Rigid-CLL: avoiding constant-distance computations in cell linked-lists algorithms.
Many of the existing molecular simulation tools require the efficient identification of the set of nonbonded interacting atoms. This is necessary, for instance, to compute the energy values or the steric contacts between atoms. Cell linked-lists can be used to determine the pairs of atoms closer than a given cutoff distance in asymptotically optimal time. Despite this long-term optimality, many spurious distances are anyway computed with this method. Therefore, several improvements have been proposed, most of them aiming to refine the volume of influence for each atom. Here, we suggest a different improvement strategy based on avoiding to fill cells with those atoms that are always at a constant distance of a given atom. This technique is particularly effective when large groups of the particles in the simulation behave as rigid bodies as it is the case in simplified models considering only few of the degrees of freedom of the molecule. In these cases, the proposed technique can reduce the number of distance computations by more than one order of magnitude, as compared with the standard cell linked-list technique. The benefits of this technique are obtained without incurring in additional computation costs, because it carries out the same operations as the standard cell linked-list algorithm, although in a different order. Since the focus of the technique is the order of the operations, it might be combined with existing improvements based on bounding the volume of influence for each atom.


Characterization of the active microbiotas associated with honey bees reveals healthier and broader communities when colonies are genetically diverse.
Recent losses of honey bee colonies have led to increased interest in the microbial communities that are associated with these important pollinators. A critical function that bacteria perform for their honey bee hosts, but one that is poorly understood, is the transformation of worker-collected pollen into bee bread, a nutritious food product that can be stored for long periods in colonies. We used 16S rRNA pyrosequencing to comprehensively characterize in genetically diverse and genetically uniform colonies the active bacterial communities that are found on honey bees, in their digestive tracts, and in bee bread. This method provided insights that have not been revealed by past studies into the content and benefits of honey bee-associated microbial communities. Colony microbiotas differed substantially between sampling environments and were dominated by several anaerobic bacterial genera never before associated with honey bees, but renowned for their use by humans to ferment food. Colonies with genetically diverse populations of workers, a result of the highly promiscuous mating behavior of queens, benefited from greater microbial diversity, reduced pathogen loads, and increased abundance of putatively helpful bacteria, particularly species from the potentially probiotic genus Bifidobacterium. Across all colonies, Bifidobacterium activity was negatively correlated with the activity of genera that include pathogenic microbes; this relationship suggests a possible target for understanding whether microbes provide protective benefits to honey bees. Within-colony diversity shapes microbiotas associated with honey bees in ways that may have important repercussions for colony function and health. Our findings illuminate the importance of honey bee-bacteria symbioses and examine their intersection with nutrition, pathogen load, and genetic diversity, factors that are considered key to understanding honey bee decline.


Polymorphism of INS VNTR is associated with glutamic acid decarboxylase antibodies and postprandial C-peptide in patients with onset of diabetes after 35 years of age.
Variability in the number of tandem repeats of the insulin gene (INS VNTR) is probably involved in the genetic regulation of insulin secretion. The aim of this study was to investigate the association of INS VNTR polymorphism with the presence of glutamic acid decarboxylase antibodies (GADA) and C-peptide levels in patients with the onset of diabetes after 35 years of age. We investigated 117 patients, median of age 63 (range 40-83) years, median of diabetes duration 8 (range 1-30) years; 31 GADA-positive and 86 GADA-negative subjects. INS VNTR polymorphism was typed indirectly using - 23HphI (T/A) polymorphism, which is in complete linkage disequilibrium with INS VNTR. The I/I, I/III and III/III genotypes were found in 22 (71 %), 8 (26 %), 1 (3 %) GADA-positive individuals and in 39 (45 %), 35 (41 %), 12 (14 %) GADA-negative individuals, respectively. The Class I allele and the genotype I/I were significantly associated with the presence of GADA (OR=2.72, CI 95 %=1.29-5.73 and OR=2.95, CI 95 %=1.22-7.13). The presence of Class III allele was significantly associated with a higher level of postprandial C-peptide in GADA-positive subjects, even when regarding the duration of diabetes. Our results of INS VNTR polymorphism in patients with the onset of diabetes after 35 years of age confirm the association of Class I INS VNTR with autoimmune diabetes and the protective effect of Class III INS VNTR on the insulin secretion in GADA-positive subjects.


Reactivation West Nile virus infection-related chorioretinitis.
West Nile Virus is a relatively uncommon infection that can involve retinal and choroidal inflammation leading to photopsias, photophobia, and orbital pain. The diagnosis is made by clinical history, serology, and characteristic funduscopic exam and fluorescein angiography findings. Treatment involves primarily supportive care as there are no known effective anti-viral agents. Visual recovery is usually full. Here we present a case of West Nile Virus Infection Related chorioretinitis that demonstrated active linear chorioretinal lesions approximately one year after the initial infection was diagnosed and treated. The patient noted new onset blurry vision and floaters for two weeks prior to presentation. Antibody titers to West Nile Virus increased from baseline levels indicating active infection. This represents the first case of reactivation West Nile Virus Infection Related chorioretinitis that has been documented.


Application of deep learning algorithm to detect and visualize vertebral fractures on plain frontal radiographs.
Identification of vertebral fractures (VFs) is critical for effective secondary fracture prevention owing to their association with the increasing risks of future fractures. Plain abdominal frontal radiographs (PARs) are a common investigation method performed for a variety of clinical indications and provide an ideal platform for the opportunistic identification of VF. This study uses a deep convolutional neural network (DCNN) to identify the feasibility for the screening, detection, and localization of VFs using PARs. A DCNN was pretrained using ImageNet and retrained with 1306 images from the PARs database obtained between August 2015 and December 2018. The accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were evaluated. The visualization algorithm gradient-weighted class activation mapping (Grad-CAM) was used for model interpretation. Only 46.6% (204/438) of the VFs were diagnosed in the original PARs reports. The algorithm achieved 73.59% accuracy, 73.81% sensitivity, 73.02% specificity, and an AUC of 0.72 in the VF identification. Computer driven solutions integrated with the DCNN have the potential to identify VFs with good accuracy when used opportunistically on PARs taken for a variety of clinical purposes. The proposed model can help clinicians become more efficient and economical in the current clinical pathway of fragile fracture treatment.


Comparison of risk factors for colon and rectal cancer.
Predictors of colorectal cancer have been extensively studied with some evidence suggesting that risk factors vary by subsite. Using data from 2 prospective cohort studies, we examined established risk factors to determine whether they were differentially associated with colon and rectal cancer. Our study population included 87,733 women from the Nurses' Health Study (NHS) and 46,632 men from the Health Professionals Follow Up Study (HPFS). Exposure information was collected via biennial questionnaires (dietary variables were collected every 4 years). During the follow-up period (NHS: 1980 to May 31, 2000; HPFS: 1986 to January 31, 2000), we identified 1,139 cases of colon cancer and 339 cases of rectal cancer. We used pooled logistic regression to estimate multivariate relative risks for the 2 outcomes separately and then used polytomous logistic regression to compare these estimates. In the combined cohort, age, gender, family history of colon or rectal cancer, height, body mass index, physical activity, folate, intake of beef, pork or lamb as a main dish, intake of processed meat and alcohol were significantly associated with colon cancer risk. However, only age and sex were associated with rectal cancer. In a stepwise polytomous logistic regression procedure, family history and physical activity were associated with statistically significant different relative risks of colon and rectal cancer. Our findings support previous suggestions that family history and physical activity are not strong contributors to the etiology of rectal cancer. Future investigations of colon or rectal cancer should take into consideration risk factor differences by subsite.


Traditional Chinese Medicine in Osteoporosis Intervention and the Related Regulatory Mechanism of Gut Microbiome.
The gut microbiome (GM) has become a crucial factor that can affect the progression of osteoporosis. A number of studies have demonstrated the impact of Traditional Chinese Medicine (TCM) on GM and bone metabolism. In this review, we summarize the potential mechanisms of the relationship between osteoporosis and GM disorder and introduce several natural Chinese medicines that exert anti-osteoporosis effects by modulating the GM. It is underlined that, through the provision of the microbial associated molecular pattern (MAMP), the GM causes inflammatory reactions and alterations in the Treg-Th17 balance and ultimately leads to changes in bone mass. Serotonin and many hormones, especially estrogen, may play a crucial role in the interaction of the GM with bone metabolism. Additionally, the GM may affect the absorption of specific nutrients in the intestine, particularly minerals like calcium, magnesium, and phosphorus. Several natural Chinese herbs, such as Sambucus Williamsii, Achyranthes bidentata Blume, Pleurotus ostreatus and Ganoderma lucidum mushrooms, Pueraria Lobata, and Agaricus blazei Murill have exhibited anti-osteoporosis effects through regulating the distribution and metabolism of the GM. These herbs may increase the abundance of Firmicutes, decrease the abundance of Bacteroides, promote the GM to produce more SCFAs, modulate the immune response caused by harmful bacteria, and increase the proportion of Treg-Th17 to indirectly affect bone metabolism. Moreover, gut-derived 5-HT is an important target for TCM to prevent osteoporosis via the gut-bone axis. Puerarin could prevent osteoporosis by improving intestinal mucosal integrity and decrease systemic inflammation caused by estrogen deficiency.


Healthcare professionals' views of a new second-level nursing associate role: A qualitative study exploring early implementation in an acute setting.
The study aimed to establish the views of a range of stakeholders about their experiences of the newly implemented nursing associate role in England and its potential to contribute to patient care. Second-level nursing roles are increasingly used internationally within the healthcare workforce. In response to registered nurse workforce deficits, a new nursing associate role has been introduced in England to augment care provided by registered nurses and enable career progression of support workers. Qualitative descriptive design. Semi-structured interviews and a focus group were conducted with a range of healthcare professionals in a large inner city acute secondary care healthcare organisation in England. Interviews were guided by the Consolidated Framework for Implementation Research and analysed using Framework Analysis. The study was reported according to COREQ guidelines. 33 healthcare professionals were interviewed-directors of nursing, ward managers, nursing associates and multidisciplinary team members. Participants perceived the role was broadly adaptable to different healthcare settings and provided a positive professional development mechanism for healthcare support workers. Managers felt training commitments made implementing the role complex and costly. Participants argued the role had limitations, particularly with intravenous medicine management. Implementation was impeded by rapid pace and consequent lack of clear communication and planning. The nursing associate role was perceived as an inclusive pathway into nursing but with limitations when working with high-acuity patients. Further evaluation is needed to investigate how the role has embedded over time. The role should be seen as both a stepping stone into registered nursing positions and valued as part of the nursing workforce. Consideration must be given to how the role can be safely implemented in different settings. Findings have relevance to healthcare leaders internationally, who continue to work in a climate of economic pressure and staffing shortages.


