Automatic segmentation of myocardium at risk from contrast enhanced SSFP CMR: validation against expert readers and SPECT.
Efficacy of reperfusion therapy can be assessed as myocardial salvage index (MSI) by determining the size of myocardium at risk (MaR) and myocardial infarction (MI), (MSI = 1-MI/MaR). Cardiovascular magnetic resonance (CMR) can be used to assess MI by late gadolinium enhancement (LGE) and MaR by either T2-weighted imaging or contrast enhanced SSFP (CE-SSFP). Automatic segmentation algorithms have been developed and validated for MI by LGE as well as for MaR by T2-weighted imaging. There are, however, no algorithms available for CE-SSFP. Therefore, the aim of this study was to develop and validate automatic segmentation of MaR in CE-SSFP. The automatic algorithm applies surface coil intensity correction and classifies myocardial intensities by Expectation Maximization to define a MaR region based on a priori regional criteria, and infarct region from LGE. Automatic segmentation was validated against manual delineation by expert readers in 183 patients with reperfused acute MI from two multi-center randomized clinical trials (RCT) (CHILL-MI and MITOCARE) and against myocardial perfusion SPECT in an additional set (n = 16). Endocardial and epicardial borders were manually delineated at end-diastole and end-systole. Manual delineation of MaR was used as reference and inter-observer variability was assessed for both manual delineation and automatic segmentation of MaR in a subset of patients (n = 15). MaR was expressed as percent of left ventricular mass (%LVM) and analyzed by bias (mean ± standard deviation). Regional agreement was analyzed by Dice Similarity Coefficient (DSC) (mean ± standard deviation). MaR assessed by manual and automatic segmentation were 36 ± 10% and 37 ± 11%LVM respectively with bias 1 ± 6%LVM and regional agreement DSC 0.85 ± 0.08 (n = 183). MaR assessed by SPECT and CE-SSFP automatic segmentation were 27 ± 10%LVM and 29 ± 7%LVM respectively with bias 2 ± 7%LVM. Inter-observer variability was 0 ± 3%LVM for manual delineation and -1 ± 2%LVM for automatic segmentation. Automatic segmentation of MaR in CE-SSFP was validated against manual delineation in multi-center, multi-vendor studies with low bias and high regional agreement. Bias and variability was similar to inter-observer variability of manual delineation and inter-observer variability was decreased by automatic segmentation. Thus, the proposed automatic segmentation can be used to reduce subjectivity in quantification of MaR in RCT. NCT01379261. NCT01374321.


The therapeutic effect of Xiaopi-I on functional dyspepsia.
To observe the therapeutic efficacy of Xiaopi-I on functional dyspepsia and its effects on gastric emptying. A total of 134 patients with functional dyspepsia were randomly assigned to 2 groups. The patients in the Xiaopi-I group (66 cases) and the Domperidone group (68 cases) were given Xiaopi-I granules and Domperidone 10 mg, 3 times a day, respectively. Another 20 healthy volunteers were chosen as the negative control group. The severity scores of the symptoms, as well as the gastric emptying, were detected before and after 4-week treatment by barium strip-trial meal. During therapy, 6 cases from the Xiaopi-I group and 8 cases from the Domperidone group were lost to follow, and 120 cases finally finished the study. Statistical differences were observed from both groups in terms of the symptoms of postprandial fullness early satiety, epigastric pain, and epigastric burning after 4-week treatment (P<0.01). The symptomatic severity scores of the Xiaopi-I group before and after the treatment were 7.48±1.64 and 2.16±1.26, respectively (P<0.01). Gastric emptying rates were also improved in the patients with delayed gastric emptying, and the effective rates were 91.3% and 75.8% in the Xiaopi-I and Domperidone groups, respectively. No obvious adverse effects were found from both groups. Xiaopi-I was an effective and safe agent in the treatment of functional dyspepsia and was worth of further development in clinical.


Six-minute walk test versus two-minute walk test in children with Duchenne muscular dystrophy: Is more time more information?
The six minute walk test is a widely accepted primary outcome parameter in most studies in Duchenne muscular dystrophy (DMD). To compare information obtained by the six minute walk distance (6MWD) test and the two minute walk distance (2MWD) in patients with DMD, a cohort of 13 voluntary DMD boys did a repeated six minute walking test. Patients had to be ambulatory with a physical disability according to Levels 1-3 on the Vignos-Scale for lower extremity. Measurements were taken at one minute intervals. Reliability was measured by intraclass correlation. Test-retest reliability for 6MWD and 2MWD in two different age classes was very good for both subgroups. Test-retest-reliability was lower in patients with more advanced disability in both tests. Walking speed remained completely stable from time points 1-6 minutes in the whole study patient collective, which indicates that physical exhaustion is not reached after six minutes even in more disabled patients. Thus the 6MWD in DMD patients does not give additional information as compared to a 2MWD.


APOE ɛ2 is associated with white matter hyperintensity volume in CADASIL.
Apolipoprotein E (APOE) increases the risk for Alzheimer's disease (ɛ4 allele) and cerebral amyloid angiopathy (ɛ2 and ɛ4), but its role in small vessel disease (SVD) is debated. Here we studied the effects of APOE on white matter hyperintensity volume (WMHV) in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a nonamyloidogenic angiopathy and inherited early-onset form of pure SVD. Four hundred and eighty-eight subjects were recruited through a multicenter consortium. Compared with APOE ɛ3/ɛ3, WMHV was increased in APOE ɛ2 (P = 0.02) but not APOE ɛ4. The results remained significant when controlled for genome-wide genetic background variation. Our findings suggest a modifying influence of APOE ɛ2 on WMHV caused by pure SVD.


Improving school lunch menus with multi-objective optimisation: nutrition, cost, consumption and environmental impacts.
To support school foods programmes by evaluating the relationship between nutritional quality, cost, student consumption and the environmental impacts of menus. Using linear programming and data from previously served menu items, the relationships between the nutritional quality, cost, student consumption and the environmental impacts of lunch menus were investigated. Optimised lunch menus with the maximum potential student consumption and nutritional quality and lowest costs and environmental impacts were developed and compared with previously served menus (baseline). Boston Public Schools (BPS), Boston Massachusetts, USA. Menu items served on the 2018-2019 BPS lunch menu (n 142). Using single-objective models, trade-offs were observed between most interests, but the use of multi-objective models minimised these trade-offs. Compared with the current weekly menus offered, multi-objective models increased potential caloric intake by up to 27 % and Healthy Eating Index scores by up to 19 % and reduced costs and environmental impacts by up to 13 % and 71 %, respectively. Improvements were made by reducing the frequency of beef and cheese entrées and increasing the frequency of fish and legume entrées on weekly menus. This work can be extrapolated to monthly menus to provide further direction for school districts, and the methods can be employed with different recipes and constraints. Future research should test the implementation of optimised menus in schools and consider the broader implications of implementation.


The effect of intervention in nickel concentrations on benthic macroinvertebrates: A case study of statistical causal inference in ecotoxicology.
Field survey-based ecological risk assessments for trace metals are conducted to examine the necessity and/or effectiveness of management intervention, such as setting of environmental quality standards. Observational datasets often involve confounders that may bias estimation of the effects of intervention (e.g., reduction of trace-metal concentrations through regulation). The field of ecotoxicology lags behind some other research fields in understanding proper analytical procedures for causal inference from observational datasets; there are only a few field survey-based ecotoxicological studies that have explicitly controlled for confounders in their statistical analyses. In the present study, we estimated the effect of intervention in nickel concentrations on Ephemeroptera, Plecoptera, and Trichoptera richness in rivers in Japan. We also provide detailed explanations for the backgrounds of spurious associations derived from confounders and on proper analytical procedures for obtaining an unbiased estimate of the targeted intervention effect by using regression analysis. We constructed a multiple regression model based on a causal diagram for aquatic insects and environmental factors, and on "the backdoor criterion," that enabled us to determine the set of covariates required to obtain an unbiased estimate of the targeted intervention effect from regression coefficients. We found that management intervention in nickel concentrations may be ineffective compared to intervention in organic pollution, and that analysis ignoring the confounders overestimated the effect of intervention in nickel concentrations. Our results highlight the fact that confounders can lead to misjudging the necessity for management of anthropogenic chemical substances. Confounders should be explicitly specified and statistically controlled to achieve a comprehensive assessment of ecological risks for various substances.


MicroRNA mediated regulation of metal toxicity in plants: present status and future perspectives.
The human population is increasing at an alarming rate, whereas heavy metals (HMs) pollution is mounting serious environmental problem, which could lead to serious concern about the future sufficiency of global food production. Some HMs such as Mn, Cu, and Fe, at lower concentration serves as an essential vital component of plant cell as they are crucial in various enzyme catalyzed biochemical reactions. At higher concentration, a vast variety of HMs such as Mn, Cu, Cd, Fe, Hg, Al and As, impose toxic reaction in the plant system which greatly affect the crop yield. Recently, microRNAs (miRNAs) that are small class of non-coding riboregulator have emerged as central regulator of numerous abiotic stresses including HMs. Increasing reports indicate that plants have evolved specialized inbuilt mechanism viz. signal transduction, translocation and sequestration to counteract the toxic response of HMs. Combining computational and wet laboratory approaches have produced sufficient evidences concerning active involvement of miRNAs during HMs toxicity response by regulating various transcription factors and protein coding genes involved in plant growth and development. However, the direct role of miRNA in controlling various signaling molecules, transporters and chelating agents of HM metabolism is poorly understood. This review focuses on the latest progress made in the area of direct involvement of miRNAs in signaling, translocation and sequestration as well as recently added miRNAs in response to different HMs in plants.


The interaction between Pseudomonas aeruginosa cells and cationic PC:Chol:DOTAP liposomal vesicles versus outer-membrane structure and envelope properties of bacterial cell.
The interactions between cationic liposomal formulations (PC:Chol:DOTAP 3:4:3) and 23 Pseudomonas aeruginosa strains were tested. The study was undertaken because different antimicrobial results had been obtained by the authors for Pseudomonas aeruginosa strains and liposomal antibiotics (Drulis-Kawa, Z., Gubernator, J., Dorotkiewicz-Jach, A., Doroszkiewicz, W., Kozubek, A., 2006. The comparison of in vitro antimicrobial activity of liposomes containing meropenem and gentamicin. Cell. Mol. Biol. Lett., 11, 360-375; Drulis-Kawa, Z., Gubernator, J., Dorotkiewicz-Jach, A., Doroszkiewicz W., Kozubek, A., 2006. In vitro antimicrobial activity of liposomal meropenem against Pseudomonas aeruginosa strains. Int. J. Pharm., 315, 59-66). The experiments evaluate the roles of the bacterial outer-membrane structure, especially outer-membrane proteins and LPS, and envelope properties (hydrophobicity and electrostatic potential) in the interactions/fusion process between cells and lipid vesicles. The interactions were examined by fluorescent microscopy using PE-rhodamine-labelled liposomes. Some of the strains exhibited red-light emission (fusion with vesicles or vesicles surrounding the cell) and some showed negative reaction (no red-light emission). The main aim of the study was to determine what kinds of bacterial structure or envelope properties have a major influence on the fusion process. Negatively charged cells and hydrophobic properties promote interaction with cationic lipid vesicles, but no specific correlation was noted for the tested strains. A similar situation concerned LPS structure, where parent strains and their mutants possessing identical ladder-like band patterns in SDS-PAGE analysis exhibited totally different results with fluorescent microscopy. Outer-membrane protein analysis showed that an 18-kDA protein occurred in the isolates showing fusion with rhodamine-labelled vesicles and, conversely, strains lacking the 18-kDA protein exhibited no positive reaction (red emission). This suggests that even one protein may be responsible for favouring stronger interactions between Pseudomonas aeruginosa cells and cationic liposomal formulations (PC:Chol:DOTAP 3:4:3).


