery for the treatment of extracranial benign tumors.
Limited data exists for the use of radiosurgery for benign extracranial tumors. The purpose of this study was to evaluate the feasibility, toxicity, and local control of patients with benign extracranial lesions treated with the CyberKnife Frameless Radiosurgery System. From September 2001 thru January 2004, 59 benign tumors in 44 patients were treated using the CyberKnife a frameless image-guided radiosurgery system. Of these tumors, there were 21 neurofibromas, ten schwannomas, eight meningiomas, eight hemangioblastomas, seven paragangliomas, two hemangiopericytomas, one pseudotumor, one ependymoma, and one arteriovenous malformation (AVM). The anatomic locations of these tumors were spinal (25 cervical, four thoracic, 14 lumbar, and two sacral), neck (eight), orbital (three), brainstem (one), and foramen magnum (one). All patients were treated in a single fraction except three lesions were treated in a fractionated manner. The median treatment delivery time per fraction was 59 minutes (range 11-194). Twenty three lesions initially underwent surgical resection. Ten lesions received prior external beam radiation with a median dose 48 Gy (range 40-54 Gy), and one lesion received two prior CyberKnife treatments for a total dose of 32 Gy to the 80% isodose line. The median follow-up was eight months (range 1-25 months). Acute and late toxicity was graded using the National Cancer Institute Common Toxicity Criteria (CTC) scale. Symptomatic response was documented as "improved," "stable," or "progression". The median tumor dose delivered was 16.0 Gy to the 80% isodose line (range 10-31 Gy). The median tumor volume was 4.3 cc (range 0.14-98.6 cc). The median spinal cord volume receiving more than 8 Gy was 0.035 cc (range 0-2.5 cc) and the median maximum spinal cord dose 11.5 Gy (range 0-19.8 Gy). There were no patients that suffered a significant (Grade 3, 4, or 5) acute toxicity. There was no observed late toxicity. 78% of patients experienced an improvement of their pre-treatment symptoms while only one patient experienced symptom progression. Of the 26 patients who underwent follow-up imaging, the local control rate was 96%. This study suggests that CyberKnife Radiosurgery is a safe and efficacious treatment modality for benign tumors, even for those patients with recurrent previously irradiated lesions.


Persistent STAT5 activation in myeloid neoplasms recruits p53 into gene regulation.
STAT (Signal Transducer and Activator of Transcription) transcription factors are constitutively activated in most hematopoietic cancers. We previously identified a target gene, LPP/miR-28 (LIM domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. miR-28 exerts negative effects on thrombopoietin receptor signaling and platelet formation. Here, we demonstrate that, in transformed hematopoietic cells, STAT5 and p53 must be synergistically bound to chromatin for induction of LPP/miR-28 transcription. Genome-wide association studies show that both STAT5 and p53 are co-localized on the chromatin at 463 genomic positions in proximal promoters. Chromatin binding of p53 is dependent on persistent STAT5 activation at these proximal promoters. The transcriptional activity of selected promoters bound by STAT5 and p53 was significantly changed upon STAT5 or p53 inhibition. Abnormal expression of several STAT5-p53 target genes (LEP, ATP5J, GTF2A2, VEGFC, NPY1R and NPY5R) is frequently detected in platelets of myeloproliferative neoplasm (MPN) patients, but not in platelets from healthy controls. In conclusion, persistently active STAT5 can recruit normal p53, like in the case of MPN cells, but also p53 mutants, such as p53 M133K in human erythroleukemia cells, leading to pathologic gene expression that differs from canonical STAT5 or p53 transcriptional programs.


Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS).
Neuromyelitis optica (NMO, Devic's syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.


Characterization of Pattern Recognition Receptor Expression and Functionality in Liver Primary Cells and Derived Cell Lines.
Different liver cell types are endowed with immunological properties, including cell-intrinsic innate immune functions that are important to initially control pathogen infections. However, a full landscape of expression and functionality of the innate immune signaling pathways in the major human liver cells is still missing. In order to comparatively characterize these pathways, we purified primary human hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells (LSEC), and Kupffer cells (KC) from human liver resections. We assessed mRNA and protein expression level of the major innate immune sensors, as well as checkpoint-inhibitor ligands in the purified cells, and found Toll-like receptors (TLR), RIG-I-like receptors, as well as several DNA cytosolic sensors to be expressed in the liver microenvironment. Amongst the cells tested, KC were shown to be most broadly active upon stimulation with PRR ligands emphasizing their predominant role in innate immune sensing the liver microenvironment. By KC immortalization, we generated a cell line that retained higher innate immune functionality as compared to THP1 cells, which are routinely used to study monocyte/macrophages functions. Our findings and the establishment of the KC line will help to understand immune mechanisms behind antiviral effects of TLR agonists or checkpoint inhibitors, which are in current preclinical or clinical development.