Mechanistic Investigation of LSW/Surfactant/Alkali Synergism for Enhanced Oil Recovery: Fluid-Fluid Interactions.
The combination of chemical enhanced oil recovery (CEOR) and low salinity water (LSW) flooding is one of the most attractive enhanced oil recovery (EOR) methods. While several studies on CEOR have been performed to date, there still exists a lack of mechanistic understanding on the synergism between surfactant, alkali and LSW. This synergism, in terms of fluid-fluid interactions, is experimentally investigated in this study, and mechanistic understanding is gained through fluid analysis techniques. Two surfactants, one cationic and one anionic, namely an alkyltrimethylammonium bromide (C19TAB) and sodium dodecylbenzenesulfonate (SDBS), were tested, together with NaOH used as the alkali, diluted formation brine used as the LSW, and the crude oil was collected from an Iranian carbonate oil reservoir. Fluids were analyzed using pendant drop method for interfacial tension (IFT) measurement, and Fourier transform infrared spectroscopy for determination of aqueous and oleic phase chemical interaction. The optimum concentration of LSW for IFT reduction was investigated to be 1000 ppm. Additionally, both surfactants reduced IFT significantly, from 28.86 mN/m to well below 0.80 mN/m, but in the presence of optimal alkali concentration the IFT dropped further to below 0.30 mN/m. IFT reduction by alkali was linked to the production of three different types of in situ anionic surfactants, while in the case of anionic and cationic surfactants, saponification reactions and the formation of the C19TAOH alcohol, respectively, were linked to IFT reduction. The critical micelle concentration and optimal alkali concentration when using cationic C19TAB were significantly lower than with the anionic surfactant; respectively: 335 vs 5000 ppm, and 500 vs 5000 ppm. However, it was found that SDBS was more compatible with NaOH than C19TAB, due to occurrence of alkali deposition with the latter beyond the optimal point.


One-Stage Immediate Breast Reconstruction: A Concise Review.
One-stage direct-to-implant immediate breast reconstruction (IBR) is performed simultaneously with breast cancer resection. We explored indications, techniques, and outcomes of IBR to determine its feasibility, safety, and effectiveness. We reviewed the available literature on one-stage direct-to-implant IBR, with or without acellular dermal matrix (ADM), synthetic mesh, or autologous fat grafting. We analyzed the indications, preoperative work-up, surgical technique, postoperative care, outcomes, and complications. IBR is indicated for small-to-medium nonptotic breasts and contraindicated in patients who require or have undergone radiotherapy, due to unacceptably high complications rates. Only patients with thick, well-vascularized mastectomy flaps are IBR candidates. Expandable implants should be used for ptotic breasts, while anatomical shaped implants should be used to reconstruct small-to-medium nonptotic breasts. ADMs can be used to cover the implant during IBR and avoid muscle elevation, thereby minimizing postoperative pain. Flap necrosis, reoperation, and implant loss are more common with IBR than conventional two-staged reconstruction, but IBR has advantages such as lack of secondary surgery, faster recovery, and better quality of life. IBR has good outcomes and patient-satisfaction rates. With ADM use, a shift from conventional reconstruction to IBR has occurred. Drawbacks of IBR can be overcome by careful patient selection.


When and How to Use PARP Inhibitors in Prostate Cancer: A Systematic Review of the Literature with an Update on On-Going Trials.
The goal of precision oncology is to use the underlying genomic characteristics of the patient and the cancer to select the optimal treatment at a given time. The recent Food and Drug Administration (FDA) approval of the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib for the treatment of advanced prostate cancer heralds the onset of precision medicine for this disease. To discuss the emerging role that PARP inhibitors may play as a personalised future treatment option in patients with prostate cancer, with a focus on patients with metastatic castration-resistant prostate cancer (mCRPC) whose tumour cells harbour mutations resulting from deficient homologous recombination repair (HRR). To identify publications relevant to this review, a systematic literature search of PubMed was conducted for articles and proceedings of relevant major congresses, published between January 2010 and March 2020, reporting the use of PARP inhibitors in the treatment of cancers. A total of 168 publications were identified, and 18 of these met the criteria for subsequent review. In addition, 15 phase 2 or on-going phase 3 (mCRPC) studies evaluating PARP inhibitors as monotherapy or in combination, which had not yet reported data, were identified through ClinicalTrials.gov. Emerging data suggest that the greatest efficacy with single-agent PARP inhibitors is seen in mCRPC patients with germline or somatic BRCA1/2 alterations (especially BRCA2 or biallelic mutations), with potential efficacy also observed in men with PALB2 and FANCA mutations. PARP inhibitors have demonstrated efficacy in mCRPC, and similar to ovarian and breast cancers, the greatest effect is observed in patients with HRR deficiency. The PARP inhibitors olaparib and rucaparib are now FDA approved for mCRPC patients with HRR mutations and BRCA1/2 mutations, respectively. Furthermore, when PARP inhibition is combined with novel hormonal therapies, a treatment benefit may be observed regardless of the HRR deficiency status. Gaps in the knowledge and understanding around PARP inhibitor use in prostate cancer, including the most appropriate diagnostic testing method for identifying an HRR mutation, remain to be resolved. The poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib are now approved by the Food and Drug Administration for the treatment of advanced prostate cancer. Here, we reviewed the literature and proceedings from meeting presentations and published papers relevant to the use of PARP inhibitors in the treatment of prostate cancer. Testing methods for detecting homologous recombination repair gene mutations, as diagnostic tools to help identify patients most likely to benefit from PARP inhibitor treatment, are also discussed.


Risk Factors of Recurrent Retinal Detachment Following Surgical Treatment for Rhegmatogenous Retinal Detachment: A Retrospective Study.
To identify potential risk factors for recurrent retinal detachment after surgical treatment for rhegmatogenous retinal detachment with choroidal detachment (RRD-CD) in a Chinese population. A total of 1212 patients with RRD-CD admitted to Beijing Tongren Hospital from 2004 to 2018 were reviewed retrospectively. The rate of recurrent retinal detachment was calculated, and risk factors were analyzed by logistic regression analysis. The average age of the patients was 48.51 years, 760 patients (62.7%) were male, and 630 patients (52.0%) had right eye disease. The recurrence rate in the same eye was 21.3%. The incidence of recurrence retinal detachment was higher in patients who were male, middle age, and with poor preoperative vision, longer axial length, and scleral buckling. Recurrence usually occurred 3 months after surgery. Male, middle age, longer axial length, and scleral buckling could be risk factors for recurrent retinal detachment following surgical treatment in patients with RRD-CD.


Oral betamimetics for maintenance therapy after threatened preterm labour.
Some women who have threatened to give birth prematurely, subsequently settle. They may then take oral tocolytic maintenance therapy to prevent preterm birth and to prolong gestation. To assess the effects of oral betamimetic maintenance therapy after threatened preterm labour for preventing preterm birth. We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 9 November 2012. Randomised controlled trials comparing oral betamimetic with alternative tocolytic therapy, placebo or no therapy, for maintenance following treatment of threatened preterm labour. Two review authors independently applied the selection criteria and carried out data extraction and quality assessment of studies. We did not identify any new trials from the updated search so the results remain unchanged as follows.We included 13 randomised controlled trials (RCTs) with a total of 1551 women. We found no differences for admission to the neonatal intensive care unit when betamimetics were compared with placebo (risk ratio (RR) 1.28, 95% confidence interval (CI) 0.68 to 2.41; two RCTs of terbutaline with 2600 women) or with magnesium (RR 0.80, 95% CI 0.43 to 1.46; one RCT of 137 women). The rate of preterm birth (less than 37 weeks) showed no significant difference in six RCTs, four comparing ritodrine with placebo/no treatment and two comparing terbutaline with placebo/no treatment (RR 1.11, 95% CI 0.91 to 1.35; 644 women). We observed no differences between betamimetics and placebo, no treatment or other tocolytics for perinatal mortality and morbidity outcomes. Some adverse effects such as tachycardia were more frequent in the betamimetics groups than the groups allocated to placebo, no treatment or another type of tocolytic. Available evidence does not support the use of oral betamimetics for maintenance therapy after threatened preterm labour.


The interplay between natural organic matter and bromide on bromine substitution.
This study examined the interplay between bromide and DOM characteristics, described with SUVA254, in terms of formation and speciation of selected DBPs [trihalomethanes (THMs), haloacetic acids (HAAs), and haloacetonitriles (HANs)] during chlorination under various water treatment conditions. Cytotoxicity evaluations were also conducted based on the types and amounts of DBPs formed and their corresponding cytotoxicity index values. The results showed that the formation of THMs and HAAs increased as the specific UV absorbance at 254 nm (SUVA254) of the waters increased; however, there was no clear trend for HANs. THM and HAN formation increased with increasing bromide levels, while there was no bromide effect on the HAA formation. Lower HAA5 (monochloroaceticacid, monobromoaceticacid, dichloroaceticacid, trichloroaceticacid, dibromoaceticacid) to HAA9 (monochloroaceticacid, monobromoaceticacid, dichloroaceticacid, trichloroaceticacid, dibromoaceticacid, bromochloroaceticacid, bromodichloroaceticacid, dibromochloroaceticacid, tribromoaceticacid) ratios, independent of SUVA254, were observed with increasing bromide levels. Bromine substitution factor (BSF) values were in the order of BSFDHAN > BSFTHAA > BSFTHM ≈ BSFDHAA. BSF values for all class of DBPs decreased with increasing SUVA254. TOX formation increased with increasing SUVA254 without an impact of bromide concentration. UTOX/TOX ratios were higher in treated low SUVA254 waters than raw waters having higher SUVA254 values, and they decreased with increasing initial bromide concentration in all sources. Increasing bromide concentration from 0.5 μM to 10 μM elevated the calculated cytotoxicity index values of waters. Despite their much lower (approximately ~10 times) formation as compared to THMs and HAAs, HANs controlled the calculated cytotoxicity of studied waters.