Targeted design of green carbon dot-CA-125 aptamer conjugate for the fluorescence imaging of ovarian cancer cell.
Aptamer-Carbon Dot (CD) bioconjugation is an attractive target-tracking strategy in detecting cell surface antigens. This study describes an effective imaging paradigm for CA-125 antigen imaging. Our experience encompasses green CD synthesis and characterization, CD-capture probe conjugation through covalent bonding, the hybridization linkage of CD-probe to aptamer and their coupling confirmation, and fluorescent targeted imaging of ovarian cancer cells. As a result, the synthesized CDs from lemon extract by hydrothermal reaction show average size of 2 nm with maximum fluorescence intensity at excitation/emission 360/450 nm. CD-probe construction was provided by functional group interactions of CD and probe via EDC/NHS chemistry. The linkage of CD-probe to aptamer was conducted by Watson-Crick nucleotide pairing. The assessment of CD-probe and CD-probe-aptamer fabrication was validated by the increase in surface roughness through AFM analysis, the diminish of fluorescence intensity of CD after bioconjugation, and particle size growth of the construct. Conjugates with negligible cytotoxicity, appropriate zeta potential, and good aptamer release were applied in cellular imaging. This targeted diagnosis method was employed the four reported DNA aptamers toward fluorescence intensity. The DOV-3 aptamer showed more qualified detection over other aptamer conjugates during fluorescent microscopy analysis. In conclusion, the CD-probe-aptamer conjugate applications as toxic-free method can open new horizons in fluorescent nano-imaging in the field of targeted cancer cell diagnosis.


High diabetes-specific distress among adults with type 1 diabetes and impaired awareness of hypoglycaemia despite widespread use of sensor technology.
Impaired awareness of hypoglycaemia (IAH) has been associated with increased diabetes distress and use of sensor technology can reduce diabetes distress. The aim of this study was to examine diabetes-specific distress (emotions, cognitions, behaviours) in relation to IAH status and use of glucose sensors in people with type 1 diabetes. Individuals with type 1 diabetes from an academic diabetes outpatient clinic completed the Clarke questionnaire (to assess hypoglycaemic awareness), Problem Areas in Diabetes (PAID-5), Hypoglycaemia Fear Survey-II (HFS-II), Attitudes to Awareness of Hypoglycaemia Survey (A2A), Nijmegen Clinical Screening Instrument Survey (NCSI) and Hyperglycaemia Avoidance Scale (HAS). Of the 422 participants (51.9% male, diabetes duration 30 [16-40] years, HbA1c 60 ± 11 mmol/mol [7.6 ± 1.0%], 351 [88.2%] used a glucose sensor; 82 [19.4%]) had IAH. Compared to individuals with normal awareness, those with IAH more often had PAID-5 scores ≥8 (35.4% vs. 21.5%, p = 0.008) and higher scores on all HFS-II subscores (total [40.2 ± 21.5 vs. 27.9 ± 17.2, p < 0.001]), HFS-II behaviour (18.5 ± 10.0 vs. 15.1 ± 8.0, p = 0.005), HFS-II worry (21.8 ± 13.5 vs. 12.7 ± 10.9, p < 0.001), HAS worries (17.5 ± 7.3 vs. 14.3 ± 7.0, p < 0.001) and NCSI hypoglycaemia items. HAS behaviour, A2A and NCSI hyperglycaemia scores did not differ between individuals with or without IAH. Restricting the analyses to individuals using a glucose sensor did not materially change the results. Diabetes-specific distress remains a major problem among individuals with type 1 diabetes, particularly those with IAH, despite the widespread use of (intermittently scanned) sensor technology. Further studies are needed to examine strategies to lower diabetes-specific distress in individuals with IAH.


Does Hürthle cell carcinoma of the thyroid have a poorer prognosis than ordinary follicular thyroid carcinoma?
Hürthle cell carcinoma (HCC) is a rare form of thyroid carcinoma and is considered an oxyphilic variant of follicular thyroid carcinoma. However, little is known about its biological characteristics or clinical behavior. We conducted a retrospective study to determine whether the prognosis of HCC differs from that of ordinary follicular thyroid carcinoma (OFC). The subjects were the 558 patients with follicular thyroid carcinoma who underwent initial surgery at our institution between 1989 and 2010 and consisted of 73 patients with HCC and 485 patients with OFC. There were 410 females and 148 males, and their median age was 51 years. A univariate analysis was conducted in relation to cumulative cause-specific survival (CSS) according to the Kaplan-Meier method for the following variables: age at the time of initial surgery, gender, tumor size, invasiveness, distant metastasis at presentation, and histological type (HCC vs OFC). Differences between groups were analyzed for significance by the log-rank test. Multivariate analysis was performed by using the Cox proportional hazard model. A total of 4 patients (5.5%) in the HCC group had distant metastasis compared with 106 patients (21.9%) in the OFC group. Significant factors in relation to CSS in the univariate analyses were age, tumor size, and invasiveness, but there were no significant differences between the HCC group and the OFC group. Multivariate analysis showed that age, tumor size, and distant metastasis at presentation were significant factors. HCC does not have a poorer prognosis than OFC.


Different strategies of mixed chimerism induction may determine stem/progenitor cell populations in recipient mice.
Mixed chimerism has been suggested to induce tolerance to transplanted alloantigens. As the precise influence of mixed chimerism induction on the host organism has still not been fully elucidated, the aim of the present study was to explore this phenomenon in relation to the stem cell compartment. The experiment was performed on B6.SJL-Ptprc(a)Pep3(b) mice. Mixed chimerism induction protocols involved 3 Gy TBI (Day -1 of the experiment), injection of 20-30 × 10(6) Balb C bone marrow cells (Day 0), and administration of blocking antibodies against CD40L (Day 0 and Day 4), anti-CD8 (Day -2) with/without anti-NK1.1 (Day -3). Selected groups of mice were also treated with cyclophosphamid (175 mg/kg) on Day 2. The presence of mixed chimerism was assessed in peripheral blood, bone marrow, and spleen, as well as in various subpopulations of leukocytes (CD4(+), CD8(+), CD45/B220(+), Gr-1(+), lin(-)/Sca-1(+)/c-kit(-), lin(-)/Sca-1(+)/c-kit(+), lin(-)/Sca-1(-)/c-kit(+)). Furthermore, the percentage of stem/progenitor cells (lin(-)/Sca-1(+)/c-kit(-), lin(-)/Sca-1(+)/c-kit(+), lin(-)/Sca-1(-)/c-kit(+), VSEL, HSC) was analysed for the first time in bone marrow and peripheral blood of chimeric mice. The range of mixed chimerism differed significantly among various cell populations: it was lowest in CD8-positive cells and lin(-)/Sca-1(+)/c-kit(-) cells, and highest in granulocytes. The induction of mixed chimerism revealed a significant impact on the stem/progenitor cell frequency in recipient mice, providing potential therapeutic insights into the long-term immunologic tolerance observed in chimeric mice. Collectively, these findings contribute to further optimization of mixed chimerism induction protocols and might help in the introduction of this phenomenon into clinical practice.


Pollen-limited seed set in pseudogamous blackberries (Rubus L. subgen. Rubus).
Pseudogamous blackberry species are polyploid and usually exhibit meiotic irregularities causing severe reduction in pollen viability. When species means were compared, relative seed set was strongly correlated with the number of good pollen grains produced per flower divided by the number of ovules (good-pollen/ovule ratio).Partial correlation analysis for percentage viable pollen and relative seed set, controlling for good-pollen/ovule ratio, revealed an almost significant relationship, presumably because meiotic irregularities have a similar effect on both pollen viability and the viability of meiotically derived embryo sacs. Seed germination, on the other hand, showed no relationship with relative seed set or with pollen viability.The automatic selfing capacity exhibited by most of these blackberry species does not appear to be related to either pollen production or relative seed set.


Can we evaluate cranial aneurysms on conventional brain magnetic resonance imaging?
To evaluate the contribution of conventional brain magnetic resonance imaging (MRI) for the determination of intracranial aneurysms. Brain MRI and computed tomography angiography (CTA) of 45 patients (29 women and 16 men; age range, 32-80 years) with aneurysm were analyzed. A comparison was made between brain MRI and CTA based on size and presence of aneurysm. The comparisons between MRI and CTA were investigated through Bland-Altman graphics, receiver operating characteristic curve, and Kappa statistics. Fifty-seven aneurysms were evaluated. Forty-five percent of 57 aneurysms on CTA were detected on conventional brain MRI. A significant correlation was found between CTA and brain MRI in the diagnosis of aneurysm (P < 0.05). In an analysis of the size measurement, a significant correlation was observed between CTA and brain MRI. Seventy-seven percent of aneurysms <4 mm was not detected and the efficiency of MRI in the detection of aneurysms <4 mm was found to be low. Aneurysms can also be appreciated on conventional brain MRI, and vascular structures should be reviewed carefully while analyzing brain MRI.


Esophageal cancer surgery in heart transplant patients.
We herein report about 2 heart transplant patients undergoing surgical resection for esophageal cancer. Both were long-term survivors after orthotopic heart transplantation for dilated cardiomyopathy. One patient underwent a transthoracic esophagectomy and gastric pull-up for an early squamous cell carcinoma of the infracarinal esophagus. The second patient underwent a resection of the cervical esophagus and interposition of a free jejunal segment after neoadjuvant radiochemotherapy for a locally advanced squamous cell carcinoma in the cervical esophagus.