Biogenesis of the inner membrane complex is dependent on vesicular transport by the alveolate specific GTPase Rab11B.
Apicomplexan parasites belong to a recently recognised group of protozoa referred to as Alveolata. These protists contain membranous sacs (alveoli) beneath the plasma membrane, termed the Inner Membrane Complex (IMC) in the case of Apicomplexa. During parasite replication the IMC is formed de novo within the mother cell in a process described as internal budding. We hypothesized that an alveolate specific factor is involved in the specific transport of vesicles from the Golgi to the IMC and identified the small GTPase Rab11B as an alveolate specific Rab-GTPase that localises to the growing end of the IMC during replication of Toxoplasma gondii. Conditional interference with Rab11B function leads to a profound defect in IMC biogenesis, indicating that Rab11B is required for the transport of Golgi derived vesicles to the nascent IMC of the daughter cell. Curiously, a block in IMC biogenesis did not affect formation of sub-pellicular microtubules, indicating that IMC biogenesis and formation of sub-pellicular microtubules is not mechanistically linked. We propose a model where Rab11B specifically transports vesicles derived from the Golgi to the immature IMC of the growing daughter parasites.


The influence of diffusional barriers on presystemic gut elimination.
A number of drugs undergo biotransformation in the gut wall or lumen. In many cases drug extraction is greater after oral administration compared with parenteral administration. This may indicate that the diffusional clearance of drug across the blood-mucosa interface is less than that across the lumen-mucosa interface. The consequence of diffusional barriers in the gut on presystemic gut elimination (PGE) have been investigated by computer simulation of a physiological pharmacokinetic model. The following was found regarding a diffusional barrier of the blood-mucosa interface: 1) it enhances PGE, 2) it invalidates certain pharmacokinetic methods to assess PGE, 3) it makes PGE sensitive to changes in drug binding in the blood, and 4) if the diffusional barrier exists for the generated metabolite but not for the drug, methods to assess drug absorption by comparing area under the curve relationships of the metabolite after oral and iv drug administration are inaccurate.


Glucose oxidase-dextran conjugates with enhanced stabilities against temperature and pH.
Multipoint covalent bonding of glucose oxidase (EC 18.104.22.168) to hydrophilic natural polymer dextran and optimization of procedures to obtain, with enhanced temperature and pH stabilities, were studied. Purified enzyme was conjugated with various molecular weight dextrans (17.5, 75, and 188 kD) in a ratio of 20:1, 10:1, 1:1, 1:5, 1:10, 1:15, and 1:20. After 1 h of incubation at pH 7, the activities of purified enzyme and conjugates were determined at different temperatures (25 degrees C, 30 degrees C, 35 degrees C, 40 degrees C, 50 degrees C, 60 degrees C, 70 degrees C, and 80 degrees C), and the results were evaluated for thermal resistance. Increases in temperature from 25 degrees C to 50 degrees C did not change the activities of the conjugates. The conjugate, which was prepared with 75 kDa dextran in a molar ratio of 1:5, showed the highest thermal resistance and even the activity still remains at 80 degrees C at pH 7.0. This conjugate also displayed activity in a wide pH range (pH 4.0-7.0) at high temperatures. Conjugate, which was synthesized with 75 kDa dextran in a molar ratio of 1:5, appears to be feasible and useful for biotechnological applications.