Differences between the sexes and age-related changes in orienteering speed.
The aim of this study was to assess the effects of the age and sex of the competitor on orienteering speed during competitive events. The results of the fastest three male and fastest three female competitors in each 5-year age band (21-79 years), from four national orienteering events, were analysed. The data for age and orienteering speed were log-transformed and regression analyses were conducted to determine the relationships between age and sex and orienteering speed. For comparison, data for the fastest Great Britain finisher in the 10,000-m track and 10-km cross-country events for age groups 40-69 years at the World Masters Championships were also analysed. The results showed that, before the age of 40 years, there was no substantial slowing in orienteering speed for males (0.5-4.2% per decade) but a moderate decline (4.7-10.0% per decade) for females. After the age of 45 years, the orienteering speed of males and females slowed by 13+/-2% and 16+/-4% per decade (mean +/- s), respectively, until around the age of 69, after which the deterioration was accentuated. The orienteering speed of the females was 81+/-4, 74+/-6 and 69+/-7% that of the males at ages 21, 45 and 65 years, respectively. The magnitudes of the age-related slowing of orienteering speed and of the difference in orienteering speed between males and females aged 45 years and over were greater than those reported for the other endurance running events. This may reflect the physical demands of running in orienteering terrain, tactical and cognitive aspects of the sport, or sociocultural aspects of the participating population.


Interexaminer repeatability of a new, modified prentice card compared with established phoria tests.
The Howell phoria card, a new modification of the Prentice design, has no previously published validity or reliability data. The purpose of this study was to compare the interexaminer repeatability of the Howell phoria card with established tests. Experienced optometrists measured the near heterophoria of 72 subjects. Heterophoria was measured in a pseudo-random order using five standardized procedures: (1) Howell phoria card continuous presentation, (2) Howell phoria card flashed presentation, (3) free-space von Graefe method, 4) Bernell Muscle Imbalance Measure (MIM) card continuous presentation, and (5) MIM card flashed presentation. The von Graefe method and the Howell phoria card flashed presentation found significantly less exophoric results than the MIM card. There was no consistent tendency for different examiners to find more exo- or more esophoric results with the phoria measurement techniques used in this study (p = 0.28). Both the Howell phoria card continuous presentation and the MIM card had significantly less variability in interexaminer differences than the Howell phoria card flashed presentation and the von Graefe method (p < 0.05). Results from this study suggest that the Howell phoria card used in a continuous presentation method has an interexaminer repeatability that is not significantly different from the MIM card but greater than the von Graefe method.


Grammatical Language Impairment in Autism Spectrum Disorder: Exploring Language Phenotypes Beyond Standardized Testing.
Linguistic and cognitive abilities manifest huge heterogeneity in children with autism spectrum disorder (ASD). Some children present with commensurate language and cognitive abilities, while others show more variable patterns of development. Using spontaneous language samples, we investigate the presence and extent of grammatical language impairment in a heterogeneous sample of children with ASD. Findings from our sample suggest that children with ASD can be categorized into three meaningful subgroups: those with normal language, those with marked difficulty in grammatical production but relatively intact vocabulary, and those with more globally low language abilities. These findings support the use of sensitive assessment measures to evaluate language in autism, as well as the utility of within-disorder comparisons, in order to comprehensively define the various cognitive and linguistic phenotypes in this heterogeneous disorder.


Physicians' perceptions of autonomy across practice types: Is autonomy in solo practice a myth?
Physicians in the United States are now less likely to practice in smaller, more traditional, solo practices, and more likely to practice in larger group practices. Though older theory predicts conflict between bureaucracy and professional autonomy, studies have shown that professions in general, and physicians in particular, have adapted to organizational constraints. However, much work remains in clarifying the nature of this relationship and how exactly physicians have adapted to various organizational settings. To this end, the present study examines physicians' autonomy experiences in different decision types between organization sizes. Specifically, I ask: In what kinds of decisions do doctors perceive autonomous control? How does this vary by organizational size? Using stacked "spell" data constructed from the Community Tracking Study (CTS) Physician Survey (1996-2005) (n = 16,519) I examine how physicians' perceptions of autonomy vary between solo/two physician practices, small group practices with three to ten physicians, and large practices with ten or more physicians, in two kinds of decisions: logistic-based and knowledge-based decisions. Capitalizing on the longitudinal nature of the data I estimate how changes in practice size are associated with perceptions of autonomy, accounting for previous reports of autonomy. I also test whether managed care involvement, practice ownership, and salaried employment help explain part of this relationship. I find that while physicians practicing in larger group practices reported lower levels of autonomy in logistic-based decisions, physicians in solo/two physician practices reported lower levels of autonomy in knowledge-based decisions. Managed care involvement and ownership explain some, but not all, of the associations. These findings suggest that professional adaptation to various organizational settings can lead to varying levels of perceived autonomy across different kinds of decisions.


Stress Transmission and Failure in Disordered Porous Media.
By means of extensive lattice-element simulations, we investigate stress transmission and its relation with failure properties in increasingly disordered porous systems. We observe a non-Gaussian broadening of stress probability density functions under tensile loading with increasing porosity and disorder, revealing a gradual transition from a state governed by single-pore stress concentration to a state controlled by multipore interactions and metric disorder. This effect is captured by the excess kurtosis of stress distributions and shown to be nicely correlated with the second moment of local porosity fluctuations, which appears thus as a (dis)order parameter for the system. By generating statistical ensembles of porous textures with varying porosity and disorder, we derive a general expression for the fracture stress as a decreasing function of porosity and disorder. Focusing on critical sites where the local stress is above the global fracture threshold, we also analyze the transition to failure in terms of a coarse-graining length. These findings provide a general framework which can also be more generally applied to multiphase and structural heterogeneous materials.


[Diagnosis and therapy of malignant lymphedema].
In addition to the typical clinical symptoms, the diagnosis "malignant lymphedema" also requires the confirmation of a tumor or a metastasis obstructing lymph flow. With the standard physical treatment of edema described by Asdonk successful clinical management of malignant lymphedema is also possible. The sole contraindication of manual lymph drainage is, we believe, locoregional tumor recurrence, which can be completely eliminated by the immediate initiation of radical tumor treatment. The tumor recurrence is the result not of falsely indicated manual lymph drainage, but of inadequate primary treatment that leaves behind residual tumor tissue, the early detection of which still remains an unresolved problem. Manual lymph drainage is indispensable for improving the quality of life of tumor patients with lymphedema.


Kinetic analysis of enzyme inactivation under second-order conditions by use of substrate-to-product progress curves: application to the inhibition of trypsin by alpha-1 proteinase inhibitor.
The inhibition of bovine pancreatic trypsin by human alpha-1 proteinase inhibitor (alpha-1 PI) was studied under second-order conditions by continuously monitoring the fluorescence change due to the enzymatic hydrolysis of N alpha-benzoyl-L-arginine 7-amido-4-methyl-coumarin as substrate. Employing equimolar starting concentrations of enzyme and inhibitor (110-220 nM), the fluorescence progress curve was analyzed according to the equation Pt = (kcat[S]/kiKm)In[ki[E]0t + 1], where ki is the second-order rate constant for the reaction, E + alpha-1 PI-->E* alpha-1 PI (inactive). ki was found to be 1.8 +/- 0.16 x 10(7) M-1 min-1 (at pH 7.0 and 25 degrees C), in close agreement with results obtained by alternative kinetic methods. The method reported appears to be valid and should be useful in the study of fast reactions where one of the reaction partners is an enzyme. An extension of the second-order progress curve approach to cover unequimolar mixtures of E and I is also offered.


Extinction, survival or recovery of large predatory fishes.
Large predatory fishes have long played an important role in marine ecosystems and fisheries. Overexploitation, however, is gradually diminishing this role. Recent estimates indicate that exploitation has depleted large predatory fish communities worldwide by at least 90% over the past 50-100 years. We demonstrate that these declines are general, independent of methodology, and even higher for sensitive species such as sharks. We also attempt to predict the future prospects of large predatory fishes. (i) An analysis of maximum reproductive rates predicts the collapse and extinction of sensitive species under current levels of fishing mortality. Sensitive species occur in marine habitats worldwide and have to be considered in most management situations. (ii) We show that to ensure the survival of sensitive species in the northwest Atlantic fishing mortality has to be reduced by 40-80%. (iii) We show that rapid recovery of community biomass and diversity usually occurs when fishing mortality is reduced. However, recovery is more variable for single species, often because of the influence of species interactions. We conclude that management of multi-species fisheries needs to be tailored to the most sensitive, rather than the more robust species. This requires reductions in fishing effort, reduction in bycatch mortality and protection of key areas to initiate recovery of severely depleted communities.


Genotoxicity and Immunotoxicity of Titanium Dioxide-Embedded Mesoporous Silica Nanoparticles (TiO2@MSN) in Primary Peripheral Human Blood Mononuclear Cells (PBMC).
Background: TiO2 nanoparticles (TiO2 NPs) are the nanomaterial most produced as an ultraviolet (UV) filter. However, TiO2 is a semiconductor and, in nanoparticle size, is a strong photocatalyst, raising concerns about photomutagenesis. Mesoporous silica nanoparticles (MSN) were synthetized incorporating TiO2 NPs (TiO2@MSN) to develop a cosmetic UV filter. The aim of this study was to assess the toxicity of TiO2@MSN, compared with bare MSN and commercial TiO2 NPs, based on several biomarkers. Materials and Methods: Human peripheral blood mononuclear cells (PBMC) were exposed to TiO2@MSN, bare MSN (network) or commercial TiO2 NPs for comparison. Exposed PBMC were characterized for cell viability/apoptosis, reactive oxygen species (ROS), nuclear morphology, and cytokines secretion. Results: All the nanoparticles induced apoptosis, but only TiO2 NPs (alone or assembled into MSN) led to ROS and micronuclei. However, TiO2@MSN showed lower ROS and cytotoxicity with respect to the P25. Exposure to TiO2@MSN induced Th2-skewed and pro-fibrotic responses. Conclusions: Geno-cytotoxicity data indicate that TiO2@MSN are safer than P25 and MSN. Cytokine responses induced by TiO2@MSN are imputable to both the TiO2 NPs and MSN, and, therefore, considered of low immunotoxicological relevance. This analytical assessment might provide hints for NPs modification and deep purification to reduce the risk of health effects in the settings of their large-scale manufacturing and everyday usage by consumers.