Initiating Opioid Use Disorder Medication via Telemedicine During COVID-19: Implications for Proposed Reforms to the Ryan Haight Act.
The Ryan Haight Act generally requires a clinician to conduct an in-person visit before prescribing an opioid use disorder (OUD) medication. This requirement has impeded use of telemedicine to expand OUD treatment, and many policymakers have called for its removal. During the COVID-19 pandemic, beginning March 16, 2020, the requirement was temporarily waived. It is unclear whether clinicians who treat OUD patients perceive telemedicine to be a safe and effective means of OUD medication initiation. To understand clinician use of and comfort level with using telemedicine to initiate patients on medication for opioid use disorder. National survey administered electronically via WebMD/Medscape's online clinician panel in fall 2020. A total of 602 clinicians (primary care providers, psychiatrists, nurse practitioners or certified nurse specialists, and physician assistants) participated in the survey. Frequency of video, audio-only, and in-person visits for medication initiation, comfort level with using video for new patient visits with OUD. Clinicians varied substantially in their use of telemedicine for medication initiation. Approximately 25% used telemedicine for most initiations while 40% used only in-person visits. The majority (55.8%) expressed at least some discomfort with using telemedicine for treating new OUD patients, although clinicians with more OUD patients were less likely to express such discomfort. Findings suggest that a permanent relaxation of the Ryan Haight requirement may not result in widespread adoption of telemedicine for OUD medication initiation without additional supports or incentives.


Biochar changes the bioavailability and bioefficacy of the allelochemical coumarin in agricultural soils.
Allelochemicals can act as biopesticides or enhance the action of synthetic pesticides. In this work, we assessed the bioavailability of the allelochemical coumarin in soils amended with fresh or field-aged biochars (BCs). The fresh BC from oak wood (Fresh BC) was prepared at 550 °C and was buried for aging in two different places: in a sandy loam soil in Spain for 15 months (Aged BC_1) and a sandy loam soil in USA for six months (Aged BC_2). Sorption experiments showed that all BCs were able to increase the affinity of soil towards coumarin, with the distribution coefficient following the order: unamended soil < Aged BC_2-amended soil < Aged BC_1-amended soil < Fresh BC-amended soil. All biochars ensure greater persistence of coumarin and the effect was more pronounced at high chemical dose (10 mg kg-1 ). Conversely, leaching studies in soil columns revealed that BCs were able to maintain coumarin within the first 5 cm of top-soil with total amount extracted ranging between 17% and 22% for BC-amended soil and <1% for unamended soil. Leaching was only observed when coumarin was added at the highest rate. Likewise, the bioefficacy of coumarin against lettuce was enhanced only at 10 kg ha-1 with BC-amended soil. Biochar application to agricultural soils is a promising tool for the management of natural compounds with potential use as biopesticides, such as coumarin, because it increases sorption, persistence and, in some cases, bioefficacy. The results reveal that this effect still persists with aging of BC in soils.


Role of habitual physical activity in modulating vascular actions of insulin.
What is the topic of this review? This review highlights the importance of increased vascular insulin sensitivity for maintaining glycaemic control and cardiovascular health. What advances does it highlight? We discuss the role of habitual physical activity in modulating vascular actions of insulin. Type 2 diabetes and cardiovascular disease commonly coexist. Current evidence suggests that impaired insulin signalling in the vasculature may be a common link between metabolic and cardiovascular diseases, including glycaemic dysregulation and atherosclerosis. Herein, we highlight the importance of the actions of insulin on the vasculature for glycaemic control and arterial health. In addition, we summarize and discuss findings from our group and others demonstrating that increased physical activity may be an effective approach to enhancing vascular insulin sensitivity. Furthermore, in light of the existing literature, we formulate the hypothesis that increased shear stress may be a prime mechanism through which habitual physical activity improves insulin signalling in the vasculature. Ultimately, we propose that targeting vascular insulin resistance may represent a viable strategy for improving glycaemic control and reducing cardiovascular risk in patients with type 2 diabetes.


Association between perception of fault for the crash and function, return to work and health status 1 year after road traffic injury: a registry-based cohort study.
To establish the association between the patient's perception of fault for the crash and 12-month outcomes after non-fatal road traffic injury. Two adult major trauma centres, one regional trauma centre and one metropolitan trauma centre in Victoria, Australia. 2605 adult, orthopaedic trauma patients covered by the state's no-fault third party insurer for road traffic injury, injured between September 2010 and February 2014. EQ-5D-3L, return to work and functional recovery (Glasgow Outcome Scale-Extended score of upper good recovery) at 12 months postinjury. After adjusting for key confounders, the adjusted relative risk (ARR) of a functional recovery (0.57, 95% CI 0.46 to 0.69) and return to work (0.92, 95% CI 0.86 to 0.99) were lower for the not at fault compared to the at fault group. The ARR of reporting problems on EQ-5D items was 1.20-1.35 times higher in the not at fault group. Patients who were not at fault, or denied being at fault despite a police report of fault, experienced poorer outcomes than the at fault group. Attributing fault to others was associated with poorer outcomes. Interventions to improve coping, or to resolve negative feelings from the crash, could facilitate better outcomes in the future.


The growth and asymmetry of neighbouring plants of white clover (Trifolium repens L.).
Transplants of white clover (Trifolium repens L.) were grown isolated from each other and in pairs placed at different distances apart. The paired plants developed asymmetrically and at the interface between paired clones both the density of nodes and of stolons appeared to reach ceiling values that were of the same order as those achieved in isolated clones. It is argued that the growth of plants of T. repens is controlled by the local conditions experienced by the plant parts and not by integrated growth of the whole. Transplants of three different genotypes of T. repens, which differed in growth form, were grown as neighbouring pairs and the calculated asymmetry of the plants was used to compare their mutual aggressivenes. The more compact (phalangeal) genotypes induced greater asymmetry in their neighbours than the more diffuse forms.


Quality of life: a dimension in multiaxial classification.
The study provides an overview of the historical aspects of multiaxial classification. Particular reference is paid to the multiaxial formats of ICD-10, DSM-IV and the WPA International Guidelines for Diagnostic Assessment (IGDA). The IGDA proposes a tetraaxial format with quality of life as one axis as well as an axis on symptomatology, an axis on adaptive functioning and an axis on environmental/psychosocial conditions. The axis on quality of life is added in recognition of the increasing importance placed upon the patient's perception of his/her capacity of self fulfillment and the attention paid to quality of life as a major descriptor of health status as well as an outcome measure of clinical care.


mTHPC mediated, systemic photodynamic therapy (PDT) for nonmelanoma skin cancers: Case and literature review.
Patients with multiple nonmelanoma skin cancers (NMSCs), like immunosuppressed or nevoid basal cell carcinomas, offer a therapeutic challenge. Photodynamic therapy (PDT) using the systemic photosensitizer meta-tetrahydroxyphenylchlorin (mTHPC) has the ability to treat multiple NMSCs up to a depth of 10 mm in a single session. These unique properties offer an attractive alternative to regular therapies (e.g., surgery or radiation) to these patients. A systemic search was carried out that focused on the main clinical studies using mTHPC-PDT on NMSCs in humans. This review describes some of the basic principles of the treatment, the most effective treatment parameters as well as its possible adverse outcomes, which is illustrated with a short description of our own experiences using this treatment modality on four patients with multiple NMSCs. To date, only four clinical studies have been published. It was demonstrated that mTHPC-PDT could be highly effective. On illuminating 1-2 days after drug administration, plasma drug levels were high and the tumor clearance rates were high (up to 100%), with relative few side effects and excellent cosmetic and functional outcomes. These results were obtained with a relatively low, patient friendly photosensitizer dose (0.04-0.05 mg/kg) as skin photosensitivity was shorter after the procedure. Although the patients personally experienced consistently good cure rates, the healing times varied greatly between anatomical areas. The head and neck areas heal well with good cosmesis, while the lower leg and foot areas show delayed, at times compromised, healing with scarring. Although mTHPC-PDT is described in the literature as an interesting and promising therapeutic option, especially for multiple NMSCs, a randomized clinical trial is lacking and personal experiences warrant too much skepticism. With the recent introduction of the hedgehog pathway inhibitor vismodegib, mTHPC-PDT seems to be less suitable as a first line of treatment; it should be considered as a last resort therapy.


The relationship between alcohol use, eating habits and weight change in college freshmen.
This study aims to improve understanding of how alcohol consumption in college freshmen affects eating patterns before, during, and after drinking, as well as its relation to body weight change. Two hundred eighty-two college freshmen (61% female; 59% Caucasian) completed measures of alcohol use, measured body mass index (BMI), and eating and activity habits before, during and following drinking episodes. Students were categorized by drinking status (non-drinker, low-risk, and moderate/high-risk) in order to explore group differences. Seventy-five percent of the sample reported past-month alcohol consumption, with 65% (N=134) of these categorized as "low-risk" drinkers and 35% (N=72) as "moderate-risk" drinkers. Moderate-risk drinkers were more likely than low-risk drinkers to report increases in appetite after drinking, with nearly half of students reporting overeating and making unhealthy food choices following drinking. Moderate-risk drinkers also demonstrated significant increases in 1st semester BMI change, relative to non-drinkers and low-risk drinkers. Eating patterns for a significant number of college students are altered before, during, and following drinking episodes, which related to change in freshman year BMI.


Lipidomic profiling reveals biosynthetic relationships between phospholipids and diacylglycerol ethers in the deep-sea soft coral Paragorgia arborea.
The cold-water gorgonian coral Paragorgia arborea is considered as a foundation species of deep-sea ecosystems in the northern Atlantic and Pacific oceans. To advance lipidomic studies of deep-sea corals, molecular species compositions of diacylglycerol ethers (DAGE), which are specific storage lipids of corals, and structural glycerophospholipids (GPL) including ethanolamine, choline, inositol and serine GPL (PE, PC, PI, and PS, respectively) were analyzed in P. arborea by HPLC and tandem mass spectrometry. In DAGE molecules, alkyl groups (16:0, 14:0, and 18:1), polyunsaturated fatty acids (PUFA), and monounsaturated FA are mainly substituted the glycerol moiety at position sn-1, sn-2, and sn-3, respectively. The ether form (1-O-alkyl-2-acyl) predominates in PE and PC, while PI is comprised of the 1,2-diacyl form. Both ether and diacyl forms were observed in PS. At position sn-2, C20 PUFA are mainly attached to PC, but C24 PUFA, soft coral chemotaxonomic markers, concentrate in PS, PI, and PE. A comparison of non-polar parts of molecules has shown that DAGE, ether PE, and ether PC can originate from one set of 1-O-alkyl-2-acyl-sn-glycerols. Ether PE may be converted to ether PS by the base-exchange reaction. A diacylglycerol unit generated from phosphatidic acid can be a precursor for diacyl PS, PC, and PI. Thus, a lipidomic approach has confirmed the difference in biosynthetic origins between ether and diacyl lipids of deep-sea gorgonians.


Further observations of transport within paddle cilia.
Rhabdopleura has densely ciliated tentacles and cephalic shield. These cilia are of two sorts, ordinary cilia and those bearing paddle-like swellings. These swellings, about 1 micron across, are in the ciliary membrane. The axoneme bundle within the cilium remains intact, keeping the usual spatial arrangements, except that in the swelling its overall diameter is reduced. It is suggested that the mechanism for moving the paddle-like swellings along the length of the cilium is the releasing and reattaching of the side filaments from the axoneme to the ciliary membrane.


