Evaluation of lamina cribrosa in pseudoexfoliation syndrome using spectral-domain optical coherence tomography enhanced depth imaging.
To evaluate the features of the lamina cribrosa (LC) in pseudoexfoliation glaucoma (PXG) patients using enhanced depth imaging (EDI) of spectral-domain optical coherence tomography (SD OCT). The results were compared with those of patients with primary open-angle glaucoma (POAG). Cross-sectional study. Patients with PXG (n = 21) and POAG (n = 35) matched for age and visual field mean deviation (VF MD). Participants were imaged using SD OCT. Lamina cribrosa thickness (LT) and anterior lamina cribrosa depth (ALD) were determined at 3 areas (mid superior, center, and mid inferior) by 2 examiners using an EDI mode of the optic nerve head. The LT and ALD were compared between PXG and POAG eyes. Mean ± standard deviation baseline untreated intraocular pressure was not significantly different between the 2 groups (PXG, 18.3 ± 8.2 mmHg; POAG, 15.3 ± 3.4 mmHg; P = 0.310). The mean VF MD was -12.7 ± 9.0 dB in the PXG group versus -11.6 ± 9.1 dB in the POAG group (P = 0.643). When compared with the POAG group, the PXG group demonstrated a significantly thinner LT in all 3 areas and a thinner mean LT (133.4 ± 14.5 μm in the POAG group vs. 121.3 ± 13.0 μm in the PXG group; P<0.001). Anterior lamina cribrosa depth did not demonstrate a significant difference in any of the 3 areas between both groups (mean ALD, 324.3 ± 91.9 μm in the POAG group vs. 358.7 ± 142.7 μm in the PXG group; P = 0.470). Of 21 eyes in the PXG group, 9 eyes demonstrated a unilateral clinical presentation. When we compared the PXG eyes and the apparently normal-looking fellow eyes of those 9 eyes, neither the LT nor ALD demonstrated a significant difference (P = 0.223 and P = 0.079, respectively). Eyes with PXG demonstrate a thinner LC compared with POAG eyes at similar levels of glaucoma severity. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Vacuum-assisted wound closure provides early fascial reapproximation in trauma patients with open abdomens.
Damage control and decompressive laparotomies salvage severely injured patients who would have previously died. Unfortunately, many of these patients develop open abdomens. A variety of management strategies exist. The end result in many cases, however, is a large ventral hernia that requires a complex repair 6 to 12 months after discharge. We instituted vacuum-assisted wound closure (VAWC) to achieve early fascial closure and eliminate the need for delayed procedures. For 12 months ending June 2000, 14 of 698 trauma intensive care unit admissions developed open abdomens and were managed with VAWC dressing. This was changed every 48 hours in the operating room with serial fascial approximation until complete closure. Fascial closure was achieved in 13 patients (92%) in 9.9 +/- 1.9 days, and 2.8 +/- 0.6 VAWC dressing changes were performed. There were 2 wound infections, no eviscerations, and no enteric fistulas. Use of VAWC can safely achieve early fascial closure in more than 90% of trauma patients with open abdomens.


Variability of specific airway resistance in patients with laryngeal hemiplegia.
This study was designed to analyze whether respiratory flows and specific airway resistance (sRaw) depend on the degree of breathiness and on the position of the paralyzed vocal fold in laryngeal hemiplegia. We performed a prospective study involving 55 patients affected by laryngeal hemiplegia. The paralyzed fold was in an intermediate position in 18 cases and in a paramedian position in 37. Breathiness was estimated with the GRBAS scale, and the patients were divided into four groups: B0 (12 patients), B1 (14), B2 (16), and B3 (13). Spirometry was used to measure the flow-volume loop, and body plethysmography was used to measure the sRaw at increasing respiratory frequencies (30 +/- 5, 60 +/- 5, and 90 +/- 5 breaths per minute). The mean inspiratory flows (PIF, FIF50) were lower than predicted (<80%) in all four groups; there was no significant intergroup difference. In all four groups, the mean FEF5o/FIF50 ratio was >1, as is typical of variable extrathoracic obstruction. The mean sRaw values increased with respiratory frequency, and the increase was higher in group B3, although the values varied widely. The frequency-dependent increase in the sRaw value was not significantly related to the degree of breathiness, nor to the position of the paralyzed fold. Furthermore, Spearman's coefficient did not reveal any correlation between the sRaw values and inspiratory flows, showing that plethysmography and spirometry explore different aspects of airway function. Respiratory flows and sRaw are not significantly influenced by either the degree of breathiness or the position of the paralyzed vocal fold.


Clinical and oncological effects of triplet chemotherapy followed by radical esophagectomy for resectable esophageal cancer associated with unfavorable prognostic factors.
The purpose of this study was to evaluate the hypothesis that the survival of patients undergoing R0 resection after triplet chemotherapy for resectable esophageal cancer with unfavorable prognostic factors (Category 3) would be similar to that of patients undergoing esophagectomy for esophageal cancer without such factors (Category 1). Patients with Category 3 tumors were assigned to receive triplet chemotherapy consisting of 5-fluorouracil, doxorubicin and nedaplatin (FAN) followed by radical esophagectomy. The outcomes of the bimodality treatment for Category 3 patients (n = 25) were compared with those of Category 1 patients (n = 41) in a prospective cohort study. Grade 3 or higher toxicity developed during chemotherapy in 32 % of the Category 3 patients, with no treatment-related deaths. No significant difference was detected in the surgery-related mortality and morbidity rates between the two groups. The recurrence-free survival was significantly worse in Category 3 than in Category 1 patients (p = 0.002), although the overall survival was not significantly different (p = 0.085) between the two groups in cases of R0 resection (5-year survival rates: 34.4 vs. 66.5 %). Although FAN chemotherapy followed by radical esophagectomy can be safely performed, this treatment modality may not have sufficient power to cure Category 3 disease.


The epidemiology of peste des petits ruminants in the Sultanate of Oman.
Virological and serological evidence was obtained to show that peste des petits ruminants virus was widely distributed in Omani sheep and goats. There was no evidence for the concomitant presence of rinderpest virus in these species. Two virus isolates were classified as peste des petits ruminants virus on the basis of their pathogenicity in experimental animals and their specific hybridisation with nucleic acid probes. However, neutralisation tests and polyacrylamide gel analysis of their nucleocapsid proteins showed that they were not identical to the highly conserved African strains of this virus.


Assessment of coronary heart disease risk by combined analysis of coagulation factors.
Prospective studies have reported a positive association of coagulation factors with risk of coronary heart disease (CHD). It is unclear whether these coagulation factors interact. Using a prospective case-cohort design, we analyzed by Cox proportional hazard regression interactions between soluble thrombomodulin (sTM) and fibrinogen, factor VIII (FVIII), FVII, or plasminogen activator inhibitor-1 (PAI-1) in 410 CHD cases and 721 non-cases from the Atherosclerosis Risk in Communities (ARIC). There was a significant interaction between sTM and fibrinogen (p=0.027). We next assessed risk ratios (RR) by combined tertile analysis. Combined analysis revealed that being in the upper sTM tertile counteracted the CHD risk imposed by higher fibrinogen whereas being in the lower sTM tertile amplified the CHD risk of higher fibrinogen. sTM and fibrinogen mutually influenced CHD incidence in a concentration-dependent manner. When analyzed as single factors by tertiles, FVIII, FVII and PAI-1 were not associated with CHD. However, when analyzed together with sTM, FVIII and PAI-1 were both positively associated with CHD for those in the lower sTM tertile. There is a complex interaction between sTM and prothrombotic coagulation factors. Combined analysis improves CHD risk assessment.


Associations between Medical Disorders and Racing Outcomes in Poorly Performing Standardbred Trotter Racehorses: A Retrospective Study.
Poor performance in racehorses is commonly associated with subclinical diseases. This study aims to evaluate the associations between medical disorders and racing results in Standardbred trotters. The clinical records of 248 poorly performing Standardbreds were retrospectively reviewed, and their racing results were extracted from an online database, concerning the periods 3 months before and 6 months after hospitalization and the entire lifetime. Generalized linear models were used to evaluate the effects of different disorders on racing outcomes. Airway neutrophilia was associated with limiting lifetime starts and wins pre- and post-hospitalization, while mastocytosis was associated with less wins in the post-hospitalization period. Therefore, lower airway inflammation showed both short- and long-term impacts on racing performance. Severe upper airway obstructions and gastric ulcers showed associations with less placings in the post-discharge period but no long-term influence on performance. The significance of exertional rhabdomyolysis was indeterminable, yet interference with the number of starts in the post-discharge period was reported and associated with lower total career earnings. Exercise-induced pulmonary hemorrhage and cardiac arrhythmias were not associated with worse racing outcomes: therefore, their role in poor performance remains unclear.


High-Efficiency Single-Cell Electrical Impedance Spectroscopy.
Single-cell impedance measurement is label free and noninvasive in characterizing the electrical properties of single cells. At present, though widely used for impedance measurement, electrical impedance flow cytometry (IFC) and electrical impedance spectroscopy (EIS) are used alone for most microfluidic chips. Here, we describe high-efficiency single-cell electrical impedance spectroscopy, which combines in one chip the IFC and EIS techniques for high-efficiency single-cell electrical property measurement. We envision that the strategy of combining IFC and EIS provides a new thought in the efforts to enhance the efficiency of electrical property measurement for single cells.


Prediction of novel and analogous folds using fragment assembly and fold recognition.
A number of new and newly improved methods for predicting protein structure developed by the Jones-University College London group were used to make predictions for the CASP6 experiment. Structures were predicted with a combination of fold recognition methods (mGenTHREADER, nFOLD, and THREADER) and a substantially enhanced version of FRAGFOLD, our fragment assembly method. Attempts at automatic domain parsing were made using DomPred and DomSSEA, which are based on a secondary structure parsing algorithm and additionally for DomPred, a simple local sequence alignment scoring function. Disorder prediction was carried out using a new SVM-based version of DISOPRED. Attempts were also made at domain docking and "microdomain" folding in order to build complete chain models for some targets.


A rare and frequently unrecognised pathology in children: femoral hernia.
A femoral hernia is the protrusion of the abdominal contents through the femoral canal. It accounts for less than 1% of all groin hernias in children and is often confused with inguinal hernia or other inguinal pathologies. Preoperative misdiagnosis has been reported to be between 40 and 75%. We believe that misdiagnosis and mistreatment usually occur due to insufficient physical examination, knowledge and experience about childhood femoral hernias. Here, we report and discuss the clinical appearance and treatment approach of three patients operated with the diagnosis of femoral hernias.