Clinically asymptomatic myocardial bridging in a child with familial subaortic stenosis.
Myocardial bridging is usually seen in the setting of hypertrophic cardiomyopathy or left ventricular hypertrophy. It is rarely reported in an asymptomatic patient with an otherwise structurally normal heart. Familial subaortic stenosis is also a rare entity, and its mode of inheritance is still unknown. Here, we described the case of a 13-year-old asymptomatic girl with a positive family history of sudden cardiac death and subaortic stenosis who was diagnosed with severe myocardial bridging concomitant with familial subaortic stenosis.


Diagnostic particle agglutination using ultrasound: a new technology to rejuvenate old microbiological methods.
Microbial antigen in clinical specimens can be detected rapidly by commercial test-card latex agglutination, but poor sensitivity is a potential difficulty. Antigen detection by immuno-agglutination of coated latex micro-particles can be enhanced in comparison with the conventional test-card method in both rate and sensitivity by the application of a non-cavitating ultrasonic standing wave. Antibody-coated micro-particles suspended in the acoustic field are subjected to physical forces that promote the formation of agglutinates by increasing particle-particle contact. This report reviews the application of ultrasound to immuno-agglutination testing with several commercial antibody-coated diagnostic micro-particles. This technique is more sensitive than commercial card-based agglutination tests by a factor of up to 500 for fungal cell-wall antigen, 64 for bacterial polysaccharide and 16 for viral antigen (in buffer). The detection sensitivity of meningococcal capsular polysaccharide in patient serum or CSF has been increased to a stage where serotyping by ultrasound-enhanced agglutination is comparable to that achievable with the PCR, but is available more rapidly. Serum antigen concentration as measured by ultrasonic agglutination has prognostic value. Increasing the sensitivity of antigen detection by increasing the acoustic forces that act on suspended particles is considered. Employing turbidimetry to measure agglutination as part of an integrated ultrasonic system would enable the turnover of large numbers of specimens. Ultrasound-enhanced latex agglutination offers a rapid, economical alternative to molecular diagnostic methods and may be useful in situations where microbiological and molecular methods are impracticable.


The bile acid deoxycholate elicits defences in Arabidopsis and reduces bacterial infection.
Disease has an effect on crop yields, causing significant losses. As the worldwide demand for agricultural products increases, there is a need to pursue the development of new methods to protect crops from disease. One mechanism of plant protection is through the activation of the plant immune system. By exogenous application, 'plant activator molecules' with elicitor properties can be used to activate the plant immune system. These defence-inducing molecules represent a powerful and often environmentally friendly tool to fight pathogens. We show that the secondary bile acid deoxycholic acid (DCA) induces defence in Arabidopsis and reduces the proliferation of two bacterial phytopathogens: Erwinia amylovora and Pseudomonas syringae pv. tomato. We describe the global defence response triggered by this new plant activator in Arabidopsis at the transcriptional level. Several induced genes were selected for further analysis by quantitative reverse transcription-polymerase chain reaction. We describe the kinetics of their induction and show that abiotic stress, such as moderate drought or nitrogen limitation, does not impede DCA induction of defence. Finally, we investigate the role in the activation of defence by this bile acid of the salicylic acid biosynthesis gene SID2, of the receptor-like kinase family genes WAK1-3 and of the NADPH oxidase-encoding RbohD gene. Altogether, we show that DCA constitutes a promising molecule for plant protection which can induce complementary lines of defence, such as callose deposition, reactive oxygen species accumulation and the jasmonic acid and salicylic acid signalling pathways.


Equivocal support for the climate variability hypothesis within a Neotropical bird assemblage.
The climate variability hypothesis posits that an organism's exposure to temperature variability determines the breadth of its thermal tolerance and has become an important framework for understanding variation in species' susceptibilities to climate change. For example, ectotherms from more thermally stable environments tend to have narrower thermal tolerances and greater sensitivity to projected climate warming. Among endotherms, however, the relationship between climate variability and thermal physiology is less clear, particularly with regard to microclimate variation-small-scale differences within or between habitats. To address this gap, we explored associations between two sources of temperature variation (habitat type and vertical forest stratum) and (1) thermal physiological traits and (2) temperature sensitivity metrics within a diverse assemblage of Neotropical birds (n = 89 species). We used long-term temperature data to establish that daily temperature regimes in open habitats and forest canopy were both hotter and more variable than those in the forest interior and forest understory, respectively. Despite these differences in temperature regime, however, we found little evidence that species' thermal physiological traits or temperature sensitivity varied in association with either habitat type or vertical stratum. Our findings provide two novel and important insights. First, and in contrast to the supporting empirical evidence from ectotherms, the thermal physiology of birds at our study site appears to be largely decoupled from local temperature variation, providing equivocal support for the climate variability hypothesis in endotherms. Second, we found no evidence that the thermal physiology of understory forest birds differed from that of canopy or open-habitat species-an oft-invoked, yet previously untested, mechanism for why these species are so vulnerable to environmental change.


[Analysis of micronuclei induced under hyperthermic conditions in human lymphocyte culture by fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY) methods].
The spectral karyotyping (SKY) method is a novel molecular cytogenetic technique which simultaneously discerns entire chromosomes. In order to elucidate the origins of micronuclei induced under hyperthermic conditions in human lymphocyte culture, peripheral blood cells were cultured at 40 degrees C or 42 degrees C for 3-24 h, using the cytokinesis-block method with cytochalasin B. The induced micronuclei were identified by the fluorescence in situ hybridization (FISH) and SKY methods. At 42 degrees C for more than 6 h, the frequency of occurrence of micronuclei in binucleated cells rose with increasing incubation time. By the FISH method, 83.3% of micronuclei induced in 24 h culture at 42 degrees C were shown to be positive for the human centromeric probes. By the SKY method, each micronucleus induced under the hyperthermic conditions was identified unequivocally and shown to contain a specific chromosome. These results suggest that the micronuclei induced under the hyperthermic conditions in human lymphocyte culture contain chromosomes which do not migrate to the poles at the anaphase of the cell cycle because of the breakdown of the spindle apparatus.


Effect of diet on creatinine clearance and excretion in young and elderly healthy subjects and in patients with renal disease.
Thirty-seven young healthy subjects with normal renal function were studied to assess the quantitative effect of protein intake on creatinine clearance. A standard 24-h urine collection and blood sample at the end of the collection were obtained for creatinine and urea concentrations. Correlations between creatinine clearance and urinary urea nitrogen excretion (r = 0.8; P less than 0.0001) and calculated protein intake (r = 0.8; P less than 0.0001) were observed. A significant relationship between creatinine clearance and urea nitrogen excretion was also demonstrated in 28 elderly healthy subjects and 33 patients with renal disease. To demonstrate a cause and effect between urea nitrogen excretion and creatinine clearance in healthy subjects, 18 of the 37 healthy subjects repeated the 24-h urine collection and blood sample after ingesting 5 g of urea in addition to their usual diet. Mean urinary urea nitrogen excretion increased from a mean value of 9.8 +/- 4.0 to 11.8 +/- 4.0 g/day. There was a strong correlation between the changes in urea nitrogen excretion and the changes in creatinine clearance. In acute studies with oral protein loading, there was a significant correlation between creatinine clearance and urinary urea nitrogen excretion. It was concluded that protein intake has a direct and quantitative effect on creatinine clearance in healthy subjects. In normal humans, it is likely that GFR is not a fixed function. Thus, a low creatinine clearance is not a categorical sign of renal disease. A low creatinine clearance adjusted for urea nitrogen excretion may be a useful clinical tool to assess renal function.


Calcified mucocele of the appendix presenting as ureteral obstruction.
Mucocele of the appendix, a rare lesion, occurs in 0.3% of patients undergoing appendectomy. Only 46 cases of calcified mucocele have been reported. Complications reported include appendiceal intussusception, rupture resulting in acute abdomen, and infection. We report the case of a 74-year-old man with a calcified mucocele of the appendix that was discovered in the evaluation of a ureteral obstruction. During exploratory surgery, the patient was found to have a 6 x 5 cm appendiceal tumor and underwent a right ileocolectomy. Pathologic examination showed calcified mucous cystadenoma of the appendix. Calcification of a mucocele is believed to denote chronicity. Our case is the first report of ureteral obstruction secondary to calcified mucocele and the second calcified mucocele to be seen on computerized tomography. Calcified mucocele should be included in the differential diagnosis of any calcified tumor in the right lower quadrant.


Association of nuclear cataract prevalence with UV radiation and heat load in lens of older people -five city study.
Epidemiological studies have reported that the frequency of nuclear cataracts (NUCs) is high among the elderly and in tropical countries. Ultraviolet (UV) irradiation and lens temperature are considered as key physical contributors, although their precise quantification is difficult. The aim of this study is to investigate the association of NUC prevalence with UV irradiation and heat load. First, we assessed the lens temperature using thermodynamic modeling considering the thermophysiological response. We then conducted a multivariate linear regression analysis for the epidemiological analysis of NUC prevalence across five cities. A strong correlation was observed between NUC prevalence and the combined effects of UV irradiation and cumulative equivalent minutes at 43 °C (CEM43°C) derived from the computed lens temperature (adjusted R2 = 0.933, p < 0.0001). Heat load significantly contributed to the prevalence at 52%, surpassing the contributions of UV irradiation (31%) and the decline in DNA repair capacity in the lens (17%). These results suggested that both UV radiation and heat load are associated with NUC, with heat load contributing more. Our findings provided important implications for future interventions, particularly in the context of global warming.