Ten new species of the spider genus Sinoderces Li & Li, 2017 from China, Laos and Thailand (Araneae, Psilodercidae).
Ten new species of the spider family Psilodercidae Machado, 1951 are described from tropical East Asia, including five species found in China: Sinoderces luohanensis Li & Li, sp. nov. (♂♀), S. xueae Li & Li, sp. nov. (♂♀), S. taichi Li & Li, sp. nov. (♂♀), S. wenshanensis Li & Li, sp. nov. (♂♀), S. aiensis Li & Li, sp. nov. (♂♀); three are from Laos: S. khanensis Li & Li, sp. nov. (♂♀), S. phathaoensis Li & Li, sp. nov. (♂♀), S. kieoensis Li & Li, sp. nov. (♂); and the rest are from Thailand: S. saraburiensis Li & Li, sp. nov. (♂), S. dewaroopensis Li & Li, sp. nov. (♂♀). Types of all new species are deposited in the Institute of Zoology, Chinese Academy of Sciences in Beijing, China.


Platelet indices in preterm premature rupture of membranes and their relation with adverse neonatal outcomes.
Preterm premature rupture of membranes (PPROM) is not only the most common distinguishable cause of preterm delivery, but is also associated with adverse neonatal outcomes. We determined the platelet indices in PPROM cases and evaluated their relationship to adverse neonatal outcomes. Fifty patients with PPROM and 50 patients who experienced spontaneous preterm labor at < 37 gestational weeks were evaluated. Complete blood counts, birth weights, Apgar scores, presence of sepsis and respiratory distress syndrome (RDS) and neonatal intensive care unit admission were recorded. Patients with PPROM had increased mean platelet volumes (9.40 vs 10; P = 0.01), plateletcrit (0.19 vs 0.21; P = 0.03) and a higher frequency of neonatal sepsis (18% vs 38%; P = 0.02). Platelet indices in the patient group were compared according to the development of RDS. Plateletcrit values were higher in the RDS positive group (0.23 ± 0.05 vs. 0.21 ± 0.04; P = 0.04). The cut-off value for plateletcrit was determined as > 0.22, and the probability of RDS increased 5.86 times when plateletcrit values exceeded 0.22 (odds ratio 5.86, 95% confidence interval 1.01-32.01; P = 0.04). A one-unit increase in platelet distribution width resulted in a 1.33-fold increase in the risk of RDS (odds ratio 1.33, 95% confidence interval 1.01-1.77; P = 0.04). Mean platelet volumes and plateletcrit significantly increased and plateletcrit had a predictive value for RDS in PPROM cases. Monitoring plateletcrit may be promising for predicting the development of RDS, one of the most common and serious complications of PPROM rupture.


Dye adsorption on unburned carbon: kinetics and equilibrium.
Unburned carbon in fly ash is an important by-product from coal combustion. In this investigation, unburned carbon has been separated from fly ash and been employed as a low cost adsorbent for a basic dye adsorption (Rhodamine B) in aqueous solution. Adsorption isotherm and kinetics of adsorption have been investigated using batch experiments. It is found that dye adsorption capacity depends on initial concentration, pH of solution, and temperature. The adsorption isotherm can be described by Langmuir model and the adsorption capacity of Rhodamine B at 30, 40, and 50 degrees C can reach 9.7 x 10(-5), 1.14 x 10(-4), and 1.5 x 10(-4)mol g(-1), respectively. The pseudo first- and second-order kinetic models have been employed to fit the dynamic adsorption. It is found that the dynamic adsorption follows the pseudo second-order model. Thermodynamic calculations indicate that the adsorption is endothermic reaction with DeltaH degrees at 25 kJ mol(-1).


Oligomeric state of the N-terminal domain of DnaT for replication restart in Escherichia coli.
DNA replication stops when chemical or physical damage occurs to the DNA. Repairing genomic DNA and reloading the replication helicase are crucial steps for restarting DNA replication. The Escherichia coli primosome is a complex of proteins and DNA responsible for reloading the replication helicase DnaB. DnaT, a protein found in the primosome complex, contains two functional domains. The C-terminal domain (89-179) forms an oligomeric complex with single-stranded DNA. Although the N-terminal domain (1-88) forms an oligomer, the specific residues responsible for this oligomeric structure have not yet been identified. In this study, we proposed that the N-terminal domain of DnaT has a dimeric antitoxin structure based on its primary sequence. Based on the proposed model, we confirmed the site of oligomerization in the N-terminal domain of DnaT through site-directed mutagenesis. The molecular masses and thermodynamic stabilities of the site-directed mutants located at the dimer interface, namely Phe42, Tyr43, Leu50, Leu53, and Leu54, were found to be lower than those of the wild-type. Moreover, we observed a decrease in the molecular masses of the V10S and F35S mutants compared to the wild-type DnaT. NMR analysis of the V10S mutant revealed that the secondary structure of the N-terminal domain of DnaT was consistent with the proposed model. Additionally, we have demonstrated that the stability of the oligomer formed by the N-terminal domain of DnaT is crucial for its function. Based on these findings, we propose that the DnaT oligomer plays a role in replication restart in Escherichia coli.


A limited sampling strategy for estimation of the cladribine plasma area under the concentration versus time curve after intermittent i.v. infusion, s.c. injection, and oral administration.
Cladribine is a newly developed antimetabolite with promising activity in lymphoproliferative disorders. Recent pharmacokinetics investigations have suggested that there is a relationship between its plasma area under the concentration versus time curve (AUC) and the degree of neutropenia posttreatment as well as the therapeutic outcome in hairy-cell leukemia. To enable a simple estimation of the plasma AUC, a limited sampling strategy was developed. Stepwise linear regression was used to determine which were the most important data points for estimation of the plasma AUC after 2-h i.v. infusion, s.c. injection (5 mg/m2), and oral administration (10 mg/m2) in 27 patients. The most important data points after i.v. infusion in 12 patients were 1, 4, and 24 h, in order of importance. The AUC could be estimated as 2.9081 x C1h + 5.1851 x C4h + 20.3265 x C24h. The accuracy and precision (mean value +/- SD for the determined/estimated AUC was 0.99 +/- 0.053) of the model could not be increased by the addition of more data points. A somewhat lower accuracy and precision (0.96 +/- 0.089) was seen with the 2-, 4-, and 24-h data points. These were used to test the regression technique prospectively for the estimation of the AUC after i.v. administration in another set of 10 patients. The accuracy and precision of the estimation of the AUC was similar in this group (1.01 +/- 0.109). In all, 11 patients were treated orally (10 mg/m2) and 10 patients were treated by s.c. injection (5 mg/m2). The most important data points for estimation of the AUC were 2.5, 24, and 0.5 h after oral administration (AUC = 0.8630 x C0.5h + 4.2337 x C2.5h + 45.4364 x C24h) and 9, 1, and 16 h after s.c. injection (AUC = 1.8821 x C1h + 16.4256 x C9h + 25.4518 x C16h). The accuracy and precision were 1.01 +/- 0.064 after oral dosing and 0.99 +/- 0.11 after s.c. injection. The derived mathematical models are reliable for estimation of the plasma AUC of cladribine after 2-h i.v. infusion, oral administration, and s.c. injection.


Preparative fractionation of amyloid proteins on a microgram scale by high-performance liquid chromatography and polyacrylamide gel electrophoresis.
Preparative separation of amyloid proteins on a microgram scale is presented. Amyloid fibrils solubilized in aqueous 50% acetonitrile containing 0.1% trifluoroacetic acid, are fractionated by reverse-phase high-performance liquid chromatography. Fractionation of amyloids obtained from patients with familial Mediterranean fever allowed isolation of a protein identical with a conventionally isolated AA-protein. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis is used for preparative separation of AL-proteins. Two protein extraction procedures from Coomassie Blue stained gels are applied using elution in 0.1% sodium dodecyl sulfate containing buffer and 6 mol/l guanidine-HCl solution. The eluted proteins are concentrated and sodium dodecyl sulfate and dye are removed by acetonitrile precipitation of sample.


Sugar composition of the nephritogenic glycopeptide, nephritogenoside, isolated from rat glomerular basement membrane.
Water-soluble and non-dialyzable glycopeptide, nephritogenoside, was isolated from the glomerular basement membrane of normal rats. The yield of the purified nephritogenic glycopeptide from the glomerular basement membrane of 1200 rats was only 17.2 mg. Hexose amounted to 24.3% by weight, and consisted only of glucose. Paper chromatographic studies on the number and length of the carbohydrate chain deduced from strong alkaline cleavage in the presence of sodium borohydride strongly suggested that the carbohydrate chain of the nephritogenic glycopeptide is composed of three glucose residues. This conclusion was supported by the 13C-NMR spectroscopic results. In the paper chromatographic studies on the monosaccharides produced from 3H-labeled oligosaccharide by alkaline degradation and then acid hydrolysis and studies on the 13C-NMR spectrum, it was demonstrated that the saccharide at the reducing terminus is glucose. Thus, the glucose residue at the reducing terminus of the nephritogenoside may be linked directly (probably N-glycosidically) to amino acid, without the intervention of N-acetylglucosamine. The proposed structure of the carbohydrate portion of the nephritogenic glycopeptide, nephritogenoside, is as follows: (formula in text)


Covalent binding design strategy: A prospective method for discovery of potent targeted anticancer agents.
Cancer remains the most serious disease that threatens human health. Molecularly targeted cancer therapies, specifically small-molecule protein kinase inhibitors, form an important part of cancer therapy. Targeted covalent modification represents a proven approach to drug discovery with the recent FDA approvals of afatanib, ibrutinib, and osimertinib agents, which were designed to undergo an irreversible hetero-Michael addition reaction with a unique cysteine residue of a specific protein. Covalent inhibitors possess numerous advantages, including increased biochemical efficacy, longer duration of action, the high potential for improved therapeutic index due to lower effective dose, and the potential to inhibit certain drug resistance mechanisms. In this regard, the novel targeted anticancer agents whose activity is presumably dependent upon a hetero-Michael addition reaction with thiols are summarized in this article.