Human cord blood stem cells generate human cytokeratin 18-negative hepatocyte-like cells in injured mouse liver.
Differentiation of adult bone marrow (BM) cells into nonhematopoietic cells is a rare phenomenon. Several reports, however, suggest that human umbilical cord blood (hUCB)-derived cells give rise to hepatocytes after transplantation into nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice. Therefore, we analyzed the hepatic differentiation potential of hUCB cells and compared the frequency of newly formed hepatocyte-like cells in the livers of recipient NOD-SCID mice after transplantation of hUCB versus murine BM cells. Mononuclear cell preparations of hUCB cells or murine BM from enhanced green fluorescent protein transgenic or wild-type mice were transplanted into sublethally irradiated NOD-SCID mice. Liver regeneration was induced by carbon tetrachloride injury with and without subsequent hepatocyte growth factor treatment. By immunohistochemistry and reverse transcriptase-polymerase chain reaction, we detected clusters of hepatocyte-like cells in the livers of hUCB-transplanted mice. These cells expressed human albumin and Hep Par 1 but mouse CK18, suggesting the formation of chimeric hepatocyte-like cells. Native fluorescence microscopy and double immunofluorescence failed to detect single hepatocytes derived from transplanted enhanced green fluorescent protein-transgenic mouse BM. Fluorescent in situ hybridization rarely revealed donor-derived hepatocyte-like cells after cross-gender mouse BM transplantation. Thus, hUCB cells have differentiation capabilities different from murine BM cells after transplantation into NOD-SCID mice, demonstrating the importance of further testing before hUCB cells can be used therapeutically.


Phase II study of divided-dose vinblastine in advanced breast cancer patients.
The pharmacokinetics of a 5-day, continuous infusion of vinblastine have been reproduced by an i.v. divided bolus at 0 and 48 h [10]; this schedule can be easily applied to outpatients. We treated 26 evaluable patients with refractory, advanced breast cancer with 3.5-4 mg/m2 vinblastine given i.v. by a divided bolus at 0 and 48 h of 21-day cycles. Neurotoxicity and myelosuppression were the main side effects: severe constipation and peripheral neurotoxicity developed in 14% and 3% of the patients, respectively; severe leukopenia and thrombocytopenia occurred in 24% and 10% of the patients, respectively. One partial response, 14 no changes, and 11 progressions were obtained. Our results do not support the use of vinblastine in divided doses in treating this disease.


Impact of age and cognitive demand on lane choice and changing under actual highway conditions.
Previous research suggests that drivers change lanes less frequently during periods of heightened cognitive load. However, lane changing behavior of different age groups under varying levels of cognitive demand is not well understood. The majority of studies which have evaluated lane changing behavior under cognitive workload have been conducted in driving simulators. Consequently, it is unclear if the patterns observed in these simulation studies carry over to actual driving. This paper evaluates data from an on-road study to determine the effects of age and cognitive demand on lane choice and lane changing behavior. Three age groups (20-29, 40-49, and 60-69) were monitored in an instrumented vehicle. The 40's age group had 147% higher odds of exhibiting a lane change than the 60's group. In addition, drivers in their 60's were less likely to drive on the leftmost lane compared to drivers in their 20's and 40's. These results could be interpreted as evidence that older adults adopt a more conservative driving style as reflected in being less likely to choose the leftmost lane than the younger groups and less likely to change lanes than drivers in their 40's. Regardless of demand level, cognitive workload reduced the frequency of lane changes for all age groups. This suggests that in general drivers of all ages attempt to regulate their behavior in a risk reducing direction when under added cognitive demand. The extent to which such self-regulation fully compensates for the impact of added cognitive demand remains an open question.


Late magnetic resonance imaging related to neurobehavioral functioning after aneurysmal subarachnoid hemorrhage.
Twenty patients who underwent early aneurysm surgery--that is, surgery within 72 hours after rupture--underwent further follow-up examination including magnetic resonance imaging (MRI) of the brain and a comprehensive neuropsychological assessment. Significant statistical correlation between tissue loss as seen on a late MRI scan and neurobehavioral deficits could not be established. Among 9 patients with no tissue loss seen on MRI, 3 exhibited substantial cognitive dysfunction and 6 had mild impairment. Three patients showed minor but corresponding tissue loss and deficits. In 3 patients with pronounced pathological indications on MRI, evidence of cognitive dysfunction was absent in 2, and 1 patient showed substantial impairment. The remaining 5 individuals displayed moderate pathological indications on MRI, with no obvious correspondence to cognitive functioning. In 7 patients, small white matter lesions, probably silent infarcts not seen on computed tomographic scan, were discovered on MRI. There was a clear relationship between arterial hypertension prior to aneurysm rupture and the extent of tissue loss seen on MRI. Absence of pathological findings on MRI scan did not exclude cognitive malfunctioning, and vice-versa.


Hepatitis C virus: evasion of the interferon-induced antiviral response.
Hepatitis C virus (HCV) is an emerging virus of great medical significance. A low drug-response rate and a high frequency of persistent infection have caused HCV to reach pandemic proportions. Many infected individuals go on to develop liver cirrhosis and hepatocellular carcinoma, and HCV is now the leading reason for liver transplants in the United States. Differences in genotype response to interferon therapy suggests that one or more viral genes may participate in evasion of the interferon-mediated cellular antiviral response. This review focuses on the viral genes that interact with the host cell to evade the interferon response and on the insights that these interactions may provide into HCV pathogenesis.


Optical motility test for the detection of trichothecenes using brine shrimps.
A new optical bio-assay using brine shrimp larvae (Anemia salina L.) has been successfully applied for monitoring the presence of highly toxic trichothecenes. The motility of the swimming animals was determined instead of their lethality. This permits more objective and precise results. The inhibition of the motility can be seen earlier, than the death of animals in toxicity tests. The relationship between time and dose is indicated for two different concentrations. This test can also be applied in the control of other harmful compounds.


A novel frameshift mutation in Allan-Herndon-Dudley syndrome.
Allan-Herndon-Dudley syndrome (AHDS) is a very rare, X-linked psychomotor disability syndrome with delayed myelination, almost exclusively affecting boys. We present a case of a 4-year-old boy with AHDS who was found cyanotic, with intermittent vomiting and paroxysmal convulsions about 4 h after his parents went out, and was then taken to the hospital, where he eventually died the next day. The autopsy revealed foreign bodies in the tiny bronchi and alveoli of the deceased, congestion, and punctate hemorrhage in multiple organs, consistent with the diagnosis of asphyxia. Compared with a normally developing 4-year-old boy, the deceased showed cerebral atrophy and cerebral edema, and Luxol Fast Blue (LFB) stain indicated delayed cerebellar, hippocampal, and basal ganglia development and myelination. A novel frameshift mutation c.584delG in the SLC16A2 gene was detected. Family lineage investigation showed that the mutation was also detected in the deceased's 8-year-old brother and biological mother. The present work enriches the profile mutations in SLC16A2 related to AHDS and emphasizes the importance of autopsy and postmortem genetic analysis in such cases.


STR frequencies for the PowerPlex 16 System Kit in a population from Northeast Spain.
The aim of this paper, was to obtain the frequencies for the 15 STR loci included in the PowerPlex 16 System Kit on a population of 204 unrelated Caucasian individuals living in Northeast of Spain in order to use for forensic purposes. Statistical analyses were performed using the programs GENEPOP version 3.3 and Powerstats version 1.2. The results showed that all the loci met Hardy-Weinberg expectations.


Correlated impurity complex in the asymmetric tunneling contact: an ideal system to observe negative tunneling conductivity.
We studied theoretically electron transport through the impurity complex localized between the tunneling contact leads by means of the generalized Keldysh diagram technique. The formation of multiple well pronounced regions with negative tunneling conductivity in the I-V characteristics was revealed. The appearance of negative tunneling conductivity is caused by the presence of both strong Coulomb correlations and the asymmetry of tunneling rates, which lead to the blockade of the electron transport through the system for a certain values of applied bias. The developed theory and obtained results may be useful for the application of impurity (dopant) atoms as a basic elements in modern nanoelectronic circuits.


Absolute quantitation of brain metabolites with respect to heterogeneous tissue compositions in (1)H-MR spectroscopic volumes.
Referencing metabolite intensities to the tissue water intensity is commonly applied to determine metabolite concentrations from in vivo (1)H-MRS brain data. However, since the water concentration and relaxation properties differ between grey matter, white matter and cerebrospinal fluid (CSF), the volume fractions of these compartments have to be considered in MRS voxels. The impact of partial volume correction was validated by phantom measurements in voxels containing mixtures of solutions with different NAA and water concentrations as well as by analyzing in vivo (1)H-MRS brain data acquired with various voxel compositions. Phantom measurements indicated substantial underestimation of NAA concentrations when assuming homogeneously composed voxels, especially for voxels containing solution, which simulated CSF (error: ≤ 92%). This bias was substantially reduced by taking into account voxel composition (error: ≤ 10%). In the in vivo study, tissue correction reduced the overall variation of quantified metabolites by up to 35% and revealed the expected metabolic differences between various brain tissues. Tissue composition affects extraction of metabolite concentrations and may cause misinterpretations when comparing measurements performed with different voxel sizes. This variation can be reduced by considering the different tissue types by means of combined analysis of spectroscopic and imaging data.


Colon cancer knowledge and attitudes in an immigrant Haitian community.
To qualitatively evaluate the views of Haitian immigrants on cancer and the influence of cultural and socio-ecological factors on cancer screening behavior. Six focus groups, consisting of 4-10 individuals each, were conducted among Haitian adults at average risk for colorectal cancer. The interviews were conducted in Haitian Creole and featured questions that addressed beliefs and attitudes about general health, access to health care, colon cancer, and screening practices. The focus groups provided insight into the health service utilization patterns in the Haitian community, as well as the factors driving them including language and the pattern of accessing healthcare only for emergencies. Many misconceptions regarding cancer and its development were evident in the discussions. However participants were willing to follow the recommendations of a physician. This highlighted the importance in this community of disseminating information at every opportunity about preventative care, including colorectal cancer screening.