Cerebellar Pathology in Familial vs. Sporadic Essential Tremor.
Familial and sporadic essential tremor (ET) cases differ in several respects. Whether they differ with respect to cerebellar pathologic changes has yet to be studied. We quantified a broad range of postmortem features (Purkinje cell (PC) counts, PC axonal torpedoes, a host of associated axonal changes, heterotopic PCs, and hairy basket ratings) in 60 ET cases and 30 controls. Familial ET was defined using both liberal criteria (n = 27) and conservative criteria (n = 20). When compared with controls, ET cases had lower PC counts, more torpedoes, more heterotopic PCs, a higher hairy basket rating, an increase in PC axonal collaterals, an increase in PC thickened axonal profiles, and an increase in PC axonal branching. Familial and sporadic ET had similar postmortem changes, with few exceptions, regardless of the definition criteria. The PC counts were marginally lower in familial than sporadic ET (respective p values = 0.059 [using liberal criteria] and 0.047 [using conservative criteria]). The PC thickened axonal profile count was marginally lower in familial ET than sporadic ET (respective p values = 0.037 [using liberal criteria] and 0.17 [using conservative criteria]), and the PC axonal branching count was marginally lower in familial than sporadic ET (respective p values = 0.045 [using liberal criteria] and 0.079 [using conservative criteria]). After correction for multiple comparisons, however, there were no significant differences. Overall, familial and sporadic ET cases share very similar cerebellar postmortem features. These data indicate that pathological changes in the cerebellum are a part of the pathophysiological cascade of events in both forms of ET.


Global warming and Australian public health: reasons to be concerned.
Studies in global warming and climate change indicate that human populations will be deleteriously affected in the future. Studies forecast that Australia will experience increasing heat waves and droughts. Heat stress caused by frequent heat waves will have a marked effect on older Australians due to physiological and pharmacological factors. In this paper we present an overview of some of the foreseeable issues which older Australians will face from a public health perspective.


Identification, investigation and management of patient-to-patient hepatitis B transmission within an inpatient renal ward in North West England.
Transmission of hepatitis B virus (HBV) is rare within healthcare settings in developed countries. The aim of the article is to outline the process of identification and management of transmission of acute hepatitis B in a renal inpatient ward. The case was identified through routine reporting to public health specialists, and epidemiological, virological and environmental assessment was undertaken to investigate the source of infection. An audit of HBV vaccination in patients with chronic kidney disease was undertaken. Investigations identified inpatient admission to a renal ward as the only risk factor and confirmed a source patient with clear epidemiological, virological and environmental links to the case. Multiple failures in infection control leading to a contaminated environment and blood glucose testing equipment, failure to isolate a non-compliant, high-risk patient and incomplete vaccination for patients with chronic kidney disease may have contributed to the transmission. Patient-to-patient transmission of hepatitis B was shown to have occurred in a renal ward in the UK, due to multiple failures in infection control. A number of policy changes led to improvements in infection control, including reducing multi-function use of wards, developing policies for non-compliant patients, improving cleaning policies and implementing competency assessment for glucometer use and decontamination. HBV vaccination of renal patients may prevent patient-to-patient transmission of HBV. Consistent national guidance should be available, and clear pathways should be in place between primary and secondary care to ensure appropriate hepatitis B vaccination and follow-up testing.


Changes in urinary excretion of water and sodium transporters during amiloride and bendroflumethiazide treatment.
To quantify changes in urinary excretion of aquaporin2 water channels (u-AQP2), the sodium-potassium-chloride co-transporter (u-NKCC2) and the epithelial sodium channels (u-ENaC) during treatment with bendroflumethiazide (BFTZ), amiloride and placebo. In a randomized, double-blinded, placebo-controlled, 3-way crossover study we examined 23 healthy subjects on a standardized diet and fluid intake. The subjects were treated with amiloride 5 mg, BFTZ 1.25 mg or placebo twice a day for 4.5 d before each examination day. On the examination day, glomerular filtration rate was measured by the constant infusion clearance technique with (51)Cr-EDTA as reference substance. To estimate the changes in water transport via AQP2 and sodium transport via NKCC2 and ENaC, u-NKCC2, the gamma fraction of ENaC (u-ENaCγ), and u-AQP2 were measured at baseline and after infusion with 3% hypertonic saline. U-NKCC2, u-ENaCγ, u-AQP2 and plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensin II (p-ANG II) and aldosterone (p-Aldo) were measured, by radioimmunoassay. Central blood pressure was estimated by applanation tonometry and body fluid volumes were estimated by bio-impedance spectroscopy. General linear model with repeated measures or related samples Friedman's two-way analysis was used to compare differences. Post hoc Bonferroni correction was used for multiple comparisons of post infusion periods to baseline within each treatment group. At baseline there were no differences in u-NKCC2, u-ENaCγ and u-AQP2. PRC, p-Ang II and p-Aldo were increased during active treatments (P < 0.001). After hypertonic saline, u-NKCC2 increased during amiloride (6% ± 34%; P = 0.081) and increased significantly during placebo (17% ± 24%; P = 0.010). U-AQP2 increased significantly during amiloride (31% ± 22%; P < 0.001) and placebo (34% ± 27%; P < 0.001), while u-NKCC2 and u-AQP2 did not change significantly during BFTZ (-7% ± 28%; P = 0.257 and 5% ± 16%; P = 0.261). U- ENaCγ increased in all three groups (P < 0.050). PRC, AngII and p-Aldo decreased to the same extent, while AVP increased, but to a smaller degree during BFTZ (P = 0.048). cDBP decreased significantly during BFTZ (P < 0.001), but not during amiloride or placebo. There were no significant differences in body fluid volumes. After hypertonic saline, u-NKCC2 and u-AQP2 increased during amiloride, but not during BFTZ. Lower p-AVP during BFTZ potentially caused less stimulation of NKCC2 and AQP2 and subsequent lower reabsorption of water and sodium.


Creation and Validation of a Photonumeric Scale to Assess Volume Deficiency in the Infraorbital Region.
The eyes are particularly important aesthetic features of the face and revitalization of the infraorbital region has become a focus of aesthetic treatments. Published infraorbital scales to date have limitations in that they have been descriptive, subjective, or have used computer-generated images. Thus, there is an unmet need for a validated scale based on actual images. To develop a practical photonumeric scale that respects the complex anatomy and age-related changes occurring in the orbital area. The Allergan Infra-oRbital Scale (AIRS) was developed through a multistep process in collaboration with 16 physicians (plastic surgeons, dermatologists, and aesthetic physicians). Scale development involved both online photographs and live assessments of subjects. Interrater and intrarater reliability was assessed using intraclass correlation coefficients (ICCs). The final AIRS showed intrarater and interrater ICCs of 0.78 to 0.86 and 0.91 to 0.98 for live validation and 0.76 to 0.82 and 0.86 to 0.91 for online validation, respectively, demonstrating robust validity. The AIRS can be considered a photonumeric scale that accurately describes volume loss in the infraorbital region. It has been validated and is appropriate for use in research or for everyday clinical use for both live and photographic assessment.


More than 10 years registration of continuing medical education as part of quality control by the Netherlands Society for Oto-Rhino-Laryngology and Cervico-Facial Surgery.
After more than 10 years registration, 93% of ENT specialists in The Netherlands fulfil the requirements for continuing medical education in spite of the fact that sanctions (no re-registration) have not been implemented to date. Improvements have been made over the years. Information about how to set up a comparable system was supplied to 10 other scientific societies. A recurrent point for discussion is whether or not to award points for presentations, papers and (co)publications. On the one hand, it seems reasonable to reward the effort but, on the other hand, it creates practical problems. As a matter of fact, all members who give papers and write articles appear to attend more than enough postgraduate education. The process of accurate registration of continuing medical education, including accreditation and certification, is time-consuming. Moreover, it requires intensive and essential supervision by an experienced colleague who has a thorough knowledge of the specialist field.


Differential expression and localization of early light-induced proteins in Arabidopsis.
The early light-induced proteins (Elips) in higher plants are nuclear-encoded, light stress-induced proteins located in thylakoid membranes and related to light-harvesting chlorophyll (LHC) a/b-binding proteins. A photoprotective function was proposed for Elips. Here we showed that after 2 h exposure of Arabidopsis (Arabidopsis thaliana) leaves to light stress Elip1 and Elip2 coisolate equally with monomeric (mLhcb) and trimeric (tLhcb) populations of the major LHC from photosystem II (PSII) as based on the Elip:Lhcb protein ratio. A longer exposure to light stress resulted in increased amounts of Elips in tLhcb as compared to mLhcb, due to a reduction of tLhcb amounts. We demonstrated further that the expression of Elip1 and Elip2 transcripts was differentially regulated in green leaves exposed to light stress. The accumulation of Elip1 transcripts and proteins increased almost linearly with increasing light intensities and correlated with the degree of photoinactivation and photodamage of PSII reaction centers. A stepwise accumulation of Elip2 was induced when 40% of PSII reaction centers became photodamaged. The differential expression of Elip1 and Elip2 occurred also in light stress-preadapted or senescent leaves exposed to light stress but there was a lack of correlation between transcript and protein accumulation. Also in this system the accumulation of Elip1 but not Elip2 correlated with the degree of PSII photodamage. Based on pigment analysis, measurements of PSII activity, and assays of the oxidation status of proteins we propose that the discrepancy between amounts of Elip transcripts and proteins in light stress-preadapted or senescent leaves is related to a presence of photoprotective anthocyanins or to lower chlorophyll availability, respectively.


Bone formation in the maxillary sinus by using platelet-rich plasma: an experimental study in sheep.
Recently, platelet-rich plasma (PRP) has been proven to be an effective regeneration adjunct when combined with autogenous bone in the reconstruction of mandibular defects. However, little is known about the effect of PRP when combined with a bone allograft in the maxillary sinus. The purpose of this study was to quantitatively evaluate the ability of PRP to enhance bone regeneration in the maxillary sinus of sheep when combined with demineralized freeze-dried bone allograft (DFDBA) and cortical cancellous freeze-dried bone allograft (CCFDBA). Ten sheep were selected for bilateral sinus augmentation DFDBA + CCFDBA + PRP (test) and DFDBA + CCFDBA (control). Five were sacrificed at 3 months and the other 5 at 6 months. Hematology tests were performed for platelet count, and histology slides were obtained for histomorphometric analysis taking 2 measures of interest: total area (square millimeters) and percentage of bone fill. Student t tests showed no significant difference between test and control groups for total area (P > .25) and percentage of bone fill (P > .80) at either 3 or 6 months. The control group showed no statistical difference for total area (P < .095) and percentage of bone fill (P <.60) between 3- and 6-month healing times. The test group, however, showed a significant increase in total area (P <.025) but not in percentage of bone fill (P <.40) for the 2 healing periods. When the treatments were compared for interactions within the animal model, no clear tendency was evident for the test group to perform in relation to the control group regarding total area (r = .766, P < .01). A moderate tendency existed between the percentages of bone filled (r = .824, P < .005). Platelet-rich plasma showed higher platelet count than did the whole blood (2 to 5 times). However, no correlation was found between the log ratio and the bone measures. Within the limitations of this study, PRP failed to enhance or accelerate bone regeneration in the maxillary sinus of sheep when combined with bone allograft.