Effect of A and B metal ion site occupancy on conformational changes in an RB69 DNA polymerase ternary complex.
Rapid chemical quench assays, as well as equilibrium and stopped-flow fluorescence experiments, were performed with an RB69 DNA polymerase (RB69 pol)-primer-template (P/T) complex containing 2-aminopurine (dAP) and a metal exchange-inert Rh(III) derivative of a deoxynucleoside triphosphate (Rh.dTTP). The objective was to determine the effect of catalytic metal ion (A site) occupancy on the affinity of an incoming Rh.dTTP for the RB69 pol-P/T binary complex and on the rate of the conformational change induced by Rh.dTTP binding. With Ca(2+) in the A site, the affinity of the incoming Rh.dTTP for the RB69 pol-P/T binary complex and the conformational change rate can be determined in the absence of chemistry. When Mg(2+) was added to a ternary complex containing Rh.dTTP opposite dAP, the templating base, nucleotidyl transfer occurred, but the rate of product formation was only one-tenth of that found with Mg.dTTP, as determined by rapid chemical quench assays. Rates of conformational change subsequent to formation of a ternary complex, in the absence of chemistry, were estimated from the rate of change in dAP fluorescence with an increase in the Rh.dTTP concentration. We have shown that there is an initial rapid quenching of dAP fluorescence followed by a second phase of dAP quenching, which has nearly the same rate as that of dTMP incorporation, as estimated from rapid chemical quench experiments. We have also demonstrated that the affinity of Rh.dTTP for occupancy of the B metal ion site is dependent on the presence of Ca(2+). However, a saturating Rh.dTTP concentration in the absence of Ca(2+) results in full quenching of dAP fluorescence, whereas a saturating Ca(2+) concentration in the absence of Rh.dTTP gives only partial quenching of dAP fluorescence. The implications of these results for the mechanism of Fingers closing, metal ion binding, and base selectivity are discussed.


Superplastic extensibility of nanocrystalline copper at room temperature
A bulk nanocrystalline (nc) pure copper with high purity and high density was synthesized by electrodeposition. An extreme extensibility (elongation exceeds 5000%) without a strain hardening effect was observed when the nc copper specimen was rolled at room temperature. Microstructure analysis suggests that the superplastic extensibility of the nc copper originates from a deformation mechanism dominated by grain boundary activities rather than lattice dislocation, which is also supported by tensile creep studies at room temperature. This behavior demonstrates new possibilities for scientific and technological advancements with nc materials.


Silica Vesicle Nanovaccine Formulations Stimulate Long-Term Immune Responses to the Bovine Viral Diarrhoea Virus E2 Protein.
Bovine Viral Diarrhoea Virus (BVDV) is one of the most serious pathogen, which causes tremendous economic loss to the cattle industry worldwide, meriting the development of improved subunit vaccines. Structural glycoprotein E2 is reported to be a major immunogenic determinant of BVDV virion. We have developed a novel hollow silica vesicles (SV) based platform to administer BVDV-1 Escherichia coli-expressed optimised E2 (oE2) antigen as a nanovaccine formulation. The SV-140 vesicles (diameter 50 nm, wall thickness 6 nm, perforated by pores of entrance size 16 nm and total pore volume of 0.934 cm3 g(-1)) have proven to be ideal candidates to load oE2 antigen and generate immune response. The current study for the first time demonstrates the ability of freeze-dried (FD) as well as non-FD oE2/SV140 nanovaccine formulation to induce long-term balanced antibody and cell mediated memory responses for at least 6 months with a shortened dosing regimen of two doses in small animal model. The in vivo ability of oE2 (100 μg)/SV-140 (500 μg) and FD oE2 (100 μg)/SV-140 (500 μg) to induce long-term immunity was compared to immunisation with oE2 (100 μg) together with the conventional adjuvant Quil-A from the Quillaja saponira (10 μg) in mice. The oE2/SV-140 as well as the FD oE2/SV-140 nanovaccine generated oE2-specific antibody and cell mediated responses for up to six months post the final second immunisation. Significantly, the cell-mediated responses were consistently high in mice immunised with oE2/SV-140 (1,500 SFU/million cells) at the six-month time point. Histopathology studies showed no morphological changes at the site of injection or in the different organs harvested from the mice immunised with 500 μg SV-140 nanovaccine compared to the unimmunised control. The platform has the potential for developing single dose vaccines without the requirement of cold chain storage for veterinary and human applications.


Preparation and characterisation of highly alkaline hydrogels for the re-alkalisation of carbonated cementitious materials.
Highly alkaline hydrogels that allow the restoration of alkaline buffer in cementitious materials can be obtained from diallyldimethylammonium hydroxide. The latter must be prepared in dilute solutions and polymerised at ambient temperatures in order to avoid decomposition. Using methacrylamide as a neutral co-monomer capable of forming hydrogen bonds, the rheological properties of the gels can be adjusted over a wide range; e.g. the viscosity increases a thousandfold from 0.35 Pa s to >350 Pa s by using 10 mol% methacrylamide. For the proof of principle experiments, gels with 9 mol% methacrylamide were used, which contain approx. 1.6 mol hydroxide ions per kg gel. Ion exchange between this and a neutral chloride containing gel provided an apparent diffusion coefficient of 4.12 × 10-7 m2 s-1 for the hydroxide ions and confirmed the transport of chloride ions into the alkaline gel. The re-alkalisation was tested on fully carbonated mortar prisms made from Portland cement. Re-alkalisation of the mortar was confirmed by the phenolphthalein test according to DIN EN 14630:2007-01 and by a control experiment with pure calcium carbonate using IR spectroscopy.