Prevalence and factors of sexual problems in Chinese males and females having sex with the same-sex partner in Hong Kong: a population-based study.
A cross-sectional, anonymous telephone survey was conducted to examine sexual problem (SP) among sexually active, Chinese homosexual adults in Hong Kong. Of the homosexual respondents, 49.1% of males and 75.6% of females reported at least one SP, of whom 36.0 and 65.7% of the males and females, respectively, felt very bothered by the SP. The prevalence of SP ranged from 3.6% (pain) to 21.8% (premature orgasm) for men and from 16.9% (anxiety) to 39.3% (lubrication problems) for females. Female homosexuals were less likely to be satisfied with their sex life and more bothered by an SP than heterosexual females and homosexual males. There were few significant differences between homosexual and heterosexual males. Female homosexuals were also more likely than male homosexuals to experience lack of orgasm and pain during intercourse. Being bothered by SP was associated with erectile dysfunction among homosexual men and lubrication problems and lack of pleasure among the homosexual women.


Factors associated with anxiety and depression in rheumatoid arthritis patients: a cross-sectional study.
The management of anxiety and depression symptoms in rheumatoid arthritis (RA) patients is vital. Previous study findings on this topic are conflicting, and the topic remains to be thoroughly investigated. This study aimed to clarify the association of RA disease activity with anxiety and depression symptoms after controlling for physical disability, pain, and medication. We conducted a cross-sectional study of RA patients from the XXX Rheumatoid Arthritis Management Alliance cohort. We assessed patients using the Disease Activity Score (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), and Hospital Anxiety and Depression Scale (HADS). Anxiety and depression symptoms were defined by a HADS score ≥ 8. We analyzed the data using multivariable logistic regression analyses. Of 517 participants, 17.6% had anxiety symptoms and 27.7% had depression symptoms. The multivariable logistic regression analysis demonstrated that DAS28 was not independently associated with anxiety symptoms (odds ratio [OR] [95% confidence interval; CI] 0.93 [0.48-1.78]; p = 0.82) and depression symptoms (OR [95% CI] 1.45 [0.81-2.61]; p = 0.22). However, DAS28 patient global assessment (PtGA) severity was associated with anxiety symptoms (OR [95% CI] 1.15 [1.02-1.29]; p = 0.03) and depression symptoms (OR [95% CI] 1.21 [1.09-1.35]; p < 0.01). Additionally, HAQ-DI scores ≤ 0.5 were associated with anxiety symptoms (OR [95% CI] 3.51 [1.85-6.64]; p < 0.01) and depression symptoms (OR [95% CI] 2.65 [1.56-4.50]; p < 0.01). Patients using steroids were more likely to have depression than those not using steroids (OR [95% CI] 1.66 [1.03-2.67]; p = 0.04). No association was found between RA disease activity and anxiety and depression symptoms in the multivariable logistic regression analysis. Patients with high PtGA scores or HAQ-DI scores ≤ 0.5 were more likely to experience anxiety and depression symptoms, irrespective of disease activity remission status. Rather than focusing solely on controlling disease activity, treatment should focus on improving or preserving physical function and the patient's overall sense of well-being.


A Bayesian re-assessment of two Phase II trials of gemcitabine in metastatic nasopharyngeal cancer.
The Simon two-stage minimax design is a popular statistical design used in Phase II clinical trials. The analysis of the data arising from the design typically involves the use of frequentist statistics. This paper presents an alternative, Bayesian, approach to the design and analysis of Phase II clinical trials. In particular, we consider how a Bayesian approach could have affected the design, analysis and interpretation of two parallel Phase II trials of the National Cancer Centre Singapore, on the activity of gemcitabine in chemotherapy-naïve and in previously treated patients with metastatic nasopharyngeal carcinoma. We begin by explaining the Bayesian methodology and contrasting it with the frequentist approach. We then carry out a Bayesian analysis of the trial results. The conclusions drawn using the Bayesian approach were in general agreement with those obtained from the frequentist analysis. However they had the advantage of allowing for different and potentially more useful interpretations to be made regarding the trial results, as well as for the incorporation of external sources of information. In particular, using a Bayesian trial design, we were able to take into account the results of the parallel trial results when deciding whether to continue each trial beyond the interim stage.


Societal decisions about climate mitigation will have dramatic impacts on eutrophication in the 21st century.
Excessive nitrogen runoff leads to degraded water quality, harming human and ecosystem health. We examine the impact of changes in land use and land management for six combinations of socioeconomic pathways and climate outcomes, and find that societal choices will substantially impact riverine total nitrogen loading (+54% to -7%) for the continental United States by the end of the century. Regional impacts will be even larger. Increased loading is possible for both high emission and low emission pathways, due to increased food and biofuel demand, respectively. Some pathways, however, suggest that limiting climate change and eutrophication can be achieved concurrently. Precipitation changes will further exacerbate loading, resulting in a net increase of 1 to 68%. Globally, increases in cropland area and agricultural intensification will likely impact vast portions of Asia. Societal and climate trends must therefore both be considered in designing strategies for managing inland and coastal water quality.


MicroRNA-351-5p mediates skeletal myogenesis by directly targeting lactamase-β and is regulated by lnc-mg.
Skeletal muscle is an important and complex organ with a variety of functions in humans and animals. Skeletal myogenesis is a multistep and complex process, and increasing evidence suggests that microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play critical roles in skeletal myogenesis. In this study the expression of miR-351-5p is dynamically regulated during skeletal myogenesis in vitro and in vivo. Cell-counting kit-8, qRT-PCR, and EdU immunofluorescence analysis showed that miR-351-5p overexpression promoted the proliferation and inhibited the differentiation of C2C12 myoblast, whereas inhibition of miR-351-5p had the opposite effect. In addition, miR-351-5p mediated the regulation of muscle fiber type transition in vivo. In vitro, loss of miR-351-5p in muscle tissues promoted muscle hypertrophy and increased slow-twitch fibers in the gastrocnemius muscles of mice. Luciferase reporter assay and functional analyses demonstrated that lactamase β ( LACTB) is a direct target of miR-351-5p involved in the regulation of skeletal myogenesis. Expression levels of a myogenesis-associated lncRNA ( lnc-mg) correlated negatively with miR-351-5p and positively with LACTB during C2C12 myoblast proliferation and differentiation. Further analyses showed that lnc-mg acted as a molecular sponge for miR-351-5p, demonstrating its involvement in the negative regulation of LACTB by miR-351-5p during skeletal myogenesis. These findings indicate that miRNA-351-5p functions in skeletal myogenesis by targeting LACTB and is regulated by lnc-mg, supporting the role of the competing endogenous RNA network in skeletal myogenesis.-Du, J., Zhang, P., Zhao, X., He, J., Xu, Y., Zou, Q., Luo, J., Shen, L., Gu, H., Tang, Q., Li, M., Jiang, Y., Tang, G., Bai, L., Li, X., Wang, J., Zhang, S., Zhu, L. MicroRNA-351-5p mediates skeletal myogenesis by directly targeting lactamase β and is regulated by lnc-mg.


Sustainability assessment for agriculture scenarios in Europe's mountain areas: lessons from six study areas.
Sustainability assessment (SA) is a holistic and long-range strategic instrument capable of assisting policy-making in electing, and deciding upon, future development priorities. The outcomes of an SA process become more relevant and strengthened when conducted with multi-stakeholder engagement, which provides for multiple dialogues and perspectives. This was the object of research of the SA team in the context of BioScene (Scenarios for Reconciling Biodiversity Conservation with Declining Agriculture Use in Mountain Areas in Europe), a three-year project (2002-2005) funded by the European Union 5th Framework Program, which aimed to investigate the implications of agricultural restructuring and decline for biodiversity conservation in the mountain areas of Europe, using three distinct methodological streams: the ecological, the socio-economic, and the SA approaches. The SA approach drew on the previous two to assess the importance for biodiversity management of different scenarios of agri-environmental change and rural policy in six countries (France, Greece, Norway, Slovakia, Switzerland, and the United Kingdom), develop causal chains, include stakeholder views, and identify potential contributions for, or conflicts with, sustainability. This article tells how SA was used, what sustainability meant in each study area through different objectives of sustainability considered, discusses the methods used in SA, and the benefits arising. The SA was conducted by a team independent of any study area, who developed and oversaw the application of the SA methodology, assisting national teams, and developing a cross-country understanding of the sustainability of proposed scenarios in the different geographical and social contexts, and their implications for policy-making. Finally, it reflects on the persistent challenges of interdisciplinary research, compounded by multi-cultural teams, and concludes on the BioScene's lessons for the further development and application of SA.


Radioguided Surgery in Insulinoma Using 68Ga Labeled Exendin-4: a Case Report.
Laparoscopic resection of tumor is often performed for benign and small insulinomas, or for those located in the body or tail of the pancreas. The precise preoperative and intraoperative localization of the insulinoma is critical to minimize the surgical intervention. Conventional imaging studies, i.e., MRI, CT, and endoscopic ultrasound have limited sensitivity due to the small size of the insulinomas. Angiography, intraarterial calcium stimulation, and venous sampling are invasive procedures with concomitant risk for complications. Exendin-4 PET/CT scan has shown to be of great value in preoperative localization of insulinomas. In the absence of the traditional gold standard, i.e., intraoperative ultrasound with manual palpation, in laparoscopic surgery, a simple enucleation procedure might not be possible. Gamma probe-assisted surgery is a new method of diagnosis and treatment which allows a small area of tissue to be identified and removed, while a large area of the organ or the system remains unaffected. We present a case of a 34-year-old man with clinical suspicion of insulinoma with negative conventional imaging and successful lesion localization with 68Ga-Exendin-4 PET/CT scan in the pancreatic body, who underwent laparoscopic enucleation of the lesion with the aid of a hand-held gamma detecting probe.


Usefulness of open lung biopsy in mechanically ventilated patients with undiagnosed diffuse pulmonary infiltrates: influence of comorbidities and organ dysfunction.
The purpose of this study was to evaluate the clinical usefulness of open lung biopsy (OLB) in patients undergoing mechanical ventilation for diffuse pulmonary infiltrates of unknown etiology. This was a 10-year retrospective study in a 10-bed medical intensive care unit. The medical records of 36 ventilator-dependent patients who underwent OLB for the diagnosis of unknown pulmonary infiltrates from 1994 to 2004 were reviewed retrospectively. Data analyzed included demographic data, Charlson age-comorbidity score, number of organ dysfunctions, Acute Physiology and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA) score, ventilation variables, and radiological patterns. Diagnostic yield, effect on subsequent treatment changes, and complications of OLB were also assessed. A specific clinico-pathologic diagnosis was obtained for 31 patients (86%). The most common diagnoses were interstitial pneumonia (n = 17, including 8 acute interstitial pneumonia) and viral pneumonia (n = 4). Therapeutic modifications were made in 64% of patients. Patients who received OLB less than 1 week after initiation of mechanical ventilation were more likely to survive (63% versus 11%; P = 0.018). There were no major complications associated with the procedure. Factors independently associated with survival were the Charlson age-comorbidity score, number of organ dysfunction and the PaO2/FiO2 ratio on the day of the OLB. OLB can provide a specific diagnosis in many ventilator-dependent patients with undiagnosed pulmonary infiltrate. Early OLB seems to be useful in critically ill patients with isolated respiratory failure.