Natural flavonoids silymarin and quercetin improve the brain distribution of co-administered P-gp substrate drugs.
P-glycoprotein (P-gp), a well known efflux transporter in the blood brain barrier inhibits the uptake of substrate drugs into brain. The main aim of this study is to evaluate the effect of natural product based P-gp inhibitors on brain penetration of various CNS drugs which are P-gp substrates. In this study, we have evaluated the inhibitory effects of natural bioflavonoids (quercetin and silymarin) on P-gp by using digoxin and quinidine as model P-gp model substrate drugs. In vitro inhibitory effects were evaluated in Caco-2 cell lines using digoxin as a model drug and in vivo P-gp inhibiting effect was evaluated in mice model using quinidine as model drug. The accumulation and bidirectional transport of digoxin in Caco-2 cells was determined in presence and absence of quercetin and silymarin. Elacridar was used as standard P-gp inhibitor and used to compare the inhibitory effects of test compounds. The apical to basolateral transport of digoxin was increased where as basolateral to apical transport of digoxin was decreased in concentration dependent manner in the presence of elacridar, quercetin and silymarin. After intravenous administration of P-gp inhibitors, brain levels of quinidine were estimated using LC-MS method. Increased brain uptake was observed with quercetin (2.5-fold) and silymarin (3.5-fold). Though the brain penetration potential of P-gp substrates was lower than that observed in elacridar, both quercetin and silymarin improved plasma quinidine levels. Caco-2 permeability studies and brain uptake indicate that both quercetin and silymarin can inhibit P-gp mediated efflux of drug into brain. Our results suggest that both silymarin and quercetin could potentially increase the brain distribution of co-administered drugs that are P-gp substrates.


Novel long non-coding RNAs are specific diagnostic and prognostic markers for prostate cancer.
Current prostate cancer (PCa) biomarkers such as PSA are not optimal in distinguishing cancer from benign prostate diseases and predicting disease outcome. To discover additional biomarkers, we investigated PCa-specific expression of novel unannotated transcripts. Using the unique probe design of Affymetrix Human Exon Arrays, we identified 334 candidates (EPCATs), of which 15 were validated by RT-PCR. Combined into a diagnostic panel, 11 EPCATs classified 80% of PCa samples correctly, while maintaining 100% specificity. High specificity was confirmed by in situ hybridization for EPCAT4R966 and EPCAT2F176 (SChLAP1) on extensive tissue microarrays. Besides being diagnostic, EPCAT2F176 and EPCAT4R966 showed significant association with pT-stage and were present in PIN lesions. We also found EPCAT2F176 and EPCAT2R709 to be associated with development of metastases and PCa-related death, and EPCAT2F176 to be enriched in lymph node metastases. Functional significance of expression of 9 EPCATs was investigated by siRNA transfection, revealing that knockdown of 5 different EPCATs impaired growth of LNCaP and 22RV1 PCa cells. Only the minority of EPCATs appear to be controlled by androgen receptor or ERG. Although the underlying transcriptional regulation is not fully understood, the novel PCa-associated transcripts are new diagnostic and prognostic markers with functional relevance to prostate cancer growth.


The relationship between heart rate and rate of oxygen consumption in Galapagos marine iguanas (Amblyrhynchus cristatus) at two different temperatures.
To enable the use of heart rate (fH) for estimating field metabolic rate (FMR) in free-ranging Galapagos marine iguanas Amblyrhynchus cristatus, we determined the relationships between fH and mass-specific rate of oxygen consumption (sVO2) in seven iguanas before and during exercise on a treadmill and during the post-exercise period. The experiments were conducted at 27 and 35 degrees C, which are the temperatures that represent the lowest and highest average body temperatures of these animals in the field during summer. There were linear and significant relationships between fH and sVO2 at both temperatures (r(2)=0.86 and 0.91 at 27 degrees C and 36 degrees C, respectively). The slopes of the two regression lines did not differ, but there were significant differences in their intercepts. Thus, while heart rate can be used to predict FMR, the effects of temperature on the intercept of the regression must be taken into account when converting fH to sVO2. On the basis of our data, this can be achieved by applying the following formula: sVO2=0.0113fH-0.2983Q(10)((T(b)-27)/10). The increase in sVO2 with elevated body temperature results from an increase in fH, with no significant change in mass-specific oxygen pulse (sO(2) pulse; cardiac stroke volume times the difference in oxygen content between arterial and mixed venous blood). However, during exercise at both temperatures, increases in fH are insufficient to provide all of the additional O(2) required and there are also significant increases in the sO(2) pulses. This creates the situation whereby the same fH at the two temperatures can represent different values of sVO2.


Identification of a UPC2 homolog in Saccharomyces cerevisiae and its involvement in aerobic sterol uptake.
Saccharomyces cerevisiae normally will not take up sterols from the environment under aerobic conditions. A specific mutant, upc2-1, of the predicted transcriptional activator UPC2 (YDR213w) has been recognized as a strain that allows a high level of aerobic sterol uptake. Another predicted transcriptional activator, the YLR228c gene product, is highly homologous to Upc2p. In fact, at the carboxy terminus 130 of the last 139 amino acids are similar between the two proteins. Since these proteins are very similar, the effect of mutations in the YLR228c open reading frame (ORF) was compared with like alterations in UPC2. First, the YLR228c ORF was insertionally inactivated and crossed with various UPC2 constructs. Deletion of YLR228c and UPC2 in combination resulted in nonviability, suggesting that the two proteins have some essential overlapping function. The upc2-1 point mutation responsible for aerobic sterol uptake was duplicated in the homologous carboxy region of the YLR228c ORF using site-directed mutagenesis. This mutation on a high-copy vector resulted in an increase in sterol uptake compared to an isogenic wild-type strain. The combination of both point mutations resulted in the greatest level of aerobic sterol uptake. When the YLR228c point mutation was expressed from a low-copy vector there was little if any effect on sterol uptake. Gas chromatographic analysis of the nonsaponifiable fractions of the various strains showed that the major sterol for all YLR228c and UPC2 combinations was ergosterol, the consensus yeast sterol.


Akt1 signalling supports acinar proliferation and limits acinar-to-ductal metaplasia formation upon induction of acute pancreatitis.
Molecular signalling mediated by the phosphatidylinositol-3-kinase (PI3K)-Akt axis is a key regulator of cellular functions. Importantly, alteration of the PI3K-Akt signalling underlies the development of different human diseases, thus prompting the investigation of the pathway as a molecular target for pharmacologic intervention. In this regard, recent studies showed that small molecule inhibitors of PI3K, the upstream regulator of the pathway, reduced the development of inflammation during acute pancreatitis, a highly debilitating and potentially lethal disease. Here we investigated whether a specific reduction of Akt activity, by using either pharmacologic Akt inhibition, or genetic inactivation of the Akt1 isoform selectively in pancreatic acinar cells, is effective in ameliorating the onset and progression of the disease. We discovered that systemic reduction of Akt activity did not protect the pancreas from initial damage and only transiently delayed leukocyte recruitment. However, reduction of Akt activity decreased acinar proliferation and exacerbated acinar-to-ductal metaplasia (ADM) formation, two critical events in the progression of pancreatitis. These phenotypes were recapitulated upon conditional inactivation of Akt1 in acinar cells, which resulted in reduced expression of 4E-BP1, a multifunctional protein of key importance in cell proliferation and metaplasia formation. Collectively, our results highlight the critical role played by Akt1 during the development of acute pancreatitis in the control of acinar cell proliferation and ADM formation. In addition, these results harbour important translational implications as they raise the concern that inhibitors of PI3K-Akt signalling pathways may negatively affect the regeneration of the pancreas. Finally, this work provides the basis for further investigating the potential of Akt1 activators to boost pancreatic regeneration following inflammatory insults. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


The myxoid tumors of somatic soft tissues.
Tumors and tumorous conditions of superficial and deep soft tissues may owe their naked-eye appearance and much of their bulk to the accumulation of mucopolysaccharide material or, on rare occasions, to edema. The so-called myxoid tumors may be chondroblastic, fibroblastic, lipoblastic, myoblastic, or neurogenic. Benign and malignant tumors may be encountered. Naked-eye and microscopic appearances are described. Pseudotumors such as bursae, ganglia, cutaneous mucinoses, fasciitis, and myxoid cysts may enter the differential diagnosis. The value of accurate documentation is stressed. Histochemistry can make a limited contribution to diagnosis. The entities described have been examined with regard to alcian blue staining with and without pretreatment with hyaluronidase. Alcian blue staining in the presence of increasing concentrations of magnesium chloride has been investigated and found to be of value in the identification of tumors of chondroblastic origin.


The Bacterial Origins of the CRISPR Genome-Editing Revolution.
Like most of the tools that enable modern life science research, the recent genome-editing revolution has its biological roots in the world of bacteria and archaea. Clustered, regularly interspaced, short palindromic repeats (CRISPR) loci are found in the genomes of many bacteria and most archaea, and underlie an adaptive immune system that protects the host cell against invasive nucleic acids such as viral genomes. In recent years, engineered versions of these systems have enabled efficient DNA targeting in living cells from dozens of species (including humans and other eukaryotes), and the exploitation of the resulting endogenous DNA repair pathways has provided a route to fast, easy, and affordable genome editing. In only three years after RNA-guided DNA cleavage was first harnessed, the ability to edit genomes via simple, user-defined RNA sequences has already revolutionized nearly all areas of biological science. CRISPR-based technologies are now poised to similarly revolutionize many facets of clinical medicine, and even promise to advance the long-term goal of directly editing genomic sequences of patients with inherited disease. In this review, we describe the biological and mechanistic basis for these remarkable immune systems, and how their engineered derivatives are revolutionizing basic and clinical research.