Chronic obstructive pulmonary disease patients increase medio-lateral stability and limit changes in antero-posterior stability to curb energy expenditure.
A relationship exists between step width and energy expenditure, yet the contribution of dynamic stability to energy expenditure is not completely understood. Chronic obstructive pulmonary disease (COPD) patients' energy expenditure is increased due to airway obstruction. Further, they have a higher prevalence of falls and balance deficits compared to controls. Is dynamic stability different between COPD patients and controls; and is the association between dynamic stability and energy expenditure different between groups? Seventeen COPD patients (64.3 ± 7.6years) and 23 controls (59.9 ± 6.6years) walked on a treadmill at three speeds: self-selected walking speed (SSWS), -20%SSWS, and +20%SSWS. Mean and variability (standard deviation) of the anterior-posterior (AP) and medio-lateral (ML) margins of stability (MOS) were compared between groups and speed conditions, while controlling for covariates. Additionally, their association to metabolic power was examined. The association between stability and power did not significantly differ between groups. However, increased metabolic power was associated with decreased MOS AP mean (p < 0.0001), independent of speed. Increased MOS AP variability (p = 0.01) and increased SSWS (p's < 0.05) were associated with increased metabolic power. The MOS ML mean for COPD patients was greater than that of healthy patients (p = 0.02). MOS AP mean decreased as speed increased and differed by group (p = 0.048). For COPD patients, a plateau was observed at SSWS and did not decrease further at +20%SSWS compared to controls. MOS AP variability (p < 0.0001), MOS ML mean (p < 0.0001), and MOS ML variability (p = 0.003) decreased as speed increased and did not differ by group. Patients with COPD operate at the upper limit of their metabolic reserve due to an increased cost of breathing. To compensate for their lack of stability, they walked with larger margins of stability in the ML direction, instead of changing the stability margins in the AP direction, due to its association with energy expenditure.


Carvacrol Promotes Cell Cycle Arrest and Apoptosis through PI3K/AKT Signaling Pathway in MCF-7 Breast Cancer Cells.
To examine the role of carvacrol in modulating PI3K/AKT signaling involved in human breast cancer pathogenesis using in vitro experimental model MCF-7 cells. MTT and lactate dehydrogenase assays were performed with cells treated with different doses of carvacrol (0-250 p mol/L) at different time points (24 and 48 h). The nuclear morphology was assessed in MCF-7 cells with propidium iodide (PI) and acridine orange/ethidium bromide (AO/EB) staining and analyzed by fluorescence microscopy. Events like cell cycle arrest, apoptosis was observed by flow cytometric analysis and expressions of p-Rb, cyclin D1, cyclin-dependent kinase 4 (CDK4), CDK6, Bax, Bcl-2, PI3K/p-AKT was analyzed by immunoblot. Carvacrol significantly reduced cell viability with the half maximal inhibitory concentration value of 200 µmol/L at 24 and 48 h (P<0.05). importantly, there was a significant increase in the accumulation of the G0/G1 phase upon treatment with carvacrol in MCF-7 cells (P<0.05 or P<0.01). A remarkable decrease in protein expressions of p-Rb, cyclin D1, CDK4 and CDK6 denotes cell cycle arrest (P<0.05 or P<0.01). In addition, carvacrol treatment significantly inhibited PI3K/p-AKT protein expressions leading to induction of apoptosis mediated by decreased Bcl2 and increased Bax protein expressions. Further, Annexin V/PI staining by FACS analysis, dual staining by AO/EB and PI staining studies suggests induction of apoptosis by carvacrol through PI3K/Akt signaling pathway in MCF-7 cells. Carvacrol significantly inhibited the breast cancer MCF-7 cell proliferation and induced apoptosis via suppressing PI3/AKT signaling pathway.


Evaluating a species phylogeny using ddRAD SNPs: Cyto-nuclear discordance and introgression in the salmonid genus Thymallus (Salmonidae).
Hybridization and introgression are very common among freshwater fishes due to the dynamic nature of hydrological landscapes. Cyclic patterns of allopatry and secondary contact provide numerous opportunities for interspecific gene flow, which can lead to discordant paths of evolution for mitochondrial and nuclear genomes. Here, we used double digest restriction-site associated DNA sequencing (ddRADseq) to obtain a genome-wide single nucleotide polymorphism (SNP) dataset comprehensive for allThymallus (Salmonidae)species to infer phylogenetic relationships and evaluate potential recent and historical gene flow among species. The newly obtained nuclear phylogeny was largely concordant with a previously published mitogenome-based topology but revealed a few cyto-nuclear discordances. These incongruencies primarily involved the placement of internal nodes rather than the resolution of species, except for one European species where anthropogenic stock transfers are thought to be responsible for the observed pattern. The analysis of four contact zones where multiple species are found revealed a few cases of mitochondrial capture and limited signals of nuclear introgression. Interestingly, the mechanisms restricting interspecific gene flow might be distinct; while in zones of secondary contact, small-scale physical habitat separation appeared as a limiting factor, biologically based reinforcement mechanisms are presumed to be operative in areas where species presumably evolved in sympatry. Signals of historical introgression were largely congruent with the routes of species dispersal previously inferred from mitogenome data. Overall, the ddRADseq dataset provided a robust phylogenetic reconstruction of the genus Thymallus including new insights into historical hybridization and introgression, opening up new questions concerning their evolutionary history.


Exosomal and intracellular miR-320b promotes lymphatic metastasis in esophageal squamous cell carcinoma.
Cancer-cell-released exosomal microRNAs (miRNAs) are important mediators of cell-cell communication in the tumor microenvironment. In this study, we sequenced serum exosome miRNAs from esophageal squamous cell carcinoma (ESCC) patients and identified high expression of miR-320b to be closely associated with peritumoral lymphangiogenesis and lymph node (LN) metastasis. Functionally, miR-320b could be enriched and transferred by ESCC-released exosomes directly to human lymphatic endothelial cells (HLECs), promoting tube formation and migration in vitro and facilitating lymphangiogenesis and LN metastasis in vivo as assessed by gain- and loss-of-function experiments. Furthermore, we found programmed cell death 4 (PDCD4) as a direct target of miR-320b through bioinformatic prediction and luciferase reporter assay. Re-expression of PDCD4 could rescue the effects induced by exosomal miR-320b. Notably, the miR-320b-PDCD4 axis activates the AKT pathway in HLECs independent of vascular endothelial growth factor-C (VEGF-C). Moreover, overexpression of miR-320b promotes the proliferation, migration, invasion, and epithelial-mesenchymal transition progression of ESCC cells. Finally, we demonstrate that METTL3 could interact with DGCR8 protein and positively modulate pri-miR-320b maturation process in an N6-methyladenosine (m6A)-dependent manner. Therefore, our findings uncover a VEGF-C-independent mechanism of exosomal and intracellular miR-320b-mediated LN metastasis and identify miR-320b as a novel predictive marker and therapeutic target for LN metastasis in ESCC.


Oncology team members' perceptions of a virtual navigation tool for cancer patients.
The Internet has become an important source of health information for patients and health care providers (HCPs) alike. Whereas studies have begun to document the effects of the internet on health behaviors and outcomes, surprisingly few studies have explored HCPs' perceptions of the internet as a key resource accessed by patients. However, as HCPs are seen as pivotal in guiding patients toward these resources, it is timely to study their perceptions. Therefore, the present inquiry explores HCPs' views of a recently developed high quality virtual navigation tool called the Oncology Interactive Navigator™ (OIN). Using a qualitative approach, in-depth interviews were conducted with 16 members of a multidisciplinary colorectal oncology team and volunteers at a large Cancer Centre in Montreal, Quebec, Canada. Content analysis revealed emerging themes centering on key benefits including: perceptions of a highly accessible, comprehensive high quality repository of cancer information; a means to further enhance HCP-patient communication and trust; and a significant catalyst to patient-family communication and support. Perceived drawbacks included patient (e.g., socio-demographic profile) and system's (e.g., professional roles and time constraints) characteristics that may limit OIN™ full implementation and uptake. The findings underscore the relevance of virtual navigation tools to ensure optimal person-centred care in cancer. Findings also suggest how virtual tools such as the OIN™ can best be used in practice as well as they guide strategies to adopt to optimize implementation of similar innovations in health care.


Surgery for glaucoma in patients with facial port wine mark.
To report the results of surgical treatment of glaucoma in patients with facial port wine mark at a single institution over a 10-year period. The study was conducted on 21 eyes (10 right eyes) of 17 children (8 males) with glaucoma associated with facial port wine mark presenting to the pediatric ophthalmology practice at a single institution between January 2008 and December 2017. All study eyes underwent combined angle and filtering surgery with antimetabolite (mitomycin C) and were followed for 2 years. Eyes were randomized for the angle component of the procedure to conventional trabeculotomy-trabeculectomy (CTT) or viscotrabeculotomy-trabeculectomy (VTT). Success was defined as intraocular pressure (IOP) of 5-16 mm Hg with no vision-threatening complications. Mean patient age was 17.4 ± 7.5 months. Mean IOP was 30.4 ± 3.7 mm Hg; mean corneal diameter, 12.4 ± 0.5 mm; mean axial length, 21.17 ± 1.63 mm; mean cup:disk ratio, 0.5 ± 0.2; and mean number of IOP-lowering drugs at presentation, 2.6 ± 0.5. At the end of the 2-year follow-up period, corresponding values were 12.9 ± 0.9 mm Hg, 12.6 ± 0.4 mm, 21.6 ± 1.7 mm, 0.6 ± 0.2, and 0.1 ± 0.3, respectively, in VTT patients and 14.3 ± 0.7 mm Hg, 12.9 ± 0.5 mm, 21.8 ± 1.7 mm, 0.6 ± 0.2, and 0.1 ± 0.4, respectively, in CTT groups. The most notable complication was a minimal self-limiting hyphema, more prevalent in the CTT group. In our study cohort, there were few postoperative complications associated with combined angle and filtering surgery with antimetabolites, which effectively treated elevated IOP, especially when medical treatment showed a modest response. The addition of viscoelastic to the procedure may provide additional benefits and slightly limit intra- and postoperative complications.


Causal pathway from telomere length to occurrence and 28-day mortality of sepsis: an observational and mendelian randomization study.
Telomeres are considered to be a physiological marker of aging. Elucidating relationship between telomere length and sepsis is an essential step towards understanding the biological processes involved in sepsis and its salvation. Mendelian randomization studies based on SNPs have given us new insights into genetic susceptibility to disease. To explore the causal pathway from telomere length to occurrence and 28-day mortality of sepsis. Leveraging genetic information resource of UK Biobank, we captured three groups of large-scale GWAS data: leukocyte telomere length (LTL), sepsis and all-cause death of 28-day. Study design consisted of three parts: forward analysis, reverse analysis and one-way analysis. Genetic instrumental variables were selected for different analyses under the premise that three MR core assumptions were satisfied. Causality was determined by means of IVW. In forward analysis, we did not observe a significant causal pathway from sepsis to LTL under IVW model: β (SE) was -0.0051 (0.0075) with a p-value of 0.499. In reverse analysis, based on the IVW model, the OR (95% CI) was 0.89 (0.80-0.99) and the p-values was 0.043; based on the results of leave out method and single SNP analysis, we obtained seven key SNPs. There were results of IVW model in the one-way analysis: β (SE) was -0.0287(0.1261). Short LTL increases susceptibility to sepsis, but sepsis does not shorten telomere length. LTL does not affect sepsis 28-day all-cause mortality and does not serve as a causal intermediate in gene regulation during the progression of sepsis to 28-day death.