Unbound bilirubin concentration is associated with abnormal automated auditory brainstem response for jaundiced newborns.
This study was conducted to determine whether incidental jaundice affects automated auditory brainstem response results. We reviewed the medical charts of jaundiced newborns of > or = 34 weeks of gestation who underwent automated auditory brainstem response testing within 4 hours of plasma total bilirubin concentration and unbound bilirubin concentration measurements. We tested the hypothesis that the likelihood of abnormal automated auditory brainstem response results would increase as total bilirubin and unbound bilirubin concentrations increased. Forty-four infants with proximate total bilirubin concentration, unbound bilirubin concentration, and automated auditory brainstem response measurements were identified, and 4 (9%) had bilateral refer automated auditory brainstem response results. The mean total bilirubin concentration of 21.4 mg/dL (SD: 4.0 mg/dL; range: 14.4-29.5 mg/dL) for the 40 infants with bilateral pass automated auditory brainstem response results was not significantly different from that of 23.0 mg/dL (range: 14.9-33.1 mg/dL) for the 4 infants with bilateral refer automated auditory brainstem response results. However, the mean unbound bilirubin concentration of 1.32 microg/dL (range: 0.22-2.99 microg/dL) for the 40 infants with bilateral pass results was significantly lower than the mean of 2.62 microg/dL (range: 0.88-4.41 microg/dL) for the 4 infants with bilateral refer results. Logistic regression showed that increasing unbound bilirubin concentrations but not increasing total bilirubin concentrations were associated with of bilateral refer automated auditory brainstem response results. The probability of bilateral refer automated auditory brainstem response results increases significantly with increasing unbound bilirubin concentrations but not with increasing total bilirubin concentrations. Because unbound bilirubin concentrations are also more closely correlated with bilirubin neurotoxicity than are total bilirubin concentrations, bilateral refer automated auditory brainstem response results for jaundiced newborns may indicate increased risk of bilirubin neurotoxicity, in addition to the possibility of congenital deafness.


Design of biopolymer-based hemostatic material: Starting from molecular structures and forms.
Uncontrolled bleeding remains as a leading cause of death in surgical, traumatic, and emergency situations. Management of the hemorrhage and development of hemostatic materials are paramount for patient survival. Owing to their inherent biocompatibility, biodegradability and bioactivity, biopolymers such as polysaccharides and polypeptides have been extensively researched and become a focus for the development of next-generation hemostatic materials. The construction of novel hemostatic materials requires in-depth understanding of the physiological hemostatic process, fundamental hemostatic mechanisms, and the effects of material chemistry/physics. Herein, we have recapitulated the common hemostatic strategies and development status of biopolymer-based hemostatic materials. Furthermore, the hemostatic mechanisms of various molecular structures (components and chemical modifications) are summarized from a microscopic perspective, and the design based on them are introduced. From a macroscopic perspective, the design of various forms of hemostatic materials, e.g., powder, sponge, hydrogel and gauze, is summarized and compared, which may provide an enlightenment for the optimization of hemostat design. It has also highlighted current challenges to the development of biopolymer-based hemostatic materials and proposed future directions in chemistry design, advanced form and clinical application.


The effect of intermittent injections of CCK-8S and the CCK-A receptor antagonist devazepide on cell proliferation in exocrine rat pancreas.
Intermittent injections of sulfated cholecystokinin-8 (CCK-8S) or devazepide caused long-lasting effects on cell proliferation in exocrine pancreas in contrast to continuous infusion. The acinar cells responded to both treatments with changes in the labeling index (LI) during the whole study period. When studying the influence of stimulation and inhibition of the CCK-A receptor on cell proliferation in the exocrine pancreas, not only are the drugs and doses of importance but also the mode of administration. Continuous infusion of CCK-8S or the CCK-A receptor antagonist devazepide induces transient changes in acinar cell proliferation in rat pancreas. The aim of the present experiments was to study whether intermittent administration of CCK-8S or devazepide prevents receptor desensitization and thereby affects exocrine pancreatic cell proliferation persistently. Male Sprague-Dawley rats were injected subcutaneously twice daily with CCK-8S (6 micrograms), devazepide (240 micrograms) or bovine serum albumin (BSA). The rats were sacrificed after 18 and 36 h and 3 and 7 d. One hour before sacrifice, the rats were injected intraperitoneally with 1 mCi/kg of tritiated thymidine. The pancreatic weight and the contents of water, protein, and DNA were determined. The LI (number of labeled cells/100 cells) of exocrine pancreatic cells was determined microscopically after autoradiography. The concentration of plasma CCK was slightly increased by devazepide, but the increase was more pronounced by CCK-8S. The pancreatic wet weight was transiently increased 18 h after the start of CCK-8S injections (+14%), whereas devazepide caused a reduction after 7 d (-22%). The protein content was uninfluenced and the DNA content was decreased at 36 h with either treatment. CCK-8S increased the LI in acinar and centroacinar cells throughout the study period, but the ductal cell LI was increased only after 18 and 36 h. Injection of devazepide was followed by decreased LI of acinar cells throughout the study period. Also, the centroacinar and ductal cell LI decreased initially but returned to control values after 7 d.


The changing pattern of otitis media in Korea.
From a nationwide survey of otitis media in Korea, 44.52% of the population were found to have some type of otitis media or its sequelae. A high prevalence rate was seen in the age group over 41 years. This finding suggests a strong relationship between socioeconomic status and incidence of otitis media. From a clinical study of surgical cases of otitis media seen in the past 10 years, we have found that the prevalence of chronic otitis media is decreasing every year. However, severity and pathological findings of otitis media were reflected remarkably in a decreased incidence of acute purulent otitis media and an increased incidence of middle ear effusion in children. In recent years our efforts to control chronic otitis media in children have focused on the treatment of chronic middle ear effusion. To prevent the latter condition, it is strongly emphasized that pediatricians and primary care physicians should be competent in diagnosing otitis media as early as possible, and that they should refer appropriate patients to otolaryngologists for further evaluation and management.


Association between commercial television exposure and fast-food consumption among adults.
To examine the association between television advertising exposure and adults' consumption of fast foods. Cross-sectional telephone survey. Questions included measures of frequency of fast-food consumption at different meal times and average daily hours spent watching commercial television. Subjects comprised 1495 adults (41 % response rate) aged >or=18 years from Victoria, Australia. Twenty-three per cent of respondents usually ate fast food for dinner at least once weekly, while 17 % consumed fast food for lunch on a weekly basis. The majority of respondents reported never eating fast food for breakfast (73 %) or snacks (65 %). Forty-one per cent of respondents estimated watching commercial television for <or=1 h/d (low viewers); 29 % watched for 2 h/d (moderate viewers); 30 % watched for >or=3 h/d (high viewers). After adjusting for demographic variables, high viewers were more likely to eat fast food for dinner at least once weekly compared with low viewers (OR = 1.45; 95 % CI 1.04, 2.03). Both moderate viewers (OR = 1.53; 95 % CI 1.01, 2.31) and high viewers (OR = 1.81; 95 % CI 1.20, 2.72) were more likely to eat fast food for snacks at least once weekly compared with low viewers. Commercial television viewing was not significantly related (P > 0.05) to fast-food consumption at breakfast or lunch. The results of the present study provide evidence to suggest that cumulative exposure to television food advertising is linked to adults' fast-food consumption. Additional research that systematically assesses adults' behavioural responses to fast-food advertisements is needed to gain a greater understanding of the mechanisms driving this association.


Survival after transfusion as assessed in a large multistate US cohort.
The only survival and mortality data on a general population of transfused patients in the United States is more than two decades old. More contemporary data are needed to reflect more current patient populations and transfusion practices. Data were extracted from Constella Health Strategies Sciences' managed-care administrative claims database that contains private health care claims. Patients were selected if they had at least one professional or facility claim indicating transfusion in 1995. Only the first transfusion in the time period was included so that each patient was counted only once and all claims were unduplicated. Survival for five years after transfusion was the primary outcome measure. A total of 6779 patients were included in the analysis. A total of 4658 (69%) patients were alive 1 year after transfusion, 4056 (60%) were alive at 2 years, and 3092 (46%) were alive 5 years after transfusion. Overall annual mortality was 31 percent in Year 1 after transfusion, 14 percent in Year 2, and 10 percent in each of Years 3 through 5. Transfusion mortality was much higher in recipients older than age 65 at the time of transfusion, who comprised 60 percent of transfused patients. These data from the mid 1990s can be used in models of the effectiveness of risk reduction interventions and in models of the disease consequences of infections transmitted through blood transfusions.


Characterizing Micro-scale Disparities in Childhood Obesity: Examining the Influence of Multilevel Factors on 4-Year Changes in BMI, Healthy Eating, and Physical Activity, Among a Cohort of Children Residing in Disadvantaged Urban Enclaves.
The childhood obesity epidemic in the United States disproportionately affects minority, low-income populations. Hispanics have one of the highest childhood obesity rates, and are the fastest growing population subgroup in the country. Past research has examined disparities in the occurrence of obesity, healthy eating, and physical activity at a macro-geographic level, with less emphasis on examining the multilevel, micro-scale determinants of childhood obesity in disadvantaged urban ethnic enclaves. The aim of our study was to identify child-, parental-, familial-, community-, and neighborhood-level factors associated with differences in 4-year changes in BMI, healthy eating, and physical activity, among children residing in low-income, predominantly Hispanic urban enclaves in Austin, Texas. This analysis used data from the Go Austin! Vamos Austin! (GAVA) Evaluation study, a cohort with 4 years of follow-up from 313 child-caregiver dyads. The dependent variables were change categories denoting 4-year increase, decrease, or no change in Body Mass Index (BMI) percentile, fruit and vegetable intake, and physical activity, among child participants. The independent variables were factors at multiple levels of the socio-ecological model: child, parental, familial, community, and environmental. Multinomial logistic regression models were used to estimate the odds of children being in the "increasing" or "decreasing" categories for the three dependent variables (vs. "no change"), in association with the studied independent variables. The results showed that among children residing in this low-income, predominantly Hispanic urban enclave, weight gain prevention and weight loss have different determinants. We identified relevant micro-scale disparities, and micro-level factors of influence on child BMI and its related health behaviors, at all levels of the socio-ecological model. Our results revealed evidence, through the characterization of positive deviance cases (children for whom decreases in BMI, increases in fruit and vegetable intake, or increases in physical activity were observed) which could potentially help mitigate established unhealthy habits among high need populations. Factors associated with positive deviance for BMI (decreases in child BMI) included male child sex (OR: 0.33, 95% CI: 0.12-0.83) and living in a food-insecure household (OR: 0.24, 95% CI: 0.13-0.79). Our findings may inform the design of obesity prevention interventions in these types of disadvantaged urban Hispanic enclaves.