The stability of the factor structure of the General Health Questionnaire.
Different versions of the General Health Questionnaire (GHQ), including the GHQ-12 and GHQ-28 have been subjected to factor analysis in a variety of countries. The World Health Organization study of psychological disorders in general health care offered the opportunity to investigate the factor structure of both GHQ versions in 15 different centres. The factor structures of the GHQ-12 and GHQ-28 extracted by principal component analysis were compared in participating centres. The GHQ-12 was completed by 26,120 patients and 5,273 patients completed the GHQ-28. The factor structure of the GHQ-28 found in Manchester in this study was compared with that found in the earlier study in 1979. For the GHQ-12, substantial factor variation between centres was found. After rotation, two factors expressing depression and social dysfunction could be identified. For the GHQ-28, factor variance was less. In general, the original C (social dysfunction) and D (depression) scales of the GHQ-28 were more stable than the A (somatic symptoms) and B (anxiety) scales. Multiple cross-loadings occurred in both versions of the GHQ suggesting correlation of the extracted factors. In Manchester, the factor structure of the GHQ had changed since its development. Validity as a case detector was not affected by factor variance. These findings confirm that despite factor variation for the GHQ-12, two domains, depression and social dysfunction, appear across the 15 centres. In the scaled GHQ-28, two of the scales were remarkably robust between the centres. The cross-correlation between the other two subscales, probably reflects the strength of the relationship between anxiety and somatic symptoms existing in different locations.


Staphylococcus aureus Enterotoxin Production in Raw, Holder-Pasteurized, and Ultraviolet-C-Treated Donated Human Milk.
Background: Some strains of Staphylococcus aureus can produce heat-stable enterotoxins that have been associated with gastritis and potentially necrotizing enterocolitis in preterm infants. Objectives/Hypothesis: To assess the impact of different storage temperatures on S. aureus growth and enterotoxin production in raw, Holder-pasteurized (HP) and ultraviolet-C (UV-C)-treated donated human milk (DHM). Materials and Methods: The milk samples from individual donors were pooled and divided into four equal portions. One portion was HP, the second was UV-C treated, the third was not treated, and the fourth was UV-C treated after being spiked with S. aureus. All samples were incubated at 37°C (18 hours) and 4°C (14 days). Bacterial colony count, enterotoxin A and B, and immune proteins were quantified. Results: At 37°C, the colony count increased in HP DHM and decreased in raw and UV-C-treated DHM. At 4°C, colony counts in HP DHM reduced and were not detected in raw and UV-C-treated DHM from day 8 of incubation. No bacteria were detected in samples that were inoculated before UV-C treatment. Enterotoxin A was only detected in HP-DHM at 37°C from the 9th hour onward. Enterotoxin B was detected in one sample at the 15th hour. Immune protein concentrations were similar in raw and UV-C DHM, and were reduced in the HP DHM. Conclusion: UV-C-treated milk reduces S. aureus growth with similar kinetics to raw milk making it a promising emerging technique to eliminate bacteria while retaining essential immune proteins in DHM.


Highly sensitive sandwich immunoassay and immunochromatographic test for the detection of Clostridial epsilon toxin in complex matrices.
Epsilon toxin is one of the four major toxins of Clostridium perfringens. It is the third most potent clostridial toxin after botulinum and tetanus toxins and is thus considered as a potential biological weapon classified as category B by the Centers for Disease Control and Prevention (CDC). In the case of a bioterrorist attack, there will be a need for a rapid, sensitive and specific detection method to monitor food and water contamination by this toxin, and for a simple human diagnostic test. We have produced and characterized five monoclonal antibodies against common epitopes of epsilon toxin and prototoxin. Three of them neutralize the cytotoxic effects of epsilon toxin in vitro. With these antibodies, we have developed highly sensitive tests, overnight and 4-h sandwich enzyme immunoassays and an immunochromatographic test performed in 20 min, reaching detection limits of at least 5 pg/mL (0.15 pM), 30 pg/mL (0.9 pM) and 100 pg/mL (3.5 pM) in buffer, respectively. These tests were also evaluated for detection of epsilon toxin in different matrices: milk and tap water for biological threat detection, serum, stool and intestinal content for human or veterinary diagnostic purposes. Detection limits in these complex matrices were at least 5-fold better than those described in the literature (around 1 to 5 ng/mL), reaching 10 to 300 pg/mL using the enzyme immunoassay and 100 to 2000 pg/mL using the immunochromatographic test.