AL721, a novel membrane fluidizer.
AL721, which is a novel lipid mixture extracted from egg yolks, is believed to be a therapeutic pharmacologic agent. AL721 interacts with membranes of various types of cells with a common mode of action. AL721 modifies cellular membrane composition and fluidity through passive extraction and/or exchange of cholesterol. Physiologically diminished cell function due to rigidification of its membrane is reversible both in vitro and in vivo by AL721. Fluidization of aged membranes with AL721 has been shown to restore brain serotonin receptor function both in vitro and in vivo. AL721 can also successfully restore deficient immune responsiveness of lymphocytes to mitogen stimulation in aged subjects. Drug tolerance to morphine and ethanol develops upon elevation of the viscosity of neuronal cell membranes in order to counteract the fluidization effect of the drug. Treatment of rigidified cellular membranes with AL721 in vivo can markedly reduce withdrawal symptoms. The virucidal effect of AL721 on the human immunodeficiency virus is believed to operate by lowering of viral membrane cholesterol thus interfering with the binding of the viral antigen to the host cell. Non-toxicity of AL721 is clearly demonstrated in animal and human safety studies.


Exercise induced "Mobitz type II" second degree AV block in a patient with chronic bifascicular block (right bundle branch block and left anterior hemiblock).
A 55 year old healthy man with chronic bifascicular block (right bundle branch block and left anterior hemiblock) had a near syncopal episode. A treadmill test showed exercise induced Mobitz type II AV block manifested clinically by paradoxical slowing of the heart rate and decreased blood pressure. True His Purkinje block and pseudo AV block due to His extrasystoles were documented by an electrophysiological study.


A phosphate-buffered saline intracanal dressing improves the biomineralization ability of mineral trioxide aggregate apical plugs.
Recently, it was shown that the biomineralization process promoted by the interaction of mineral trioxide aggregate (MTA) with dentin in phosphate-buffered saline (PBS) positively influenced the push-out bond strength of the cement. This study investigated if the use of a PBS intracanal dressing promotes the biomineralization process of MTA apical plugs using an ex vivo apexification model. White MTA was introduced into single-rooted teeth with standardized artificially created open apices to form 5-mm-thick apical plugs. The specimens were randomly divided into the following three groups of 10 samples each: group 1: the remaining canal space was filled with PBS as an intracanal dressing; group 2: the root segments were introduced in plastic vials containing floral foams with 20 mL of PBS; and group 3: the root segments were placed in the floral foams with 20 mL of PBS and a PBS intracanal dressing was used. After 2 months, the samples were processed for scanning electron microscopic observations. Data were analyzed by using the Kruskall-Wallis test. In group 1, the formation of an interfacial layer (IL) with intratubular mineralization (ITM) was more evident at the cervical third; however, no mineralization was revealed at the apical third. In group 2, there was no IL and/or ITM formation at the cervical third, but samples denoted IL and ITM formation at the apical third. Group 3 displayed the formation of IL and ITM at the different levels. It was concluded that the use of a PBS intracanal dressing promotes the biomineralization process at the inner side of MTA apical plugs.


Irreversible inhibition of zinc-containing protease by oxazolidinone derivatives. Novel inactivation chemistry.
alpha-Benzyl-2-oxo-1,3-oxazolidine-4-acetic acid (BOOA) having (alpha R,4S) and (alpha S,4R) configurations were designed and synthesized as a novel type of mechanism-based inactivators for carboxypeptidase A (CPA), and kinetic analysis demonstrated that they indeed inhibit the enzyme in a time-dependent manner with the second order inhibitory rate constants (kinact/KI) of 1.52 and 1.39 M-1 s-1 for (alpha S,R4)-BOOA and (alpha R,4S)-BOOA, respectively.


Structure-Guided Design and Synthesis of a Mitochondria-Targeting Near-Infrared Fluorophore with Multimodal Therapeutic Activities.
An urgent challenge for imaging-guided disease-targeted multimodal therapy is to develop the appropriate multifunctional agents to meet the requirements for potential applications. Here, a rigid cyclohexenyl substitution in the middle of a polymethine linker and two asymmetrical amphipathic N-alkyl side chains to indocyanine green (ICG) (the only FDA-approved NIR contrast agent) are introduced, and a new analog, IR-DBI, is developed with simultaneous cancer-cell mitochondrial targeting, NIR imaging, and chemo-/PDT/PTT/multimodal therapeutic activities. The asymmetrical and amphipathic structural modification renders IR-DBI a close binding to albumin protein site II to form a drug-protein complex and primarily facilitates its preferential accumulation at tumor sites via the enhanced permeability and retention (EPR) effect. The released IR-DBI dye is further actively taken up by cancer cells through organic-anion-transporting polypeptide transporters, and the lipophilic cationic property leads to its selective accumulation in the mitochondria of cancer cells. Finally, based on the high albumin-binding affinity, IR-DBI is modified into human serum albumin (HSA) via self-assembly to produce a nanosized complex, which exhibits significant improvement in the cancer targeting and multimodal cancer treatment with better biocompatibility. This finding may present a practicable strategy to develop small-molecule-based cancer theranostic agents for simultaneous cancer diagnostics and therapeutics.


Coupling and environmental implications of in situ formed biogenic Fe-Mn minerals induced by indigenous bacteria and oxygen perturbations for As(III) immobilization in groundwater.
Iron (Fe)-manganese (Mn) minerals formed in situ can be used for the natural remediation of the primary poor-quality groundwater with coexistence of arsenite [As(III)], Mn(II), and Fe(II) (PGAMF). However, the underlying mechanisms of immobilization and coupling of As, Mn, and Fe during in-situ formation of Fe-Mn minerals in PGAMF remains unclear. The simultaneous immobilization and coupling of arsenic (As), Mn, and Fe in PGAMF during in-situ formation of biogenic Fe-Mn minerals induced by O2 perturbations and indigenous bacteria (Comamonas sp. RM6) were investigated at the different molar ratios of Fe(II):Mn(II) (1:1, 2:1, and 3:1). Compared with systems without Fe(II) in the presence of Mn(II), the coexisted Fe(II) significantly enhanced Mn(II) bio-oxidation and mineral precipitation, resulting in As immobilization increased by 5, 7, and 7 times at initial Fe(II) concentration of 0.3, 0.6, and 0.9 mM, respectively. Moreover, the As(III) immobilization efficiencies in Mn(II) and Fe(II) mixed system at initial Fe(II) concentration of 0.3, 0.6, and 0.9 mM were 73%, 91%, and 92%, respectively, that were significantly higher than those of single Fe(II) system (30%, 59%, and 74%) and those of single Mn(II) system (12%), indicating that Fe(II) and Mn(II) oxidation synergically enhanced As(III) immobilization. This was mainly attributed to the formation and As adsorption capacity of biogenic Fe-Mn minerals (BFMM). The formed BFMM significantly facilitated simultaneous immobilization of Fe, Mn, and As in PGAMF by oxidation, adsorption, and precipitation/coprecipitation, a coupling of biological, physical, and chemical processes. Fe component was mainly responsible for As fixation, and Mn component dominated As(III) oxidation. Based on the results from this work, biostimulation and bioaugmentation techniques can be developed for in-situ purification and remediation of PGAMF. This work provides insights into the simultaneous immobilization of pollutants in PGAMF, as well as promising strategies for in-situ purification and remediation of PGAMF.


Novel insight into the correlation between hernia orifice of cystocele and lower urinary tract function: a pilot study.
It has been hypothesized that women with significant pelvic organ prolapse (POP), particularly of the anterior vaginal wall, may have voiding dysfunction (VD). Although the VD mechanism due to cystocele is not fully understood, different vaginal compartments have rarely been closely examined. This study attempted to further elucidate the correlation between POP and VD through a new subgroup classification using cystoscopy. This study reviewed clinical records of 49 women who underwent cystocele repair. All patients were scheduled for laparoscopic sacrocolpopexy, preoperatively underwent uroflowmetry and postvoid residual urine volume (PVR) measurement, and completed pelvic floor function questionnaires. Bladder examination by cystoscopy was additionally performed using the lithotomy position with the Valsalva maneuver. Subjects were divided into four groups according to hernia orifice presence determined by cystoscopy, which included the trigone type, posterior wall type, trigone and urethra type, and trigone and posterior wall type. The posterior wall type had statistically higher PVR values versus the trigone and posterior wall type (P = 0.013). The posterior wall type had statistically lower values for average urine flow rate versus the urethra and trigone type (P = 0.020). There were no significant differences noted in the pelvic floor function questionnaires among the four groups. A new bladder defect classification based upon hernia orifice location was associated with lower urinary tract function. Posterior wall hernia presence caused significant voiding function deterioration. This new subgroup classification, which can more clearly identify and indicate bladder function, is also comparable among patients.


Whole-brain monosynaptic inputs and outputs of leptin receptor b neurons of the nucleus tractus solitarii in mice.
The nucleus tractus solitarii (NTS) is the primary central station that integrates visceral afferent information and regulates respiratory, gastrointestinal, cardiovascular, and other physiological functions. Leptin receptor b (LepRb)-expressing neurons of the NTS (NTSLepRb neurons) are implicated in central respiration regulation, respiratory facilitation, and respiratory drive enhancement. Furthermore, LepRb dysfunction is involved in obesity, insulin resistance, and sleep-disordered breathing. However, the monosynaptic inputs and outputs of NTSLepRb neurons in whole-brain mapping remain to be elucidated. Therefore, the exploration of its whole-brain connection system may provide strong support for comprehensively understanding the physiological and pathological functions of NTSLepRb neurons. In the present study, we used a cell type-specific, modified rabies virus and adeno-associated virus with the Cre-loxp system to map monosynaptic inputs and outputs of NTSLepRb neurons in LepRb-Cre mice. The results showed that NTSLepRb neurons received inputs from 48 nuclei in the whole brain from five brain regions, including especially the medulla. We found that NTSLepRb neurons received inputs from nuclei associated with respiration, such as the pre-Bötzinger complex, ambiguus nucleus, and parabrachial nucleus. Interestingly, some brain areas related to cardiovascular regulation-i.e., the ventrolateral periaqueductal gray and locus coeruleus-also sent a small number of inputs to NTSLepRb neurons. In addition, anterograde tracing results demonstrated that NTSLepRb neurons sent efferent projections to 15 nuclei, including the dorsomedial hypothalamic nucleus and arcuate hypothalamic nucleus, which are involved in regulation of energy metabolism and feeding behaviors. Quantitative statistical analysis revealed that the inputs of the whole brain to NTSLepRb neurons were significantly greater than the outputs. Our study comprehensively revealed neuronal connections of NTSLepRb neurons in the whole brain and provided a neuroanatomical basis for further research on physiological and pathological functions of NTSLepRb neurons.


Leucism in sharks: a histological examination.
Isolated cases of skin pigment disorders, including leucism, in sharks and rays have been reported for multiple species. Nonetheless, the morphological basis behind these chromatic anomalies has not been examined histologically. In this study, the authors quantified and compared the presence of melanin in multiple tissue samples of leucistic and fully pigmented blacktip sharks Carcharhinus limbatus. The authors' results support lack of melanin to be responsible for leucistic colouration. The histological differences responsible were evaluated.