Congenital malignant mesothelioma. A case report and electron-microscopic study.
Malignant mesothelioma was diagnosed in a 16-day-old boy. As far as we know this is the first report of a congenital case of this disease.


The effect of chromium intake on oxidative stress parameters: A systematic review and meta-analysis.
Trivalent chromium is a trace element thought to have a beneficial effect on oxidative stress (OS) parameters and inflammation. This review aimed to investigate the dose-response of chromium and summarize the effects of chromium supplementation on OS parameters in the literature. MEDLINE, Scopus, Web of Science and Cochrane CENTRAL databases were searched for RCTs published from inception to January 2021 evaluating the effect of chromium supplementation on OS parameters, namely MDA, TBARS, SOD, TAS, CAT, GPx, and GSH. A random-effects model was used to pool data and calculated standard mean difference and 95 % confidence intervals. Quantified heterogeneity among studies was assessed through Cochrane's I2 values. Nine studies enrolling 550 participants met the inclusion criteria. The obtained results indicate that chromium supplementation significantly increases TAC (SMD: 0.46; 95 % CI: 0.08, 0.84; I2 = 00.0 % n = 2) and significantly decreases MDA levels (SMD: -0.46; 95 % CI: -0.86, -0.07; I2 = 52.4 % n = 5). Supplementation did not significantly change CAT, GPx, GSH, SOD, TAS, and TBARS. Chromium supplementation may improve OS parameters, however, due to high heterogeneity observed in the included studies, these findings should be interpreted with caution. Large RCTs on various patient groups evaluating the impact of chromium supplementation are needed to allow an adequate generalization of the benefits of chromium on human health.


[Individual differences in the reactions to acute stress related to behavioral type. Resistance (predisposition) to behavioral and sleep disorders].
Resistance (predisposition) to behavior and sleep disturbances after acute stress was studied in rats with different types of behavior in open field and forced swimming tests. The highest resistance to stress (the least alterations of behavior and sleep parameters) was found in rats with the active type of behavior, the least resistance to stress--in the middle group, and rats with the passive type of behavior held the intermediate position. The comparison of the present data with previously obtained results showed a positive correlation between the resistance to stress and the resistance to circulatory cerebral hypoxia induced by bilateral common carotid arteries occlusion. The biological significance of the association of resistance to stress and to cerebral hypoxia with the type of behavior is discussed.


Opinion of the Scientific Committee on Consumer Safety (SCCS) - Revision of the opinion on o-Phenylphenol, Sodium o-phenylphenate and Potassium o-phenylphenate (OPP), in cosmetic products.
o-Phenylphenol, Sodium o-phenylphenate, Potassium o-phenylphenate, CAS n. 90-43-7, 132-27-4, 13707-65-8 as preservatives are regulated in Annex V/7 of the Cosmetics Regulation (EC) n. 1223/2009 at a maximum concentration of 0.2% (as phenol). In February 2013, the Commission received a risk assessment submitted by the French Agency ANSM (Agence nationale de sécurité des médicaments et des produits de santé) which rose concerns about the use of o-Phenylphenol as preservatives in cosmetic products. In the context of the ANSM report (Evaluation du risque lié à l'utilisation de l'orthophénylphénol CAS n. 90-43-7 dans les produits cosmétiques) o-Phenylphenol has been identified as likely to be an endocrine disruptor. The report concludes that the maximum authorised concentration (currently of 0.2%) of o-Phenylphenol for use as a preservative should be revised due to low margin of safety. In January 2014, in response to a call for data on o-Phenylphenol by the Commission, Industry submitted a safety dossier in order to defend the current use of o-Phenylphenol, Sodium o-phenylphenate, Potassium o-phenylphenate, CAS n. 90-43-7, 132-27-4, 13707- 65-8 as preservatives in cosmetic formulations at a maximum concentration of 0.2% (as phenol). o-Phenylphenol as preservative with a maximum concentration of 0.2% in leave-on cosmetic products is not safe. Also, in view of further exposures including noncosmetic uses (see Anses, 2014), the maximum concentration of o-Phenylphenol in leave-on cosmetic products should be lowered. However, the proposed maximum use concentration of up to 0.15% by the applicant can be considered safe. The use of o-Phenylphenol as preservative with a maximum concentration of 0.2% in rinse-off cosmetic products is considered safe. Based on the information provided, no conclusions of safe use can be drawn for Sodium o-phenylphenate and Potassium o-phenylphenate. In vitro data indicate an absent or very weak binding affinity of OPP to the oestrogen receptor, in line with limited stimulation of proliferation in oestrogen responsive cells. No information is available on androgenic and anti-androgenic effects of OPP in vitro. Agonistic or antagonistic effects on thyroid hormones were not observed with OPP. There might be a potential of injury to the vision system attributable to OPP. Aggregate exposure to OPP should be considered.


The variability of isokinetic ankle strength is different in healthy older men and women.
In the elderly, weak lower limb muscles impair functional tasks' performance. To evaluate the healthy elderly's ankle dorsiflexion and plantarflexion maximum torque and its variability in two sets of 5 RM isokinetics evaluation. 50 women (68.0 ± 4.6 years old) and 50 men (72.7 ± 8.5 years old) did two sets of ankle plantar flexor and dorsiflexor isokinetic tests at 30°/s. Peak torque, total work, and coefficient of variation were analyzed. Men did the strongest plantarflexion torque (p < 0.05) and dorsiflexion torque (p < 0.05); their highest peak torque occurred at set 2 (p < 0.05), while the largest plantarflexion torque variability (p < 0.05), dorsiflexion torque variability (p < 0.05), and the largest plantarflexion torque variability occurred at set 1 (p < 0.05). Men did the highest plantarflexion and dorsiflexion total work (p < 0.05) at set 2 (p < 0.05). Older men are stronger than older women. The torque variability, in men, was higher during the first set, suggesting an adaptation to the isokinetics evaluation. Clinicians and researchers should consider that different muscles might need different numbers of sets and trials to measure their maximal muscle strength.


Bullying in Virtual Learning Communities.
Bullying through the internet has been investigated and analyzed mainly in the field of social media. In this paper, it is attempted to analyze bullying in the Virtual Learning Communities using Natural Language Processing (NLP) techniques, mainly in the context of sociocultural learning theories. Therefore four case studies took place. We aim to apply NLP techniques to speech analysis on communication data of online communities. Emphasis is given on qualitative data, taking into account the subjectivity of the collaborative activity. Finally, this is the first time such type of analysis is attempted on Greek data.


Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders.
The diagnosis of mitochondrial disorders (MDs) is occasionally difficult because patients often present with solitary, or a combination of, symptoms caused by each organ insufficiency, which may be the result of respiratory chain enzyme deficiency. Growth differentiation factor 15 (GDF-15) has been reported to be elevated in serum of patients with MDs. In this study, we investigated whether GDF-15 is a more useful biomarker for MDs than several conventional biomarkers. We measured the serum levels of GDF-15 and fibroblast growth factor 21 (FGF-21), as well as other biomarkers, in 48 MD patients and in 146 healthy controls in Japan. GDF-15 and FGF-21 concentrations were measured by enzyme-linked immunosorbant assay and compared with lactate, pyruvate, creatine kinase, and the lactate-to-pyruvate ratio. We calculated sensitivity and specificity and also evaluated the correlation based on two rating scales, including the Newcastle Mitochondrial Disease Rating Scale (NMDAS). Mean GDF-15 concentration was 6-fold higher in MD patients compared to healthy controls (2,711 ± 2,459 pg/ml vs 462.5 ± 141.0 pg/mL; p < 0.001). Using a receiver operating characteristic curve, the area under the curve was significantly higher for GDF-15 than FGF-21 and other conventional biomarkers. Our date suggest that GDF-15 is the most useful biomarker for MDs of the biomarkers examined, and it is associated with MD severity. Our results suggest that measurement of GDF-15 is the most useful first-line test to indicate the patients who have the mitochondrial respiratory chain deficiency.


Association of Electronic Nicotine Delivery System Use With Cigarette Smoking Progression or Reduction Among Young Adults.
The prevalence of electronic nicotine delivery systems (ENDS) use, including e-cigarettes, among US young adults (YAs) has raised questions about how these products may affect future tobacco and nicotine use among YAs. Given this prevalence and that young adulthood is a critical period for the establishment of tobacco and nicotine use, it is important to consider the association between ENDS use and cigarette smoking specifically in this age group. To examine whether ENDS use frequency or intensity is associated with changes in cigarette smoking among US YA ever smokers during 1 year. This cohort study used 3 waves of data (2013-2014, 2014-2015, and 2015-2016) from the Population Assessment of Tobacco and Health (PATH) Study, an ongoing longitudinal cohort study of adults and youth. Unweighted 1:6 propensity score matching was used to match participants on wave 1 risk factors for ENDS use at wave 2. The changes in smoking between wave 2 and wave 3 were assessed using the matched sample. In total, 1096 ENDS-naive, ever cigarette-smoking YAs (18-24 years of age) at wave 1 who participated in wave 2 and wave 3 and who had complete data in the PATH Study were included in the analyses, which were conducted from August 2018 to October 2019. Never ENDS use (n = 987), any previous 30-day ENDS use (n = 109), 1 to 5 days of ENDS use in the previous 30 days (n = 75), and 6 or more days ENDS use in the previous 30 days at wave 2 (n = 34). The analytic sample was selected using multiple variables based on peer-reviewed literature supporting associations with ENDS use. The main outcomes-changes in cigarette smoking behavior between wave 2 and wave 3-were defined using 2 measures: (1) change in smoking frequency, defined as the number of smoking days in the previous 30 days at wave 3 vs wave 2, and (2) change in smoking intensity, defined as the number smoking days in the previous 30 days multiplied by the mean number of cigarettes consumed on smoking days at wave 3 vs wave 2. The present cohort analyses included 1096 YA ever smokers who were ENDS naive at wave 1. The majority of the sample were women (609 [55.6%]) and White individuals (698 [63.7%]), and the mean (SD) age was 21.4 (1.9) years. In wave 1, 161 YAs (14.7%) were daily smokers in the previous 30 days. After propensity score matching, no statistically significant associations were observed between any definition of wave 2 ENDS use and changes in either the frequency or intensity of smoking at wave 3. In this cohort study of US YA ever smokers, ENDS use was not associated with either decreased or increased cigarette smoking during a 1-year period. However, it is possible that the rapidly evolving marketplace of vaping products may lead to different trajectories of YA cigarette and ENDS use in the future.