Population Study of Hand and Wrist Manifestations of Congenital Insensitivity to Pain.
Background: Congenital insensitivity to pain is a rare autosomal recessive condition characterized by insensitivity to painful stimuli due to absence of sensory and sympathetic post ganglionic neurons in the skin and skeletal system leading to lack of protective sensation and altered joint propioception. This study was performed to assess hand and wrist manifestations of patients with congenital insensitivity to pain in the Maltese Islands. Methods: Records of public and private hospitals were reviewed to identify patients suffering from this condition. A review of notes, patients, and imaging was performed. A Disabilities of the Arm, Shoulder, and Hand score was obtained to assess level of function. Results: Nine patients were identified. Mean age of diagnosis was 8.9 years. Interphalangeal joints were most commonly affected. Multiple spontaneous or posttraumatic fingertip ulceration occurred in 5 patients. Anhidrosis resulted in more protracted ulcers and infections, requiring amputation of distal and middle phalanges due to osteomyelitis. The wrist joint was less commonly involved and showed more complex joint involvement. Conclusion: The hand and wrist are involved in different ways, with fingertip ulceration leading to potential infection and osteomyelitis in the hand, whereas the wrist joint is involved in cases of increased axial loading and load transfer, such as following prolonged use of walking and mobility aids. The latter should be borne in mind during management of lower limb conditions. Hand care and hygiene is important in all patients, especially in cases of anhidrosis due to the increased rate of ulceration and osteomyelitis requiring surgical intervention. Despite the severity of the condition, patients report good overall function.


Strong tangential force within a small trapping volume under near-field Laguerre-Gaussian beam illumination.
Near-field rotation of a trapped particle under focused evanescent Laguerre-Gaussian beam illumination is theoretically investigated by mapping the two-dimensional transverse trapping efficiency exerting on the particle. It is revealed that the severe focal field deformation associated with a focused evanescent Laguerre-Gaussian beam causes a significant impact on the transverse trapping performance of the microparticle. Compared with the far-field trapping force, strong tangential force components have been observed in the transverse efficiency mapping, which potentially lead to rotational motions to the particle within a small trapping volume in the optical near-field.


Not published, not indexed: issues in generating and finding hospice and palliative care literature.
Accessing new knowledge as the evidence base for hospice and palliative care grows has specific challenges for the discipline. This study aimed to describe conversion rates of palliative and hospice care conference abstracts to journal articles and to highlight that some palliative care literature may not be retrievable because it is not indexed on bibliographic databases. Substudy A tracked the journal publication of conference abstracts selected for inclusion in a gray literature database on www.caresearch.com.au . Abstracts were included in the gray literature database following handsearching of proceedings of over 100 Australian conferences likely to have some hospice or palliative care content that were held between 1980 and 1999. Substudy B looked at indexing from first publication until 2001 of three international hospice and palliative care journals in four widely available bibliographic databases through systematic tracing of all original papers in the journals. Substudy A showed that for the 1338 abstracts identified only 15.9% were published (compared to an average in health of 45%). Published abstracts were found in 78 different journals. Multiauthor abstracts and oral presentations had higher rates of conversion. Substudy B demonstrated lag time between first publication and bibliographic indexing. Even after listing, idiosyncratic noninclusions were identified. There are limitations to retrieval of all possible literature through electronic searching of bibliographic databases. Encouraging publication in indexed journals of studies presented at conferences, promoting selection of palliative care journals for database indexing, and searching more than one bibliographic database will improve the accessibility of existing and new knowledge in hospice and palliative care.