The Effect of Strict Segregation on Pseudomonas aeruginosa in Cystic Fibrosis Patients.
Segregation of patients with cystic fibrosis (CF) was implemented to prevent chronic infection with epidemic Pseudomonas aeruginosa strains with presumed detrimental clinical effects, but its effectiveness has not been carefully evaluated. The effect of strict segregation on the incidence of P. aeruginosa infection in CF patients was investigated through longitudinal protocolized follow-up of respiratory tract infection before and after segregation. In two nested cross-sectional studies in 2007 and 2011 the P. aeruginosa population structure was investigated and clinical parameters were determined in patients with and without infection with the Dutch epidemic P. aeruginosa clone (ST406). Of 784 included patients 315 and 382 were at risk for acquiring chronic P. aeruginosa infection before and after segregation. Acquisition rates were, respectively, 0.14 and 0.05 per 1,000 days at risk (HR: 0.66, 95% CI [0.2548-1.541]; p = 0.28). An exploratory subgroup analysis indicated lower acquisition after segregation in children < 15 years of age (HR: 0.43, 95% CI[0.21-0.95]; p = 0.04). P. aeruginosa population structure did not change after segregation and ST406 was not associated with lung function decline, death or lung transplantation. Strict segregation was not associated with a statistically significant lower acquisition of chronic P. aeruginosa infection and ST406 was not associated with adverse clinical outcome. After segregation there were no new acquisitions of ST406. In an unplanned exploratory analysis chronic acquisition of P. aeruginosa was lower after implementation of segregation in patients under 15 years of age.


Deep dysphasia: an analog of deep dyslexia in the auditory modality.
A right-handed patient, with two left hemisphere lesions, a small one in the prefrontal lobe and a larger one in the temporal, presents an unusual syndrome: a massive deficit for oral language (expression and comprehension) contrasting with a fairly good preservation of written language (expression and comprehension). The processing of isolated words and sentences has been extensively tested with repetition and dictation tasks. The patient performs rather well with nouns, verbs, and adjectives, poorly with adverbs and function words, and completely fails with nonsense words. A remarkable feature of his repetition is the frequency of semantic paraphasias. Thus, this patient exhibits a behavior rather similar to deep dyslexia, hence the possible label "deep dysphasia." The paper presents a "preunderstanding" hypothesis to account for such behaviors.


One enzyme, many reactions: structural basis for the various reactions catalyzed by naphthalene 1,2-dioxygenase.
Rieske nonheme iron oxygenases (ROs) are a well studied class of enzymes. Naphthalene 1,2-dioxygenase (NDO) is used as a model to study ROs. Previous work has shown how side-on binding of oxygen to the mononuclear iron provides this enzyme with the ability to catalyze stereospecific and regiospecific cis-dihydroxylation reactions. It has been well documented that ROs catalyze a variety of other reactions, including mono-oxygenation, desaturation, O- and N-dealkylation, sulfoxidation etc. NDO itself catalyzes a variety of these reactions. Structures of NDO in complex with a number of different substrates show that the orientation of the substrate in the active site controls not only the regiospecificity and stereospecificity, but also the type of reaction catalyzed. It is proposed that the mononuclear iron-activated dioxygen attacks the atoms of the substrate that are most proximal to it. The promiscuity of delivering two products (apparently by two different reactions) from the same substrate can be explained by the possible binding of the substrate in slightly different orientations aided by the observed flexibility of residues in the binding pocket.


Molecular epidemiological view on Shiga toxin-producing Escherichia coli causing human disease in Germany: Diversity, prevalence, and outbreaks.
Infections by intestinal pathogenic Escherichia coli (E. coli) are among those causing a high mortality and morbidity due to diarrheal disease and post infection sequelae worldwide. Since introduction of the Infection Protection Act in Germany 2001, these pathogens rank third among bacterial infections of the gastrointestinal tract. As a major pathovar Shiga toxin-producing E. coli (STEC) which include enterohemorrhagic E. coli (EHEC) play a leading role in occurrence of sporadic cases and disease outbreaks. An outstanding example is the large outbreak in spring 2011 caused by EHEC/EAEC O104:H4. To monitor and trace back STEC infections, national surveillance programs have been implemented including activities of the German National Reference Centre for Salmonella and other Enteric Bacterial Pathogens (NRC). This review highlights advances in our understanding of STEC in the last 20 years of STEC surveillance by the NRC. Here important characteristics of STEC strains from human infections and outbreaks in Germany between 1997 and 2013 are summarized.


Histopathology of the heart from rats fed rapeseed oils.
The cardiopathogenicity of oils from new, low erucic acid (EA) rapeseed, Brassica napus, cv Tower (0.88 per cent EA) and Brassica napus, cv 1788 (3.6 per cent EA) were tested on rats following 18 weeks of feeding. Oil from Brassica napus, cv Target, with 38.9 per cent EA served as a positive control and corn oil as the negative control. Tower and 1788 rapeseed oils showed noticeable cardiopathogenicity, and a few mild lesions were also noted in the corn oil group. The main pathological change was from fresh to relatively old foci of myocardial necrosis. The presence of droplets accompanying the platelet aggregates suggested the possibility of their involvement in the development of the lesions. The pathological changes in the small and minute blood vessel walls were interpreted as one of the predisposing factors for the development of fatty embolism and subsequently of myocardial necrosis.


[Prevention of cardiovascular disease in patients with type 2 diabetes].
The modern life style is often characterized by a lack of physical activity as well as unhealthy diet leading to a worldwide rise in obesity. This goes along with an increased incidence of type 2 diabetes, accompanied by an accelerated atherosclerosis. Life style changes and normalization of body weight therefore represent the cornerstones of diabetes prevention. In addition, a multi-factorial approach focusing on cardiovascular risk factors like dyslipidemia, hypertension and hyperglycemia enables an effective means for the prevention of micro- or macrovascular complications.


The human papillomavirus vaccine in Canada.
Clinical studies have shown the human papillomavirus (HPV) vaccines to be very effective at preventing persistent infection by vaccine serotypes. The development of these new vaccines heralds a new era in cancer prevention. Gardasil, Merck's quadravalent HPV vaccine, has recently been licensed in Canada for women aged 9 to 26 years of age. It necessitates that health professionals become familiar with the vaccine, the evidence supporting its effectiveness and issues related to vaccine strategy, cost effectiveness, and remaining research questions. The vaccine is recommended in Canada for females aged 9 to 13 years and should also be offered to females aged 14 to 26 years. Ongoing research will determine the duration of protection conferred by the vaccine, and the potential need for booster doses. In conjunction with continued screening programs, the HPV vaccine offers the potential to dramatically reduce the burden of cervical cancer in Canada, and to do so in a cost-effective manner.


Activated leukocyte cell adhesion molecule on human oligodendrocytes mediates CD4 T cell adhesion.
Multiple sclerosis is a chronic neuroinflammatory disorder characterized by demyelination, oligodendrocyte damage/loss and neuroaxonal injury in the context of immune cell infiltration in the central nervous system. No neuroprotective therapy is available to promote the survival of oligodendrocytes and protect their myelin processes in immune-mediated demyelinating diseases. Pro-inflammatory CD4 Th17 cells can interact with oligodendrocytes in multiple sclerosis and its animal model, causing injury to myelinating processes and cell death through direct contact. However, the molecular mechanisms underlying the close contact and subsequent detrimental interaction of Th17 cells with oligodendrocytes remain unclear. In this study we used single cell RNA sequencing, flow cytometry and immunofluorescence studies on central nervous system tissue from multiple sclerosis subjects, its animal model and controls to characterize the expression of cell adhesion molecules by mature oligodendrocytes. We found that a significant proportion of human and murine mature oligodendrocytes express melanoma cell adhesion molecule and activated leukocyte cell adhesion molecule in multiple sclerosis, in experimental autoimmune encephalomyelitis and in controls, although their regulation differs between human and mouse. We observed that exposure to pro-inflammatory cytokines or to human activated T cells are associated with a marked downregulation of the expression of melanoma cell adhesion molecule but not of activated leukocyte cell adhesion molecule at the surface of human primary oligodendrocytes. Furthermore, we used in vitro live-imaging, immunofluorescence, and flow cytometry to determine the contribution of these molecules to Th17-polarized cell adhesion and cytotoxicity towards human oligodendrocytes. Silencing and blocking activated leukocyte cell adhesion molecule but not melanoma cell adhesion molecule limited prolonged interactions between human primary oligodendrocytes and Th17-polarized cells, resulting in decreased adhesion of Th17-polarized cells to oligodendrocytes and conferring significant protection of oligodendrocytic processes. In conclusion, we showed that human oligodendrocytes express melanoma and activated leukocyte cell adhesion molecules, which are differently modulated by inflammation and T cell contact. We found that activated leukocyte cell adhesion molecule is a ligand for Th17-polarized cells, contributing to their capacity to adhere and induce damage to human oligodendrocytes, and therefore could represent a relevant target for neuroprotection in multiple sclerosis.


RNA polymerase I subunit RPA43 activates rRNA expression and cell proliferation but inhibits cell migration.
The products synthesized by RNA polymerase I (Pol I) play fundamental roles in several cellular processes, including ribosomal biogenesis, protein synthesis, cell metabolism, and growth. Deregulation of Pol I products can cause various diseases such as ribosomopathies, leukaemia, and solid tumours. However, the detailed mechanism of Pol I-directed transcription remains elusive, and the roles of Pol I subunits in rRNA synthesis and cellular activities still need clarification. In this study, we found that RPA43 expression levels positively correlate with Pol I product accumulation and cell proliferation, indicating that RPA43 activates these processes. Unexpectedly, RPA43 depletion promoted HeLa cell migration, suggesting that RPA43 functions as a negative regulator in cell migration. Mechanistically, RPA43 positively modulates the recruitment of Pol I transcription machinery factors to the rDNA promoter by activating the transcription of the genes encoding Pol I transcription machinery factors. RPA43 inhibits cell migration by dampening the expression of c-JUN and Integrin. Collectively, we found that RPA43 plays opposite roles in cell proliferation and migration except for driving Pol I-dependent transcription. These findings provide novel insights into the regulatory mechanism of Pol I-mediated transcription and cell proliferation and a potential pathway to developing anti-cancer drugs using RPA43 as a target.


Messenger RNA synthesis in synchronized Chinese hamster ovary cells.
Chinese hamster ovary cells were synchronized without inhibitors by mitotic selection and labelled in G1, S or G2 phase by incubation for 90 min with [3H]- OR [14C]uridine. Purified polyribosomes were extracted with phenol and the polyadenylated mRNA prepared by poly(U)-Sepharose chromatography. Poly-adenylated [3H]uridine-labelled mRNA from the G1 phase of the cell cycle was compared by exponential polyacrylamide gel electrophoresis in formamide with [14C] uridine-labelled polyadenylated nRNA from the S or G2 phase. The electrophoretic patterns obtained correspond to the size range expected for mRNA (7-28 S). No prominent differences were detected between mRNAs synthesized in different phases of the cell cycle. From these data we conclude that the major size classes of polyribosomal poly(A)-containing mRNA are synthesized in equal ratios throughout the cell cycle.