Listeners' Perception of Vocal Effects During Singing.
Effective communication is a key feature of vocal music. Singers can communicate during singing by changing their voice qualities to express emotion. Varying acceptable standards are used by performers for voice quality secondary to musical genre. Types of voice qualities that are historically perceived as abusive by some teachers of singing (ToS) and speech-language pathologists (SLPs) are vocal effects. This study investigates the perceptions of vocal effects in professional and nonprofessional listeners (NPLs). Participants (n = 100) completed an online survey. Participants were divided into four professional groups; Classical ToS, Contemporary ToS, SLPs, and NPLs. Participants completed an identification task to assess their ability to identify the use of a vocal effect. Secondly, participants analyzed a singer performing a vocal effect, rated their preferences towards the effect, and gave objective performance ratings using a Likert scale. Finally, participants were asked if they had concerns about the singer's voice. If the participant responded yes, they were asked who they would refer the singer to, a SLP, ToS or medical doctor (MD). Statistically significant differences were observed in SLPs ability to identify the use of vocal effects compared to classical ToS (P = 0.01), contemporary ToS (P = 0.001) as well as NPLs compared to contemporary ToS (P = 0.009). NPLs were reported to have a lesser rate of concern statistically compared to professional listeners (P = .006). Statically significant differences were found when comparing performance rating scores secondary to preference for the vocal effect when comparisons were larger than one Likert rating interval. With listeners giving higher performance ratings, if they reported higher preference ratings. Finally, no significant differences were identified when comparing referral scores secondary to occupation. Findings provide support for the presence of specific biases towards the use of vocal effects although no bias was found in management and care recommendations. Future research is recommended to investigate the nature of these biases.


Anticonvulsant active inhibitor of GABA transporter subtype 1, tiagabine, with activity in mouse models of anxiety, pain and depression.
Tiagabine, a selective inhibitor of GABA transporter subtype 1 is used as an add-on therapy of partial seizures in humans but its mechanism of action suggests other potential medical indications for this drug. In this research we assess its pharmacological activity in several screening models of seizures, pain, anxiety and depression in mice. For pharmacological tests tiagabine was administered intraperitoneally 60 min before the assay. Behavioral tests were performed using models of chemically and electrically induced seizures, thermal acute pain and formalin-induced tonic pain. Anxiolytic-like properties were evaluated using the four plate test and the elevated plus maze test. Antidepressant-like activity was assessed in the forced swim test. In addition, to exclude false positive results in these assays, the influence of tiagabine on animals' locomotor activity and motor coordination was investigated, too. Tiagabine demonstrated anticonvulsant properties in chemically induced seizures (pentylenetetrazole and pilocarpine seizures). At the dose of 100mg/kg it also elevated the seizure threshold for electrically induced seizures by 31.6% (p<0.01), but it had no activity in the maximal electroshock seizure test. Tiagabine showed anxiolytic-like and antidepressant-like effects. Although it apparently reduced animals' nociceptive responses in pain tests, these activities rather resulted from its sedative and motor-impairing properties demonstrated in the locomotor activity and the rotarod tests, respectively. The results obtained in the present study suggest that tiagabine, apart its anticonvulsant effect, has anxiolytic-like, sedative and antidepressant-like properties. In view of this, it can be potentially used in the treatment of anxiety and mood disorders.


Repair of acetyl-aminofluorene modified pBR322 DNA in Xenopus laevis oocytes and eggs; effect of diadenosine tetraphosphate.
Using Xenopus laevis oocytes and unfertilized eggs, we have developed a system which allows the study of DNA repair upon microinjection of pBR 322 DNA which has been previously modified in vitro by N-acetyl-aminofluorene, under controlled conditions. In unfertilized eggs, an efficient repair of pBR-18AAF DNA takes place, leading to a restoration of the transforming activity of the plasmid DNA towards Escherichia coli. The repaired DNA is even efficiently replicated, the egg being "activated" by the microinjection. In the oocyte, a partial repair is observed as shown by the incorporation of labelled dCTP in the modified plasmid DNA, even in the presence of aphidicolin, an inhibitor of DNA polymerase alpha. However, the repair appears to be very limited, since it does not restore the transforming activity of the modified plasmid DNA. This inefficient repair in the oocyte may be due to the rapid packaging of foreign DNA into a minichromosome and/or to a very low level of DNA polymerase beta. This system was used to study the effect of diadenosine tetraphosphate (Ap4A) on DNA repair. Ap4A seems not to interfere with repair processes in the oocyte, but significantly inhibits the replication following the repair of AAF-modified plasmid DNA in unfertilized eggs. These results suggest that Ap4A could be involved in switching off the replication machinery when DNA is badly damaged, thus helping to avoid the perpetuation of DNA modifications in the daughter cells. This hypothesis is consistent with many previous reports on the accumulation of dinucleoside polyphosphates under stress conditions, which are known to result in modification of DNA.


Neural correlates of resilience to the effects of hippocampal atrophy on memory.
Cognitive reserve can be defined as a property of the brain that enables an individual to sustain cognitive performance in spite of age-related neural changes. This study uses brain imaging to identify which cognitive reserve mechanisms protect against the detrimental effect of hippocampal atrophy on associative memory. The study included 108 older adults from the Quebec Consortium for the early identification of Alzheimer's disease. They received a magnetic resonance imaging examination to measure memory-related activations and hippocampal volume. Participants also completed a reserve-proxy questionnaire, and received a comprehensive clinical assessment. Higher scores on the reserve questionnaire were associated with more activation in the right inferior temporal and left occipital fusiform gyri. The activation of the right temporal gyrus moderated the relationship between the volume of the hippocampus and face-name memory. A smaller volume was associated with weaker memory in participants with lower activation, but not in those with greater activation. Recruitment of the temporal lobe protects against the detrimental effect of hippocampal atrophy on associative memory and contributes to cognitive reserve.


In vitro-in vivo correlation on delivery of drug candidates to articular cartilage.
In the treatment of osteoarthritis (OA), some of the therapeutic approaches require delivery of drug(s) to the diseased cartilage. Presence of adequate drug levels in the cartilage is one of the important criteria in selection and ranking of lead compounds. The purpose of this study was to investigate the correlation in cartilage compound levels between in vitro experiments and in vivo animal studies. Bovine cartilage samples were incubated with test compounds of various concentrations in a culture medium, in the absence or presence of 25 mg/ml of serum albumin which served as an artificial synovial fluid (SF). The test compounds were also dosed to rabbits, the animal model used for efficacy studies, over a six-week treatment period. Test article concentrations in plasma, SF, and cartilage were determined by LC/MS/MS analysis. A correlation in cartilage drug concentration was observed between in vitro and in vivo studies. Plasma protein binding and the test article's affinity to cartilage were the major determining factors for drug delivery to cartilage in vivo.


Influence of atomic force microscopy acquisition parameters on thin film roughness analysis.
A reliable procedure for measuring parameters connected to surface roughness is needed to compare the gas sensing properties of various thin films or the effect of different fabrication procedures on the surface roughness and the sensing properties. In this article, we propose to investigate how the acquisition parameters specific to atomic force microscopy investigations such as pixel size, scan area and scan speed influence the roughness parameters, namely root mean square and surface area ratio, commonly used for characterizing the gas sensing properties of porphyrins and other materials.


A new trihydroxy fatty acid from the ascomycete, Chinese truffle Tuber indicum.
From the chloroform/methanol extract of the fruiting bodies of the ascomycete Chinese truffle Tuber indicum Cooke et Massee, a new trihydroxylated monounsaturated fatty acid (1) has been isolated. The structure of this new linoleic acid-derived metabolite was established as 9,10,11-trihydroxy-(12Z)-12-octadecenoic acid by means of spectroscopic and chemical methods. The fatty acid composition of the chloroform-soluble fraction of this fungus was analyzed by gas chromatography-mass spectrometry. The content of the predominant unsaturated fatty acids (oleic and linoleic acids) is as high as 68%. The use of dimethyl disulfide adduct was effective in the determination of the position of the double bond, and the glycol oxidation fission reaction with sodium metaperiodate supported on silica gel was helpful in establishing the location of the trihydroxylic groups in the new fatty acid.


A secondary EWMA-based dictionary learning algorithm for polynomial phase signal denoising.
Under the influence of additive white Gaussian noise, sparse representation cannot effectively remove noise associated with the polynomial phase signal (PPS) via most dictionary learning algorithms whose training data come from the noisy signal, such as K-SVD and RLS-DLA. In this paper, we present a novel dictionary learning algorithm based on secondary exponentially weighted moving average (SEWMA) to denoise PPS. In the proposed algorithm, we first estimate the signal-to-noise (SNR) of the PPS to set the optimal rate of a weighted decline using covariance matrix model. Second we use RLS-DLA to train the dictionary. Thirdly, SEWMA is used to refine atoms in the learned dictionary. In this way, the SNR of the reconstructed signal obtained using the proposed algorithm is clearly higher than that of other algorithms, whereas the mean squared error is lower than that of other algorithms. To obtain the optimal denoising performance, the optimal rate of a weighted decline is set based on the estimated SNR. Simulation results show that the proposed method outperforms the K-SVD, RLS-DLA in mean square error and the SNR.