The multidrug resistance protein breast cancer resistance protein (BCRP) protects adipose-derived stem cells against ischemic damage.
Adipose tissue-derived stem cells (ASCs) are promising candidates for regenerative therapy, like after myocardial infarction. However, when transplanted into the infarcted heart, ASCs are jeopardized by the ischemic environment. Interestingly, it has been shown that multidrug resistance (MDR) proteins like the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) have a protective effect in haematopoietic stem cells. In ASC, however, only expression of BCRP was shown until now. In this study, we therefore analysed the expression and functional activity of BCRP and P-gp and their putative function in ischemia in ASC. BCRP and P-gp protein expression was studied over time (passages 2-6) using western blot analysis and immunohistochemical staining. MDR activity was analysed using protein-specific substrate extrusion assays. Ischemia was induced using metabolic inhibition. All analyses demonstrated protein expression and activity of BCRP in ASCs. In contrast, only minor expression of P-gp was found, without functional activity. BCRP expression was most prominent in early passage ASCs (p2) and decreased during culture. Finally, ischemia induced expression of BCRP. In addition, when BCRP was blocked, a significant increase in dead ASCs was found already after 1 h of ischemia. In conclusion, ASCs expressed BCRP, especially in early passages. In addition, we now show for the first time that BCRP protects ASCs against ischemia-induced cell death. These data therefore indicate that for transplantation of ASCs in an ischemic environment, like myocardial infarction, the optimal stem cell protective effect of BCRP theoretically will be achieved with early culture passages ASCs.


Effects of ultrasonication on the interfacial interactions between poly(3-hexylthiophene) and graphene oxide.
The interactions between poly(3-hexylthiophene) (P3HT) and graphene oxide (GO) have endowed the P3HT/GO composite with excellent properties. Controlling these interactions is important to improve the performance of P3HT-based devices. In this work, ultrasonication was used to regulate the nanostructures of P3HTs (high Mw and low Mw), and further strongly affected the interactions between P3HTs and GO. Atomic force microscopy (AFM), UV-vis absorption spectroscopy, Raman spectroscopy, and grazing incidence X-ray diffraction (GIXRD) were used to study the effects of ultrasonication on the interfacial interactions between P3HTs and GO. With prolonged ultrasonication time, the molecular order of high Mw P3HT nanofibers increased, but that of low Mw P3HT nanofibers decreased. Molecular order is a crucial factor affecting the interfacial interactions between P3HTs and GO, and the amounts of P3HT nanofibers absorbed onto the GO surface increased with the decreased molecular order of the nanofibers. After absorption, the overall molecular order of P3HT/GO composite nanofibers was determined by the nanofibers absorbed onto the GO surface and the nanofibers nucleated by GO. Compared with the molecular order of the nanofibers before absorption, the overall molecular order of the composites with high Mw P3HT increased, but that of composites with low Mw P3HT decreased. These findings can help to understand and modulate the interactions between P3HT nanofibers and GO to provide more information in the field of interfacial engineering of conjugated polymers in polymer-based devices.


Psychological distress and pain significantly increase before death in metastatic breast cancer patients.
This study was designed to examine the course of psychological distress and pain from study entry to death in 59 women with metastatic breast cancer participating in a randomized trial of the effects of group psychotherapy on psychosocial outcomes and survival. It was hypothesized that psychological distress would increase significantly before death independent of changes in pain. Data were collected as part of a larger study (N = 125). Analyses were based on data from a subset of women who had died and for whom we had data from at least three assessments. Mean levels of mood, trauma symptoms, depression symptoms, well-being, and pain over three time points were examined: at baseline (T1), the second-to-last assessment before death (T2), and the last assessment before death (T3). Results indicate that while psychological distress remained relatively constant or declined from T1 to T2, means on all measures significantly changed in the hypothesized direction from T2 to T3. Neither self-reported pain, nor the passage of time, appeared to account for these changes. Additionally, participation in group psychotherapy did not have a significant impact on this change in distress proximal to death. Results suggest that specialized end-stage clinical interventions are particularly needed for cancer patients as they approach death. Moreover, intervention studies for patients with deteriorating illnesses may need to take this "spike" in psychological distress and pain proximal to death into account to avoid Type II errors in evaluations of psychological outcomes.