Dronedarone vs. placebo in patients with atrial fibrillation or atrial flutter across a range of renal function: a post hoc analysis of the ATHENA trial.
Use of antiarrhythmic drugs (AADs) in patients with chronic kidney disease (CKD) is challenging owing to issues with renal clearance, drug accumulation, and increased proarrhythmic risks. Because CKD is a common comorbidity in patients with atrial fibrillation/atrial flutter (AF/AFL), it is important to establish the efficacy and safety of AAD treatment in patients with CKD. Dronedarone efficacy and safety in individuals with AF/AFL and varying renal functionality [estimated glomerular filtration rate (eGFR): ≥60, ≥45 and <60, and <45 mL/min] was investigated in a post hoc analysis of ATHENA (NCT00174785), a randomized, double-blind trial of dronedarone vs. placebo in patients with paroxysmal or persistent AF/AFL plus additional cardiovascular (CV) risk factors. Log-rank testing and Cox regression were used to compare the incidence of endpoints between treatments. Overall, 4588 participants were enrolled from the trial. There was no interaction between treatment group and baseline eGFR assessed as a continuous variable (P = 0.743) for the first CV hospitalization or death from any cause (primary outcome). This outcome was lower with dronedarone vs. placebo across a wide range of renal function. First CV hospitalization and first AF/AFL recurrence were both lower in the two least renally impaired subgroups with dronedarone vs. placebo. Treatment emergent adverse events leading to treatment discontinuation were more frequent with dronedarone vs. placebo and occurred more often in patients with severe renal impairment. Dronedarone is an effective AAD in patients with AF/AFL and CV risk factors across a wide range of renal function.


Fertility-Sparing Management Using Progestin for Young Women with Endometrial Cancer From a Population-Based Study.
For young women with complex atypical endometrial hyperplasia (CAH) and endometrial cancer (EC) who choose to preserve fertility, progestin therapy is the mainstay of treatment. The objective of this study was to evaluate oncologic and reproductive outcomes associated with progestin therapy among these women from a population-based cancer registry. This was a retrospective population-based cohort study of women under age 45 in British Columbia from 2003 to 2015 with CAH or grade I endometrioid EC who used progestins as initial management. Demographics, treatment type, response to treatment, determinants of definitive surgery (hysterectomy), pathologic findings, and obstetrical outcomes were reviewed. There were 50 women under age 45 with CAH (n = 29) and EC (n = 21). Median age at diagnosis was 36 years (range 25-41), and most were nulliparous (88%) with a median BMI of 32.9 (range 21-70). After 6 months of therapy, 58% of women had persistent disease, and only 35% had full resolution at last follow-up (median 23 months). There were 32 women who had a hysterectomy, including 27 because of persistent/recurrent disease, and 5 who chose surgery despite complete response to progestins. The majority of hysterectomy specimens (85%) had minimal or no residual pathology, even among those with disease on preoperative biopsy. Only 10% of women had successful pregnancies. There is a moderate to high risk of persistence of CAH or EC on progestin therapy. However, for those undergoing hysterectomy, the vast majority has low-risk disease confined to the endometrium, implying the possibility of further conservative management of persistent disease.


Serotonergic mechanisms of cocaine effects in humans.
The objective of this study was to investigate the role of serotonin (5-HT) in mediating the effects of cocaine in humans. To accomplish this, 12 subjects each participated in two randomized, double-blind test sessions separated by 1 week. In one session, subjects underwent acute depletion of the 5-HT amino acid precursor tryptophan (TRP), followed by a test dose of intranasal cocaine. In the other session, the cocaine test dose was preceded by sham depletion. Subject ratings of cocaine "high" were significantly lower following active TRP depletion than after the sham procedure. Subjects also showed an earlier but less sustained rise in self-rated nervousness during active TRP depletion. These findings are consistent with the hypothesis that 5-HT may be involved in mediating the euphorigenic and modulating the anxiogenic effects of cocaine in humans, either directly or through actions on other (e.g., dopaminergic) systems.


Acceptance of pharmaceutical gifts. Variability by specialty and job rank in a Saudi healthcare setting.
To examine the variability in accepting different types of gifts by clinical specialty as well as job rank among physicians working in Saudi Arabia. This cross-sectional study was carried out between March and July of 2012 in different regions of Saudi Arabia. A self-administrated questionnaire was developed and administered to all participants, both in paper and electronic formats. A total of 281 participants answered the question `do you accept pharmaceutical gifts and/or promotions?` Most of the participants (80.1%) admitted acceptance of pharmaceutical gifts of any type. The most common gifts accepted were free drug samples (58.2%), stationary items such as pens and notepads (52.9%), free meals (37.8%), financial support to attend educational activities (33.3%), prepaid promotion cards/codes (7.1%), and funding research (5.8%).While there were no significant differences in the overall gift acceptance by job rank or specialty, there were significant differences in type-specific gift acceptance by job rank and specialty. There were some differences in the reasons behind gift acceptance by specialty and job rank. The results of this study indicate that gift acceptance among physicians working in Saudi Arabia is common; however, there was no significant differences in the overall gift acceptance by job rank or specialty. Nevertheless, there were significant differences in type-specific gift acceptance by job rank and specialty.


Body Perception, Self-Esteem, and Comorbid Psychiatric Disorders in Adolescents Diagnosed with Polycystic Ovary Syndrome.
To investigate adolescents with polycystic ovary syndrome (PCOS) in terms of body perception, self-esteem, and comorbid psychiatric diseases by comparing them with their healthy peers. Cross-sectional design. The Department of Child and Adolescent Psychiatry and the Department of Pediatric Endocrinology outpatient clinic of Cumhuriyet University in Sivas, Turkey. Fifty female adolescents aged 12-18 years who were diagnosed as having PCOS and 37 healthy adolescents aged 12-18 years. All adolescents were evaluated by a child and adolescent psychiatrist using a semistructured interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children) and asked to complete the Rosenberg Self-Esteem Scale, Children's Depression Inventory, and Body Image Scale. The rate of psychiatric disorders in the PCOS group was significantly higher than in the control participants (16/50 (32%) vs 5/37 (13.5%), respectively; P = .046). The most common disorder was major depressive disorder. The Rosenberg Self-Esteem Scale and Body Image Scale scores of the PCOS group were lower (P = .03; P < .001, respectively), and Children's Depression Inventory scores were higher (P = .03) than in the control group. There was no significant relationship between obesity, hirsutism, and insulin resistance with any psychiatric disorders in the PCOS group. Adolescents with PCOS had more psychopathology than their peers. Moreover, their self-esteem was lower and their body perceptions were more dissatisfied compared with their peers.


A Single-Crystal Monomer to Single-Crystal Polymer Reaction Activated by a Triplet Excimer in a Zipper Mechanism.
A combined experimental and theoretical study focused on the elucidation of the polymerization mechanism of the crystal monomer to crystal polymer reaction of a bisindenedione compound in the solid state. The experimental description and characterization of the polymer product have been reported elsewhere and, in this article, we address the first detailed description of the polymerization process. This reaction pathway consists of the initial formation of a triplet excimer state that relaxes to an intermolecularly bonded triplet state that is the starting point of the propagation step of the polymerization. The overall process can be visualized in the monomer starting state as an open zipper in which a cursor or slider is formed by light absorption and the whole zipper is then closed by propagation of the cursor. To this end, variable-temperature electron spin resonance (ESR), femtosecond transient absorption spectroscopy, and vibrational Raman spectroscopic data have been implemented in combination with quantum chemical calculations. The presented mechanistic insight is of great value to understand the intricacies of such an important reaction and to envisage and diversify the products produced thereof.


Maternal and perinatal outcome of severe pre-eclampsia in Enugu, Nigeria after introduction of Magnesium sulfate.
Magnesium sulfate (MgSO4) is the most effective seizure prophylaxis in the management of severe pre-eclampsia, and its use is progressively spreading in our environment. It was introduced at the pioneer teaching hospital of southeastern Nigeria in 2007. A study on the outcome of its use is therefore necessary. The objective was to determine the effect of introducing MgSO4 on the maternal and perinatal outcomes of severe pre-eclampsia in Enugu, South eastern Nigeria. A retrospective study of all cases of severe pre-eclampsia managed at the University of Nigeria Teaching Hospital Enugu (UNTH), Nigeria, from 1 January 2005 to 31 December 2008 - 2 years before, and 2 years after the introduction of MgSO4 - was performed. The prevalence of severe preeclampsia within the study period was 3.3%. The mean age of study participants was 24.5 ± 2.9 years. Thirty women received MgSO4 while 47 women received diazepam. Eclampsia occurred only in a member of the diazepam group but there were no maternal deaths. Babies from the diazepam group were more likely to have low 1 minute Apgar scores but the association was not significant [OR = 3.08 (95% CI 0.78, 13.33)]. Longer hospital stay was significantly lower among women who received MgSO4 [OR = 0.32 (95% CI 0.11, 0.93)]. Perinatal mortality did not differ between the groups. MgSO4 is effective in the management of severe pre-eclamptics at the UNTH, Enugu. Therefore, its accessibility and wider use should be promoted.


Purification, characterization, and biological cytotoxic activity of the extracellular cholesterol oxidase produced by Castellaniella sp. COX.
A new bacterial strain producing extracellular cholesterol oxidase (ChOx) was isolated and identified as Castellaniella sp. COX. The ChOx was purified by salting-out and ion-exchange chromatography up to 10.4-fold, with a specific activity of 15 U/mg with a molecular mass of 59 kDa. The purified ChOx exhibited pH 8.0 and temperature 40°C for its optimum activity. The enzyme showed stability over a wide pH range and was most stable at pH value 7.0, and at pH 8.0, it retained almost 86% of its initial activity after 3 h of incubation at 37°C. The enzyme possessed a half-life of 8 h at 37°C, 7 h at 40°C, and 3 h at 50°C. A Lineweaver-Burk plot was calibrated to determine its Km (0.16 mM) and Vmax (18.7 μmol·mg-1 ·min-1 ). The ChOx activity was enhanced with Ca2+ , Mg2+ , and Mn2+ while it was inhibited by Hg2+ , Ba2+ , Fe2+ , Cu2+ , and Zn2+ ions. Organic solvents like acetone, n-butanol, toluene, dimethyl sulfoxide, chloroform, benzene, and methanol were well tolerated by the enzyme while iso-propanol and ethanol were found to enhance the activity of purified ChOx. ChOx induced cytotoxicity with an IC50 value of 1.78 and 1.88 U/ml against human RD and U87MG established cell lines, respectively, while broadly sparing the normal human cells.