Melatonin effects on metabolism independent of gonad function.
We previously demonstrated that daily melatonin administration to middle-aged rats, restoring nocturnal plasma melatonin to young adult levels, decreased body weight and suppressed visceral fat and plasma leptin. In some species, metabolic and some neuronal responses to melatonin are mediated or dependent at least in part on gonadal steroid levels. Thus, melatonin-induced changes in gonadal steroid secretion may have mediated the aging-dependent melatonin-induced metabolic responses in our previous studies. To address this issue, melatonin (0.4 micro g/mL) or vehicle (0.01% ethanol) was administered for 10 wk in the drinking water of both castrate and sham-operated Sprague-Dawley male rats, starting 1 mo after surgery at 9 mo of age. Melatonin treatment decreased (p < 0.05) body weight in sham-operated rats by 7 +/- 2% relative to control (n = 7/treatment), comparable to our previous results; melatonin likewise decreased (p < 0.05) body weight in castrate rats by 6 +/- 2% relative to control (n = 7/treatment). Melatonin treatment also decreased both intraabdominal fat and plasma leptin levels in both intact and castrate rats, with no significant differences of percentage suppression in the intact versus castrate rats. These results demonstrate that suppression of body weight, visceral adiposity, and plasma leptin levels by daily melatonin administration to middle-aged rats was independent of gonadal function.


[Importance of some apudocytes in gastric ulcer bleeding prediction].
In 6 patients with uncomplicated gastric ulcer (GU) and 8 patients with GU complicated by acute bleeding morphohistochemical and ultrastructural analysis of apudocytes of gastric mucous membrane in the ulcer, periulcer and remote zone was carried out with detection of morphofunctional changes predicting ulcer bleeding. It is established that G- and ECL-apudocytes hyperplasia and hyperfunction in these zones have stable, irreversible nature in gastric ulcer bleeding, and are reliable prognostic criteria of this complication.


Nifedipine-induced morphological differentiation of rat pheochromocytoma cells.
Extension of neuronal processes is fundamental for the establishment of the intricate network of the nervous system. The rat PC12 pheochromocytoma cell line is a well-known model system for the study of neuronal differentiation. In the present study the effect of a high-voltage-activated calcium channel blocker, nifedipine, on the cell differentiation was investigated. In cells cultured in a modified medium containing nifedipine (at 2.5 microM or 5.0 microM) a decrease of mitotic activity took place on the third day of culturing. An increase of total length and number of processes occurred on the fifth day. A higher concentration of nifedipine (10.0 microM) considerably suppressed vital functions of the cells. Retraction of processes together with blocking of proliferation activity was observed. In parallel with these changes, a reduction of [Ca2+]i from 100 +/- 6 nM to 50 +/- 2 nM was detected on the second day of cultivation in 2.5 microM and 5.0 microM nifedipine containing medium. At 10.0 microM concentration of nifedipine in the medium a decrease in [Ca2+]i was observed on the first day only (to 76 +/- 8 nM); then the level of free calcium concentration rose dramatically. The data obtained allow us to suggest that the decrease of [Ca2+]i during first two days of PC12 cells culturing in a nifedipine-containing medium could be a factor which stimulated their morphological differentiation.


Isolation and sequencing of pig Blm and Ubl-1/SUMO-1 genes that relate to the recombination machinery.
The gene knockout technique is important in xenotransplantation research. Herein we have described the molecular cloning of two genes that are candidates to overcome the poor rate of homologous recombination. Candidate cDNA fragments were amplified by polymerase chain reaction (PCR) with the corresponding primer sets deduced from a multiple alignment analysis of other mammalian genes from a cDNA library prepared from pig spleen tissue. To obtain the full-length cDNA, a 5'- and 3'-RACE PCR experiments was performed. We successfully isolated the cDNA sequences of two pig genes--BLM, a Bloom's syndrome-related gene, and UBL-1/SUMO-1--which are closely related to homologous recombination events. As a result, we verified the sequences of pig BLM and pig UBL-1/SUMO-1. The nucleic acid and amino acid coding sequence homologies of pig BLM gene with the corresponding human gene were 87.3% and 82.9%, respectively. The nucleic acid and amino acid coding sequence homologies of the pig UBL-1/SUMO-1 gene with the human gene were 96.4% and 100%, respectively. Current research into homologous recombination provides the possibility for improvement of gene knockout efficiency by regulating the gene expression profiles of recombination-related genes. Transient interference with the expression of pig UBL-1/SUMO-1 and BLM is expected to improve gene targeting. The results of the present study provided important information to design siRNA knockdown vectors. They were also useful for ex ante evaluation of expression profiles of these genes in primary cultures of somatic cells, which may enhance the production of gene knockout pigs.


Associated pathways between neighborhood environment, community resource factors, and leisure-time physical activity among Mexican-American adults in San Diego, California.
To examine pathways between individual, social, and environmental factors associated with leisure-time physical activity (LTPA) among Mexican-American adults. Cross-sectional design using random-digit dialing to administer a structured telephone interview. Mexican-American adults living in a U.S.-Mexican border community in San Diego, California (N = 672). Data were collected on LTPA, demographic characteristics, acculturation, and other psychosocial and environmental factors associated with LTPA. Structural equation modeling to test an a priori model of LTPA. Participants were mostly female (71%) with a mean age of 39 years (SD = 13). Only 32% of participants met PA guidelines in their leisure time, with men (39%) meeting the guidelines more than women (29%). Using structural equation modeling, neighborhood factors, both social and environmental, showed indirect relationships with meeting PA guidelines through community resource factors. Significant covariates included marital status and age. Individual, social, and environmental factors were associated with LTPA in this sample of Mexican-American adults. These findings can inform intervention studies that aim to increase LTPA in this population.


Three New Pregnanes Isolated from the Cynanchum auriculatum.
Three new compounds named cynansteroid A (1), cynansteroid B (2) and cynansteroid C (3), together with nine known C21 -steroidal pregnane sapogenins (4-12) were isolated from the hydrolytic extract of the roots of Cynanchum auriculatum. The structures of cynansteroid A-C (1-3) were ascertained via the detailed analysis of the HR-ESI-MS, 1D and 2D NMR, and the calculated and experimental ECD data of cynansteroid B (2). Compound 11 displayed moderate inhibitory activity toward Verticillium dahliae Kleb (IC50 =37.15 μM), furthermore, compounds 11 and 12 showed significant inhibitory activity against Phomopsis sp. (IC50 =16.49 μM and 17.62 μM, respectively).


Superoxide Formation in Cardiac Mitochondria and Effect of Phenolic Antioxidants.
Since mitochondria are the main cellular source of reactive oxygen species, it is important to study the effect of dietary phenolic compounds on the level of ROS in these organelles. Using the EPR spectroscopy and TIRON probe, the ability of the investigated phenols (quercetin, rutin, caffeic acid, curcumin, and resveratrol) to scavenge superoxide anion radicals generated by isolated heart mitochondria of Wistar rats under variable oxygen partial pressure was studied. It was shown that during a 10 min incubation, caffeic acid in concentrations of 10-500 μM most effectively scavenged superoxide radicals formed in the complex III of the mitochondrial respiratory chain. A comparable antioxidant effect of rutin under these experimental conditions was observed at higher concentrations of 1-10 mM. The antioxidant activity of quercetin in the concentration range of 10-500 μM during the first minutes of incubation was higher than that of caffeic acid. Of the phenolic compounds studied, curcumin had the least effect on the superoxide radicals.


Motif mediated protein-protein interactions as drug targets.
Protein-protein interactions (PPI) are involved in virtually every cellular process and thus represent an attractive target for therapeutic interventions. A significant number of protein interactions are frequently formed between globular domains and short linear peptide motifs (DMI). Targeting these DMIs has proven challenging and classical approaches to inhibiting such interactions with small molecules have had limited success. However, recent new approaches have led to the discovery of potent inhibitors, some of them, such as Obatoclax, ABT-199, AEG-40826 and SAH-p53-8 are likely to become approved drugs. These novel inhibitors belong to a wide range of different molecule classes, ranging from small molecules to peptidomimetics and biologicals. This article reviews the main reasons for limited success in targeting PPIs, discusses how successful approaches overcome these obstacles to discovery promising inhibitors for human protein double minute 2 (HDM2), B-cell lymphoma 2 (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP), and provides a summary of the promising approaches currently in development that indicate the future potential of PPI inhibitors in drug discovery.


Primary care physician attitudes and practice patterns in the management of obese adults: results from a national survey.
Obesity remains a serious public health problem. The purpose of this study was to identify the current attitudes and practices of primary care physicians (PCPs) with respect to obesity. A survey was systematically developed and administered electronically to PCPs, who received a small honorarium for their time. Results were analyzed to identify specific attitudes and practices and their associations with each other and with demographic and other variables. Physicians expressed little confidence in their ability to manage obesity. In general, however, they believed that obesity could be successfully managed. Lifestyle changes were perceived to be the most effective available method for patients to lose weight, and respondents were more likely to recommend this approach over pharmacotherapy or bariatric surgery. Respondents perceive the greatest barrier to managing obese patients to be a lack of patient motivation. Physicians were significantly more likely to initiate discussions with obese patients about their weight if they believed they had positive attitudes about and knowledge of weight management, and adequate resources to manage the problem. Physicians report a lack of confidence in managing obesity. Lack of patient motivation is perceived to be the greatest barrier. Physicians with greater knowledge, more positive attitudes toward obesity management, and access to more resources are more likely to provide weight management in primary care settings.


Captopril does not improve insulin action in essential hypertension: a double-blind placebo-controlled study.
To compare the effect of captopril with that of placebo on peripheral and hepatic insulin action in essential hypertension, in light of evidence that insulin resistance is associated with cardiovascular risk. Randomized, double-blind, placebo-controlled, crossover trial, with 8 week treatment periods of captopril and placebo preceded and separated by 6 weeks of placebo. Belfast teaching hospital. Eighteen Caucasian nondiabetic patients (10 males), aged under 65 years, with essential hypertension, recruited from general practices in the greater Belfast area. Captopril at 50 mg twice a day or placebo twice a day for two 8 week treatment periods. Peripheral and hepatic insulin sensitivity assessed by glucose clamps. Fourteen patients completed the study. Mean (+/- SEM) levels of fasting glucose, fasting insulin and postabsorptive hepatic glucose production were similar after captopril and placebo (5.4+/-0.1 versus 5.4+/-0.1 mmol/l, 10.6+/-2.2 versus 9.5+/-1.1 mU/l, 11.2+/-0.6 versus 11.0+/-0.5 mmol/kg per min, respectively). During hyperinsulinaemia, hepatic glucose production was suppressed to comparable levels after both treatments (4.8+/-0.6 versus 4.3+/-0.6 mmol/kg per min) and exogenous glucose infusion rates required to maintain euglycaemia were also similar (30.0+/-2.6 versus 30.3+/-2.6 mmol/kg per min). Captopril therapy in uncomplicated essential hypertension has no effect on peripheral or hepatic insulin sensitivity.