Glomerular basement membrane metabolism in the diabetic rat. In vivo studies.
The effect of diabetes on the metabolism of the renal glomerular basement membrane has been studied in the rat with the aid of injected tracer doses of tritiated proline. At various times after administration of the labeled amino acid, the specific radioactivities of the proline and hydroxyproline of the basement membranes from alloxan diabetic rats were determined and compared with those of age-matched normal rats. In both normal and diabetic animals the incorporation of radioactivity into the basement membrane was slow and, after a maximum was reached, an extended period of almost constant specific activity of proline and hydroxyproline was observed. The diabetic basement membrane, however, differed from the normal by attaining specific activities of the amino acids which were about twice as high as normal (P less than 0.001 at 42 h after injection of radioisotope). Although the proline concentration of serum and renal cortical fluid was the same in normal and diabetic rats, there were substantial differences in the specific activity of this precursor amino acid in these pools that had to be taken into account to compare the two types of animals. The results of the present study are consistent with an accelerated rate of glomerular basement membrane polypeptide synthesis and proline hydroxylation in diabetes.


Seed dispersal by weta.
Weta are giant, flightless grasshoppers that are endemic to New Zealand. In the absence of native mammals, weta are thought to perform similar ecological functions. As such, they might be expected to be important seeds dispersers. However, insects are not known to consume fleshy fruits and to disperse seeds after gut passage. We conducted a series of observations and experiments to test whether weta form mutualistic partnerships with fleshy-fruited plants as seed dispersers, similar to small mammals elsewhere in the world. Results showed that weta are indeed effective seeds dispersers, providing an example of ecological convergence between unrelated organisms.


TIP120A associates with cullins and modulates ubiquitin ligase activity.
The cullin-containing ubiquitin-protein isopeptide ligases (E3s) play an important role in regulating the abundance of key proteins involved in cellular processes such as cell cycle and cytokine signaling. They have multisubunit modular structures in which substrate recognition and the catalysis of ubiquitination are carried out by distinct polypeptides. In a search for proteins involved in regulation of cullin-containing E3 ubiquitin ligases we immunopurified CUL4B-containing complex from HeLa cells and identified TIP120A as an associated protein by mass spectrometry. Immunoprecipitation of cullins revealed that all cullins tested specifically interacted with TIP120A. Reciprocal immunoaffinity purification of TIP120A confirmed the stable interaction of TIP120A with cullin family proteins. TIP120A formed a complex with CUL1 and Rbx1, but interfered with the binding of Skp1 and F-box proteins to CUL1. TIP120A greatly reduced the ubiquitination of phosphorylated IkappaBalpha by SCF(beta-TrCP) ubiquitin ligase. These results suggest that TIP120A functions as a negative regulator of SCF E3 ubiquitin ligases and may modulate other cullin ligases in a similar fashion.


A Generalized Semiempirical Approach to the Modeling of the Optical Band Gap of Ternary Al-(Ga, Nb, Ta, W) Oxides Containing Different Alumina Polymorphs.
A generalization of the modeling equation of optical band gap values for ternary oxides, as a function of cationic ratio composition, is carried out based on the semiempirical correlation between the differences in the electronegativity of oxygen and the average cationic electronegativity proposed some years ago. In this work, a novel approach is suggested to account for the differences in the band gap values of the different polymorphs of binary oxides as well as for ternary oxides existing in different crystalline structures. A preliminary test on the validity of the proposed modeling equations has been carried out by using the numerous experimental data pertaining to alumina and gallia polymorphs as well as the crystalline ternary Ga(1-x)AlxO3 polymorphs (α-Ga(1-x)AlxO3 and β-Ga(1-x)AlxO3) covering a large range of optical band gap values (4.50-8.50 eV). To make a more rigorous test of the modeling equation, we extended our investigation to amorphous ternary oxides anodically formed on Al-d-metal alloys (Al-Nb, Al-Ta, and Al-W) covering a large range of d-metal composition (xd-metal ≥ 0.2). In the last case, the novel approach allows one to overcome some difficulties experienced in fitting the optical band gap dependence from the Al-d-metal mixed anodic oxide composition as well as to provide a rationale for the departure, at the lowest d-metal content (xd-metal < 0.2), from the behavior observed for anodic films containing higher d-metal content.