Running exercise with end-expiratory breath holding up to the breaking point induces large and early fall in muscle oxygenation.
The goal of this study was to assess the effects of repeated running bouts with end-expiratory breath holding (EEBH) up to the breaking point on muscle oxygenation. Eight male runners participated in three randomised sessions each including two exercises on a motorised treadmill. The first exercise consisted in performing 10-12 running bouts with EEBH of maximum duration either (separate sessions) at 60% (active recovery), 80% (passive recovery) or 100% (passive recovery) of the maximal aerobic velocity (MAV). Each repetition started at the onset of EEBH and ended at its release. In the second exercise of the session, subjects replicated the same procedure but with normal breathing (NB). Arterial oxygen saturation (SpO2), heart rate (HR) and the change in vastus lateralis muscle deoxy-haemoglobin/myoglobin (Δ[HHb/Mb]) and total haemoglobin/myoglobin (Δ[THb/Mb]) were continuously monitored throughout exercises. On average, the EEBHs were maintained for 10.1 ± 1.1 s, 13.2 ± 1.8 s and 12.2 ± 1.7 s during exercise at 60%, 80% and 100% of MAV, respectively. In the three exercise intensities, SpO2 (mean nadir values: 76.3 ± 2.5 vs 94.5 ± 2.5%) and HR were lower with EEBH than with NB at the end of the repetitions; whereas, the mean Δ[HHb/Mb] (12.6 ± 5.2 vs 7.7 ± 4.4 µm) and Δ[THb/Mb] (- 0.6 ± 2.3 vs 3.8 ± 2.6 µm) were, respectively, higher and lower with EEBH (p < 0.05). This study showed that performing repeated bouts of running exercises with EEBH up to the breaking point induced a large and early drop in muscle oxygenation compared with the same exercise with NB. This phenomenon was probably the consequence of the strong arterial oxygen desaturation induced by the maximal EEBHs.


An experimental examination of catastrophizing-related interpretation bias for ambiguous facial expressions of pain using an incidental learning task.
Individuals with pain-related concerns are likely to interpret ambiguous pain-related information in a threatening manner. It is unknown whether this interpretation bias also occurs for ambiguous pain-related facial expressions. This study examined whether individuals who habitually attach a catastrophic meaning to pain are characterized by negative interpretation bias for ambiguous pain-related facial expressions. Sixty-four female undergraduates completed an incidental learning task during which pictures of faces were presented, each followed by a visual target at one of two locations. Participants indicated target location by pressing one of two response keys. During the learning phase, happy and painful facial expressions predicted target location. During two test phases, morphed facial expressions of pain and happiness were added, equally often followed by a target at either location. Faster responses following morphs to targets at the location predicted by painful expressions compared to targets at the location predicted by happy expressions were taken to reflect pain-related interpretation bias. During one test phase, faces were preceded by either a safe or threatening context cue. High, but not low, pain-catastrophizers responded faster following morphs to targets at the location predicted by painful expressions than to targets at the other location (when participants were aware of the contingency between expression type and target location). When context cues were presented, there was no indication of interpretation bias. Participants were also asked to directly classify the facial expressions that were presented during the incidental learning task. Participants classified morphs more often as happy than as painful, independent of their level of pain catastrophizing. This observation is discussed in terms of differences between indirect and direct measures of interpretation bias.


Surface Modified Thread-Based Microfluidic Analytical Device for Selective Potassium Analysis.
This paper presents a thread-based microfluidic device (μTAD) that includes ionophore extraction chemistry for the optical recognition of potassium. The device is 1.5 cm × 1.0 cm and includes a cotton thread to transport the aqueous sample via capillary wicking to a 5 mm-long detection area, where the recognition chemistry is deposited that reaches equilibrium in 60 s, changing its color between blue and magenta. A complete characterization of the cotton thread used as well as the sensing element has been carried out. The imaging of the μTAD with a digital camera and the extraction of the H coordinate of the HSV color space used as the analytical parameter make it possible to determine K(I) between 2.4 × 10(-5) and 0.95 M with a precision better than 1.3%.


Lowered PON1 activities are strongly associated with depression and bipolar disorder, recurrence of (hypo)mania and depression, increased disability and lowered quality of life.
Objectives: Mood disorders (MDs) frequently co-exist with cardiovascular disease (CVD) and immune-inflammatory and oxidative stress are important shared pathophysiological pathways. Even though there has been an extensive investigation of the enzyme paraoxonase 1 (PON1) as a biomarker of susceptibility for CVD, there are few reports studying PON1 in MDs. The aim of this study was to determine the association between PON1 activities as well as functional genotypes and MD diagnosis, clinical characteristics and outcomes. Methods: PON1 activities and functional genotypes were assayed in 58 bipolar disorder (BD) and 32 major depressed patients (MDD) and compared with 59 controls. Results: Our findings show significantly lower PON1 total and CMPAase activities in MDs, which are partly related to the number of previous depressive and manic episodes. Lowered CMPAase activity is associated with a worse outcome of MDs as indicated by lowered quality of life (WHOQoL-BREF scale) and increased disability in the Sheeham scale. Conclusions: We hypothesise that lowered PON1 total and CMPAase activities may play a role in the pathophysiology of MDs by lowering antioxidant defences thereby increasing the risk of lipid peroxidation and inflammation; lowered inhibition of quorum-sensing lactones thereby increasing bacterial proliferation; and attenuated homocysteine thiolactone catabolism which may trigger immune-inflammatory response and/or induce neurotoxicity.


Identification of biologically relevant enhancers in human erythroid cells.
Identification of cell type-specific enhancers is important for understanding the regulation of programs controlling cellular development and differentiation. Enhancers are typically marked by the co-transcriptional activator protein p300 or by groups of cell-expressed transcription factors. We hypothesized that a unique set of enhancers regulates gene expression in human erythroid cells, a highly specialized cell type evolved to provide adequate amounts of oxygen throughout the body. Using chromatin immunoprecipitation followed by massively parallel sequencing, genome-wide maps of candidate enhancers were constructed for p300 and four transcription factors, GATA1, NF-E2, KLF1, and SCL, using primary human erythroid cells. These data were combined with gene expression analyses, and candidate enhancers were identified. Consistent with their predicted function as candidate enhancers, there was statistically significant enrichment of p300 and combinations of co-localizing erythroid transcription factors within 1-50 kb of the transcriptional start site (TSS) of genes highly expressed in erythroid cells. Candidate enhancers were also enriched near genes with known erythroid cell function or phenotype. Candidate enhancers exhibited moderate conservation with mouse and minimal conservation with nonplacental vertebrates. Candidate enhancers were mapped to a set of erythroid-associated, biologically relevant, SNPs from the genome-wide association studies (GWAS) catalogue of NHGRI, National Institutes of Health. Fourteen candidate enhancers, representing 10 genetic loci, mapped to sites associated with biologically relevant erythroid traits. Fragments from these loci directed statistically significant expression in reporter gene assays. Identification of enhancers in human erythroid cells will allow a better understanding of erythroid cell development, differentiation, structure, and function and provide insights into inherited and acquired hematologic disease.


Detection of spreading depression features from the scalp of epileptic patients.
Spreading depression (SD), a pathological cortical negative DC potential, is caused by an elevation of potassium ions in the extracellular space. This leads to a transient relocation of ions within neurons and a slow spread through brain tissue. Our previous research established a correlation between scalp SD and seizures in patients with intractable epilepsy using our novel electroencephalography (EEG). In this study, we enhanced our EEG system by incorporating a Near-infrared spectroscopy (NIRS) module for multi-modal EEG-NIRS measurements. The aim is to provide an investigation into the defining characteristics and methods for detecting SD.Clinical Relevance-: The detection of SD serves as a novel biomarker for epilepsy, capable of forewarning seizures within a time range from 10 secs to 30 min. This detection plays a crucial role in predicting and preventing seizures and providing diagnostic information for drug-resistant epilepsy patients.


Evaluating spectral overlap with the degree of quenching in UCP luminescence energy transfer systems.
The use of organic-based fluorophores has been firmly established as a key tool in the biological sciences, with many biological-sensing methods taking advantage of Förster Resonance Energy Transfer (FRET) between different fluorescent organic-based dyes following one photon excitation. Nevertheless, the employment of UV-visible absorbing dyes as fluorescent tags and markers typically suffer from several drawbacks including relatively high energy of excitation wavelength, photobleaching and competitive autofluorescence, which often limit their effectiveness and longevity both in vitro and in vivo. As an alternative, lanthanide-doped upconverting phosphors (UCP) have emerged as a new class of materials for use in optical imaging and FRET sensing; they exhibit high photo- and chemical stability and utilise near infrared (nIR) excitation. Approaches to sensing a given analyte target employing upconverting phosphors can be achieved by engineering the UCP to operate analogously to fluorescent dyes via Luminescence Resonance Energy Transfer (LRET) and such systems are now becoming central to optically sensing low concentrations of biologically important species and performing distance measurements. Similarly to FRET, the LRET process is distance dependent and requires spectral overlap between the absorption of the acceptor luminophore and the emission of the donor moiety, yet essential measures of the relationship between spectral overlap and the degree of quenching have not yet been established. To address this, we have investigated the Stern-Volmer relationship for a set of six commonly functionalised organic dyes and seven biomolecules that contain key chromophoric co-factors with Gd2SO4:Yb:Er (PTIR545) and Gd2SO4:Yb:Tm (PTIR475) UCPs under low power nIR excitation, and found that for the organic dyes a linear relationship between spectral overlap and degree of quenching is observed. However, this linear relationship is observed to break down for all the biomolecules investigated.