The hepatitis B virus (HBV) core protein enhances the transcription activation of CRE via the CRE/CREB/CBP pathway.
We previously reported that hepatitis B virus core protein (HBc) can bind to the Enhancer I (Enh I) domain and can accumulate with transcription coactivator cAMP response element (CRE). This raises the possibility that HBc may interact with CRE/CREB and regulate CRE transcription activation. In this study, we investigated the function and mechanisms of HBc in regulating CRE transcriptional activation using the HepG2 cell line. Our results showed the following: (1) HBc expression significantly increases HBV CRE transcriptional activation; (2) phosphorylation of the serine residues in the arginine-rich domain (ARD) of HBc protein impacts the function of transcriptional activation by the CRE; (3) HBc protein significantly increases HBV CRE transcriptional activation following forskolin treatment; (4) HBc nonspecifically binds to CRE and enhances the binding of the cAMP response element-binding protein (CREB) to CRE; and (5) HBc increases the concurrent accumulation of CREB and CBP at the CRE region. HBc activates Enh I through its binding to CRE, increasing the concurrent accumulation of CREB/CBP on CRE, and thus increases CRE transcriptional activation.


Immunological studies in combined factor V and factor VIII deficiency.
Plasma samples from patients with inherited combined factor V and factor VIII deficiency were examined by immunological methods for the presence of factor V and Factor VIII-related antigens. A factor V-related antigen was consistently demonstrated in all plasma samples by inhibitor neutralization assay using a non-precipitating rabbit antibody. Factor VIII-related antigens were detected by inhibitor neutralization using human antibody and by electroimmunoassay using a precipitating rabbit antibody. The amounts of factor V and factor VIII-related antigens present in the patient's samples were similar to those found in normal human plasma. The findings confirm the presence of normal levels of factor VIII-related antigen in the plasma of these patients and suggest that inactive antigenic determinants of procoagulant factor V and procoagulant factor VIII are also present. The results are consistent with the possibility that a common precursor of porcoagulant factor V and factor VIII is defective in these patients.


Examining the inorganic elemental composition of lobster phyllosoma (Panulirus ornatus) with X-ray fluorescence microscopy.
The ornate spiny rock lobster, Panulirus ornatus, is an attractive candidate for aquaculture. The larval stages of spiny lobsters, known as phyllosoma, are complex with many developmental stages. Very little is known about the inorganic element composition of phyllosoma. In this study, a novel method using synchrotron X-ray fluorescence microscopy (XFM) was applied to investigate the distributions of metals potassium (K), calcium (Ca), copper (Cu), zinc (Zn), the metalloid arsenic (As), and nonmetal bromine (Br) within individual phyllosoma at stages 3, 4, and 8 of their development. For the first time, 1 µm resolution synchrotron XFM images of whole phyllosoma as well as closer examinations of their eyes, mouths, setae, and tails were obtained. Elements accumulated in certain locations within phyllosoma, providing insight into their likely biological role for these organisms. This information may be useful for the application of dietary supplementation in the future to closed larval cycle lobster aquaculture operations.


Clinical comorbidities, treatment patterns, and healthcare costs among patients with fibromyalgia newly prescribed pregabalin or duloxetine in usual care.
To assess comorbidities, pain-related pharmacotherapy, and healthcare resource use among patients with fibromyalgia (FM) newly prescribed pregabalin or duloxetine (index event) in usual care settings. Using the LifeLink™ Health Plan Claims Database, patients with FM (International Classification of Diseases, Ninth Revision, Clinical Modification code 729.1X) were identified. Patients initiated on duloxetine were propensity score-matched with patients initiated on pregabalin (n = 826; mean age [standard deviation] of 48.3 [9.3] years for both groups). Prevalence of comorbidities, pain-related pharmacotherapy, and healthcare resource use/costs were examined during the 12-month pre-index and follow-up periods. Both patient groups had multiple comorbidities and a substantial pain-related and adjuvant medication burden. In the pregabalin group, use of other anticonvulsants decreased significantly (31.6% vs 24.9%), whereas use of serotonin-norepinephrine reuptake inhibitors (SNRIs; 16.5% vs 22.5%) and topical agents (10.1% vs 13.2%) increased in the follow-up period (p < 0.01). In the duloxetine group, there were significant decreases in the use of other SNRIs (13.0% vs 5.7%), selective serotonin reuptake inhibitors (41.3% vs 21.7%), and tricyclic antidepressants (18.8% vs 13.2%), and an increase in the use of anticonvulsants (28.6% vs 40.1%; p < 0.0001). There were significant increases (p < 0.0001) in pharmacy and total healthcare costs in both cohorts, and a significant increase in outpatient costs (p = 0.0084) in the duloxetine cohort from pre-index to follow-up. There were no significant differences in median total healthcare costs between the pregabalin and duloxetine groups in both the pre-index ($10,159 vs $9,556) and follow-up ($11,390 vs $11,746) periods. Limitations of this study are typical of those associated with retrospective database analyses. Patients with FM prescribed pregabalin or duloxetine were characterized by a significant comorbidity and pain/adjuvant medication burden. Although healthcare costs increased in both groups, there were no statistically significant differences in direct healthcare costs between the two groups.


Plasma microRNA-195, -34c, and - 1246 as novel biomarkers for the diagnosis of trastuzumab-resistant HER2-positive breast cancer patients.
Recently, miRNAs have been regarded as potential candidates for mediating therapeutic functions by targeting genes related to drug response. In this study, we suggested that plasma miRNAs may be correlated with response to trastuzumab in HER2-positive breast cancer patients. To determine whether miR-195, miR-23b-3p, miR-1246, and miR-34c-3p are involved in trastuzumab resistance, we screened their expressions in the BT-474 cell line, which was followed by plasma analysis from 20 trastuzumab-resistant HER2-positive breast cancer patients and 20 nonresistance subjects. Then, TargetScan, Pictar, and miRDB were applied to find the possible targets of the selected miRNAs. In addition, the expression status of admitted targets was evaluated. Our results showed that in resistant BT-474 cells, miR-1246, and miR-23b-3p were significantly upregulated, and miR-195-5p and miR-34c-3p were downregulated. In plasma analysis, we found miR-195-5p, miR-34c-3p, and miR-1246 meaningfully diminished in the resistant group, while the expression of miR-23b-3p was not statistically different. The expression levels of confirmed targets by qRT-PCR showed that the expression of RAF1, AKT3, c-MET, CCND1, PHLPP2, MYB, MAP2K1, and PTEN was significantly upregulated, while the expression of CCNG2 was significantly downregulated. The networks of miRNAs with their confirmed targets improved comprehension of miRNA-mediated therapeutic responses to trastuzumab and might be proposed for more characterization of miRNA functions. Moreover, these data indicated that miR-195-5p, miR-34c-3p, and miR-1246 could be possible biomarkers for prognosis and early detection of the trastuzumab-resistant group from the sensitive group of HER2-positive breast cancer patients.


A molecular level mechanism for uranium (VI) toxicity through Ca(2+) displacement in pyrroloquinoline quinone-dependent bacterial dehydrogenase.
Dipicolinic acid (DPA), a small molecule analogue for the pyrroloquinoline quinone (PQQ) bacterial dehydrogenase cofactor, was used to model displacement of the complexing ion, Ca(2+), by a uranium (VI) dioxo-cation, UO2(2+). Complexation of UO2(2+) with DPA through the displacement of Ca(2+) was examined with UV/visible spectroscopy, ESI (electrospray ionization)-Mass spectrometry, and density functional theory based-modeling. The UO2(2+) displacement of other biologically important metal cations (Zn(2+), Cu(2+), Ni(2+), and Fe(3+)) from DPA was also examined. Results show that UO2(2+) has a distinctly higher binding affinity (logβ = 10.2 ± 0.1) for DPA compared to that of Ca(2+) (logβ = 4.6 ± 0.1), and provide molecular level insight into the mechanism of uranium toxicity associated with the {ONO} site. These results support those of VanEngelen et al. (2011) where a key interaction between PQQ and UO2(2+) produced significant uranium toxicity in bacteria. The observed toxicity mechanism was determined to be the displacement of a Ca(2+) cation bound to the {ONO} site on PQQ and was observed even at submicromolar UO2(2+) concentrations. Here we couple experimental findings with density functional theory (DFT) calculations to investigate the electronic and structural properties that make the {ONO} site so distinctively favorable for UO2(2+) binding. This novel approach using integrated experimental and fundamental atomic based models opens the path to identify a library of potential uranium interactions with critical biological molecules.


A novel small-molecule YLT256 inhibits proliferation and induces apoptosis both in vitro and in vivo in solid tumors.
Pancreatic carcinoma is a still unsolved health problem all over the world with poor prognosis and high mortality rate. YLT256, a novel synthesized chemical small inhibitor, displays potent antineoplastic activities via inducing apoptosis both in vitro and in vivo. In this study, we found that YLT256 showed growth inhibition against a broad spectrum of human cancer cell lines and pancreatic cancer cell line BxPc-3 was the most sensitive with an IC50 of 0.42μM. We also found YLT256 could induce apoptosis of BxPc-3 cells in a dose-dependent manner. Western blot analysis revealed that the occurrence of its apoptosis was associated with activation of caspases-3 and -9, up-regulation of pro-apoptotic Bak, and down-regulation of anti-apoptotic Bcl-2. Moreover, YLT256-treated resulted in changes of mitochondrial membrane potential (Δψm), and generation of reactive oxygen species (ROS). Furthermore, our data also revealed that YLT256 suppressed the growth of established tumor-bearing xenograft models without obvious side effects. Immunohistochemical analyses and TUNEL assay revealed an increase in cleaved caspase-3-positive cells and TUNEL-positive cells, a decrease in Ki67-positive cells upon YLT256. Together, all the results of present study provided evidence demonstrating that YLT256 could be a promising potential drug candidate for pancreatic cancer therapy.