Dihydrotestosterone stimulates amino acid uptake and the expression of LAT2 in mouse skeletal muscle fibres through an ERK1/2-dependent mechanism.
Dihydrotestosterone (DHT) has acute/non-genomic actions in adult mammalian skeletal muscles whose physiological functions are still poorly understood. Therefore, the primary aim of this study was to investigate the acute/non-genomic effects of DHT on amino acid uptake as well as the cellular signal transduction events underlying these actions in mouse fast- and slow-twitch skeletal muscle fibre bundles. 14C-Labelled amino acids were used to investigate the effects of DHT and testosterone (T) on amino acid uptake and pharmacological interventions were used to determine the cellular signal transduction events mediating these actions. While T had no effect on the uptake of isoleucine (Ile) and α-methylaminoisobutyric acid (MeAIB) in both fibre types, DHT increased their uptake in the fast-twitch fibre bundles. This effect was reversed by inhibitors of protein translation, the epidermal growth factor receptor (EGFR), system A, system L, mTOR and MEK. However, it was relatively insensitive to inhibitors of transcription, androgen receptors and PI3K/Akt. Additionally, DHT treatment increased the expression of LAT2 and the phosphorylation of the EGFR in the fast-twitch fibre bundles and that of ERK1/2, RSK1/2 and ATF2 in both fibre types. Also, it decreased the phosphorylation of eEF2 and increased the incorporation of Ile into proteins in both fibre types. Most of these effects were reversed by EGFR and MEK inhibitors. From these findings we suggest that another physiological function of the acute/non-genomic actions of DHT in isolated mammalian skeletal muscle fibres is to stimulate amino acid uptake. This effect is mediated through the EGFR and involves the activation of the MAPK pathway and an increase in LAT2 expression.


Similar Efficacies of Endoscopic Ultrasound Gallbladder Drainage With a Lumen-Apposing Metal Stent Versus Percutaneous Transhepatic Gallbladder Drainage for Acute Cholecystitis.
Acute cholecystitis in patients who are not candidates for surgery is often managed with percutaneous transhepatic gallbladder drainage (PT-GBD). Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) with a lumen-apposing metal stent (LAMS) is an effective alternative to PT-GBD. We compared the technical success of EUS-GBD versus PT-GBD, and patient outcomes, numbers of adverse events (AEs), length of hospital stay, pain scores, and repeat interventions. We performed a retrospective study to compare EUS-GBD versus PT-GBD at 7 centers (5 in the United States, 1 in Europe, and 1 in Asia), from 2013 through 2015, in management of acute cholecystitis in patients who are not candidates for surgery. A total of 90 patients (56 men) with acute cholecystitis (61 calculous, 29 acalculous) underwent EUS-GBD (n = 45) or PT-GBD (n = 45). Data were collected on technical success, clinical success (resolution of symptoms or laboratory and/or radiologic abnormalities within 3 days of intervention), and need for repeat intervention. Characteristics were compared using Student t tests for continuous variables and the chi-square test, or the Fisher exact test, when appropriate, for categorical variables. Adverse events were graded according to American Society for Gastrointestinal Endoscopy definitions and compared using the Fisher exact test. Postprocedure pain scores were compared using the Mann-Whitney U test. Baseline characteristics, type, and clinical severity of cholecystitis were comparable between groups. In the EUS-GBD group, noncautery LAMS were used in 30 patients and cautery-enhanced LAMS were used in 15. Technical success was achieved for 98% of patients in the EUS-GBD and 100% of the patients in the PT-GBD group (P = .88). Clinical success was achieved by 96% of patients in the EUS-GBD group and 91% in the PT-GBD group (P = .20). There was a nonsignificant trend toward fewer AEs in the EUS-GBD group (5 patients; 11%) than in the PT-GBD group (14 patients; 32%) (P = .065). There were no significant differences in the severity of the AEs: mild, 2 in the EUS-GBD group versus 5 in the PT-GBD group (P = .27); moderate, 4 versus 3 (P = .98); severe, 1 versus 3 (P = .62); or deaths, 1 versus 3 (P = .61). The mean postprocedure pain score was lower in the EUS-GBD group than in the PT-GBD group (2.5 vs 6.5; P < .05). The EUS-GBD group had a shorter average length of stay in the hospital (3 days) than the PT-GBD group (9 days) (P < .05) and fewer repeat interventions (11 vs 112) (P < .05). The average number of repeat interventions per patients was 0.2 ± 0.4 EUS-GBD group versus 2.5 ± 2.8 in the PT-GBD group (P < .05). Median follow-up after drainage was comparable in EUS-GBD group (215 days; range, 1-621 days) versus the PT-GBD group (265 days; range, 1-1638 days). EUS-GBD has similar technical and clinical success compared with PT-GBD and should be considered an alternative for patients who are not candidates for surgery. Patients who undergo EUS-GBD seem to have shorter hospital stays, lower pain scores, and fewer repeated interventions, with a trend toward fewer AEs. A prospective, comparative study is needed to confirm these results.