Regulation of the rebound depolarization and spontaneous firing patterns of deep nuclear neurons in slices of rat cerebellum.
Current-clamp recordings were made from the deep cerebellar nuclei (DCN) of 12- to 15-day-old rats to understand the factors that mediate intrinsic spontaneous firing patterns. All of the cells recorded were spontaneously active with spiking patterns ranging continuously from regular spiking to spontaneous bursting with the former predominating. A robust rebound depolarization (RD) leading to a Na(+) spike burst was elicited after the offset of hyperpolarizing current injection. The voltage and time dependence of the RD was consistent with mediation by low-threshold voltage-gated Ca(2+) channels. In addition, induction of a RD also may be affected by activation of a hyperpolarization-activated cation current, I(h). A RD could be evoked efficiently after brief high-frequency bursts of inhibitory postsynaptic potentials (IPSPs) induced by stimulation of Purkinje cell axons. IPSP-driven RDs were typically much larger and longer than those elicited by direct hyperpolarizing pulses of approximately matched amplitude and duration. Intracellular perfusion of the Ca(2+) buffer bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) dramatically enhanced the RD and its associated spiking, sometimes leading to a plateau potential that lasted several hundred milliseconds. The effects of BAPTA could be mimicked partly by application of apamin, a blocker of small conductance Ca(2+)-gated K(+) channels, but not by paxilline, which blocks large conductance Ca(2+)-gated K(+) channels. Application of both BAPTA and apamin, but not paxilline, caused cells that were regularly spiking to burst spontaneously. Taken together, our data suggest that there is a strong relationship between the ability of DCN cells to elicit a RD and their tendency burst spontaneously. The RD can be triggered by the opening of T-type Ca(2+) channels with an additional contribution of hyperpolarization-activated current I(h). RD duration is regulated by small-conductance Ca(2+)-gated K(+) channels. The RD also is modulated tonically by inhibitory inputs. All of these factors are in turn subject to alteration by extrinsic modulatory neurotransmitters and are, at least in part, responsible for determining the firing modes of DCN neurons.


[Effect of hypocapnia/alkalosis on the fluid filtration rate in isolated and perfused rabbit lungs].
Hypocapnia/alkalosis is a consequence of several lung and metabolic pathologies. The aim of this study was to determine whether the increase of fluid filtration rate (FFR) that occurs during Hypocapnia/alkalosis circumstances is determined by hypocapnia, alkalosis or both. 7 groups were formed (N=36) using isolated rabbit lungs. Group 1: Control (PCO2 6%, pH: 7.35-7.45); Group 2 (n=6): Hypocapnia/Alkalosis (CO2 1%, pH: 7.9); Group 3 (n=6): Hypocapnia/Normo-pH (CO2 1% pH 7.35-7.45), Group 4 (n=6) Normocapnia/Alcalosis (CO2 6%, pH: 7.9). Fenoterol, papaverine and hydrocortisone were added to Groups 5, 6 and 7 (n=4) respectively, all under Normocapnia/Alkalosis. FFR and Pulmonary Arterial Pressure (Pap) were considerably higher in group 2 than in control (FFR: 1.92g/min +/- 0.6 vs 0.0 g/min +/- 0.006). A strong influence exerted by pH was observed when Group 3 and group 4 were compared (FFR: 0.02 g/min +/- 0.009 vs 2.3 g/min +/- 0.9) and (Pap: 13.5 cmH2O +/- 1.4 vs 90 cmH2O +/- 15). A reduced effect was observed in groups 5 and 6 (papaverine and hydrocorisone) and a totally abolished effect was observed in group 7 (fenoterol) (FFR: 0.001 +/- 0.0003 mL/min and Pap: 14 +/- 0.8 cmH2O). Pulmonary edema induced by Hypocapnia/alkalosis is a consequence of alkalosis and not of hypocapnia. This effect could be due to inflammatory damage in the lung parenchyma and alkalosis-mediated vasoconstriction.


NUP98-MLL fusion in human acute myeloblastic leukemia.
Posttranscriptional modifications of histones play important roles in the control of chromatin structure and transcription. H3K4 (histone H3 lysine 4) methylation by the SET domain of the trithorax-group protein MLL (mixed-lineage leukemia) is important for the control of homeobox (HOX) gene expression during development. MLL is tethered to the HOXA locus through interaction of its amino-terminus with menin. MLL fusion proteins associated with human leukemia contain the menin interaction peptide and frequently recruit H3K79 (histone H3 lysine 79) methylation activity. This allows sustained expression of HOXA genes important for cellular transformation. We have characterized a novel recurrent chromosomal aberration, inv(11)(p15q23), as an isolated chromosomal abnormality in 2 patients with acute myeloid leukemia. This aberration is predicted to result in the expression of an NUP98 (nucleoporin 98 kDa)-MLL fusion protein that is unable to interact with menin. As expected, low levels of HOXA gene expression were observed in the patients' samples. This fusion protein is predicted to participate in cellular transformation by activating MLL targets other than HOXA genes.


Endocannabinoid system modulator use in everyday clinical practice in the UK and Spain.
Spasticity is a disabling complication of multiple sclerosis. Some commonly used oral medications include baclofen, tizanidine, anticonvulsants and benzodiazepines, but their benefits are modest. Sativex® (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain) is a unique cannabinoid-based medicine with two main active ingredients; 9-δ-tetrahydrocannabinol, which acts mainly on cannabinoid 1 receptors in the CNS and plays a key role in the modulation of spasticity and spasms, and cannabidiol, which has different properties, including minimization of the psychoactivity associated with 9-δ-tetrahydrocannabinol. Sativex is indicated for symptomatic improvement in adult patients with moderate-to-severe multiple sclerosis-related spasticity who have not responded adequately to other first- or second-line antispasticity medications, and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. Over the past couple of years, Sativex has been approved for use in a number of European countries and ongoing postmarketing studies are evaluating the possible risks associated with Sativex treatment by systematically collecting all suspected adverse reactions that occur in patients from the start of treatment. Interim data from the UK as well as Spanish Sativex safety registries confirm that clinical benefit is maintained over the longer term despite the expected trend for deterioration owing to disease progression. Even after more than 2 years of use, no new safety/tolerability signals have emerged with Sativex, including no evidence of driving impairment and no relevant incidence of falls or other adverse events of concern, such as psychiatric or nervous system events. Sativex appears to be a well-tolerated and useful add-on therapy in patients who have not achieved an adequate response with traditional antispastic agents.


Gamma Rhythm and Theta-gamma Coupling Alternation in Chronic Unpredictable Stress (CUS)-induced Depression Rats.
Depression is a debilitating disease, which, in severe cases, can lead to suicide. However, objective and reliable biomarker for the diagnosis of depression is lack. In this preclinical study, we recorded resting local field potentials (LFPs) from chronic unpredictable stress (CUS)-induced depressed (n =20) and control (n = 20) rats and then compared their gamma activities in terms of single-band and cross-frequency coupling patterns. Both theta-gamma coupling and relative power in total gamma band revealed significant abnormalities in gamma rhythm in the right auditory cortex of depressed rats. These findings implied that resting-state gamma rhythms may be a promising objective diagnostic biomarker for depression. Furthermore, our research provided direct evidence from the perspective of source signals in deep brain sites, which might be useful for clinical applications.Clinical Relevance- This research showed that resting gamma in the auditory cortex is a promising biomarker for depression diagnosis.


Toward real-time polyp detection using fully CNNs for 2D Gaussian shapes prediction.
To decrease colon polyp miss-rate during colonoscopy, a real-time detection system with high accuracy is needed. Recently, there have been many efforts to develop models for real-time polyp detection, but work is still required to develop real-time detection algorithms with reliable results. We use single-shot feed-forward fully convolutional neural networks (F-CNN) to develop an accurate real-time polyp detection system. F-CNNs are usually trained on binary masks for object segmentation. We propose the use of 2D Gaussian masks instead of binary masks to enable these models to detect different types of polyps more effectively and efficiently and reduce the number of false positives. The experimental results showed that the proposed 2D Gaussian masks are efficient for detection of flat and small polyps with unclear boundaries between background and polyp parts. The masks make a better training effect to discriminate polyps from the polyp-like false positives. The proposed method achieved state-of-the-art results on two polyp datasets. On the ETIS-LARIB dataset we achieved 86.54% recall, 86.12% precision, and 86.33% F1-score, and on the CVC-ColonDB we achieved 91% recall, 88.35% precision, and F1-score 89.65%.


Niche construction and Dreaming logic: aboriginal patch mosaic burning and varanid lizards (Varanus gouldii) in Australia.
Anthropogenic fire is a form of ecosystem engineering that creates greater landscape patchiness at small spatial scales: such rescaling of patch diversity through mosaic burning has been argued to be a form of niche construction, the loss of which may have precipitated the decline and extinction of many endemic species in the Western Desert of Australia. We find evidence to support this hypothesis relative to one keystone species, the sand monitor lizard (Varanus gouldii). Paradoxically, V. gouldii populations are higher where Aboriginal hunting is most intense. This effect is driven by an increase in V. gouldii densities near successional edges, which is higher in landscapes that experience extensive human burning. Over time, the positive effects of patch mosaic burning while hunting overwhelm the negative effects of predation in recently burned areas to produce overall positive impacts on lizard populations. These results offer critical insights into the maintenance of animal communities in the desert, supporting the hypothesis that the current high rate of endemic species decline among small animals may be linked to the interaction between invasive species and mid-century removal of Aboriginal niche construction through hunting and patch mosaic burning.


Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1.
Mutations in the parkin gene cause early-onset, autosomal recessive Parkinson's disease. Parkin functions as an E3 ubiquitin ligase to mediate the covalent attachment of ubiquitin monomers or linked chains to protein substrates. Substrate ubiquitination can target proteins for proteasomal degradation or can mediate a number of non-degradative functions. Parkin has been shown to preserve mitochondrial integrity in a number of experimental systems through the regulation of mitochondrial fission. Upon mitochondrial damage, parkin translocates to mitochondria to mediate their selective elimination by autophagic degradation. The mechanism underlying this process remains unclear. Here, we demonstrate that parkin interacts with and selectively mediates the atypical poly-ubiquitination of the mitochondrial fusion factor, mitofusin 1, leading to its enhanced turnover by proteasomal degradation. Our data supports a model whereby the translocation of parkin to damaged mitochondria induces the degradation of mitofusins leading to impaired mitochondrial fusion. This process may serve to selectively isolate damaged mitochondria for their removal by autophagy.